Cluvot 250 i.m.

Package Leaflet: Information for the Patient

Cluvot 250 IU

Powder and solvent for solution for injection/infusion
Human blood coagulation factor XIII

Read the package leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this package leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this package leaflet, please inform your doctor or pharmacist. See section 4.

Table of Contents of the Package Leaflet

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

1. What is Cluvot and what is it used for

What is Cluvot
Cluvot is a medicine that comes as a white powder and solvent. The reconstituted solution should be administered by intravenous injection.
Cluvot is human blood coagulation factor XIII (F XIII) produced from human plasma (the liquid part of the blood) and plays an important role in the process of haemostasis (stopping bleeding).
What is Cluvot used for
Cluvot is indicated for use in adults, children, and adolescents.

• for prophylactic treatment of congenital factor XIII deficiency and
• in perioperative management to treat bleeding during surgical procedures in patients with congenital factor XIII deficiency.

2. Important information before using Cluvot

This section of the package leaflet contains information that you should consider before starting treatment with Cluvot.

When not to use Cluvot:

Tell your doctor if you have an allergy to any medicine or food.

Warnings and precautions:

Administration of Cluvot must be stopped immediately (i.e., stop the injection or infusion). In case of shock, treatment should be given according to current medical standards.
• the formation of inhibitors (antibodies that neutralize) is known as a complication of treatment and means that the treatment stops working. If bleeding is not controlled with Cluvot, you should inform your doctor immediately. You should be closely monitored for the development of inhibitors.

Your doctor should always weigh the benefits of treatment against the risk of complications.
Viral safety
When medicines are made from human blood or plasma, various measures are taken to prevent the transmission of infectious agents. These measures include:

• careful selection of blood and plasma donors to exclude the risk of transmitting infectious agents
• testing each donation and plasma pool for the presence of virus markers/infections.
• introducing steps in the manufacturing process that can inactivate or remove viruses.

Despite these measures, it cannot be completely excluded that the transmission of infectious agents cannot be completely excluded when administering a medicinal product derived from human blood or plasma. This risk also applies to unknown or newly discovered viruses and other infectious agents.
The measures taken are effective against enveloped viruses such as human immunodeficiency virus (HIV, the virus that causes AIDS), hepatitis B virus (HBV, which causes hepatitis B), and hepatitis C virus (HCV, which causes hepatitis C), as well as non-enveloped viruses such as hepatitis A virus (HAV, which causes hepatitis A) and parvovirus B19.
For patients receiving repeated doses of products derived from human plasma, consideration should be given to vaccination against hepatitis A and B.
It is recommended that the date of administration, batch number, and administered volume be recorded in the patient's medical record each time Cluvot is administered.

Cluvot and other medicines

• Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including those obtained without a prescription.
• No interactions between factor XIII concentrate and other medicinal products are known.
• Cluvot must not be mixed with other medicinal products, solvents, or diluents, except for those mentioned in section 6, and should be administered using separate infusion sets.

Pregnancy and breastfeeding

• If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
• Limited data on the clinical use of Cluvot in pregnancy do not indicate any negative effects on pregnancy and embryonic/foetal development. Cluvot may be used during pregnancy if necessary.
• The extent of transfer of Cluvot into human milk is unknown, but considering its high molecular mass, the likelihood of excretion into breast milk is very low, and due to its protein nature, absorption of intact molecules by the newborn is also unlikely. Therefore, Cluvot can be used during breastfeeding.
• No data are available on the effects of Cluvot on fertility.

Driving and using machines

No studies have been conducted on the effects on the ability to drive and use machines.

Important information about some of the ingredients of Cluvot

Cluvot contains sodium.

It should be noted that Cluvot contains sodium. This is important for patients on a controlled low-sodium diet. Cluvot contains between 124.4 and 195.4 mg (5.41 to 8.50 mmol) of sodium per dose (40 IU/kg body weight - assuming an average body weight of 70 kg), if the recommended dose (2800 IU = 44.8 ml) is administered.

3. How to use Cluvot

• Cluvot is usually administered by a doctor.
• Cluvot is intended for intravenous administration only.

Dosage

Your doctor will calculate the appropriate dose and decide how often Cluvot should be administered to you, taking into account your progress.
More detailed recommendations can be found in the section "Information intended for healthcare professionals only".
Overdose
No cases of overdose have been reported and are not expected when the medicine is administered by medical personnel.

4. Possible side effects

Like all medicines, Cluvot can cause side effects, although not everybody gets them.
The following side effects have been observed rarely(in more than 1 in 10,000 patients and less than 1 in 1,000)

• Allergic reactions such as generalized urticaria (itchy swelling of the skin), rash, decreased blood pressure (which can cause dizziness or fainting), and difficulty breathing.
• Increased body temperature

The following side effects have been observed very rarely(in less than 1 in 10,000 patients):

• Formation of inhibitors of FXIII.

If you experience allergic reactions, administration of Cluvot should be stopped immediately and appropriate treatment should be initiated. Current medical standards should be applied to treat shock.

Side effects in children and adolescents

It is expected that side effects in children are the same as in adults.

Reporting of side effects

If you experience any side effects, including those not listed in the package leaflet, please inform your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, Website: https://smz.ezdrowie.gov.pl. Side effects can also be reported to the marketing authorization holder. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Cluvot

• Store in a refrigerator (2°C - 8°C).
• Do not freeze.
• Store in the outer packaging to protect from light.
• Cluvot does not contain preservatives. The product should be used immediately after reconstitution. If not used immediately, storage at room temperature should not exceed 4 hours. Do not store in a refrigerator and do not freeze the reconstituted solution.
• Keep the medicine out of the sight and reach of children.
• Do not use Cluvot after the expiry date stated on the label and outer packaging after the abbreviation EXP.
• The batch number of the medicinal product is stated on the outer packaging and label after the abbreviation: Lot.

6. Contents of the pack and other information

What Cluvot contains Active substance:

Human blood coagulation factor XIII (FXIII) concentrate containing 250 IU per vial.
Excipients:
Human albumin, glucose monohydrate, sodium chloride, sodium hydroxide (in small amounts to adjust pH).
Solvent:Water for injections

What Cluvot looks like and contents of the pack

Cluvot comes as a white powder and solvent, which is water for injections. The reconstituted solution should be clear or slightly opalescent. The Pack sizesare:
One pack of 250 IU contains:
1 vial of powder
1 vial of 4 ml water for injections
1 Mix2Vial transfer system with filter
Administration set (inner packaging):
1 single-use 5 ml syringe
1 injection set
2 alcohol swabs
1 non-sterile plaster

Marketing authorization holder and manufacturer

CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
Date of last revision of the package leaflet:August 2021
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Information intended for healthcare professionals only: Dosage

1 ml is approximately equal to 62.5 IU, and 100 IU is equivalent to 1.6 ml.
Important:
The amount to be administered and the frequency of administration should always be adjusted according to the individual patient's clinical efficacy.
Dosage
Dosage should be individually tailored based on body weight, laboratory results, and the patient's clinical condition.
Routine dosing schedule for prophylaxis
Initial dose

• 40 international units (IU) per kilogram of body weight.
• The infusion rate should not exceed 4 ml per minute

Subsequent doses

• Dosage should be determined based on the current level of FXIII activity, and doses should be administered at 28-day intervals (4 weeks) to maintain a minimum FXIII activity level of approximately 5 to 20%.
• Recommended dose adjustment of +/- 5 IU/kg body weight should be calculated based on the minimum FXIII activity level as shown in Table 1 and the patient's clinical condition.
• Dose adjustment should be based on a specific, sensitive test used to determine FXIII levels. Examples of dose adjustment using the standard Berichrom activity test are presented in the following Table 1.

Table 1: Dose adjustment using the Berichrom activity test
Activity is expressed in units using the Berichrom activity test, referring to the current International Standard for Plasma Factor XIII. Therefore, one unit is equivalent to one International Unit.
Perioperative prophylaxis.

After the last dose administered in routine prophylaxis, in case of a planned surgical procedure:

• Between 21 and 28 days after the last dose - a full dose should be administered to the patient immediately before surgery, and the next prophylactic dose should be administered 28 days later.
• Between 8 and 21 days after the last dose - an additional dose (full or partial) may be administered before surgery. The dose should be based on the patient's FXIII activity level, clinical condition, and should be adjusted according to the half-life of the medicinal product Cluvot.
• Within 7 days of the last dose - additional administration may not be necessary.

Dose adjustment may differ from the recommended dose and should be individually tailored based on FXIII activity level and the patient's clinical condition. All patients should be closely monitored during and after surgery.
In this regard, it is recommended to monitor the increase in FXIII activity level based on the FXIII test. In case of major surgical procedures and significant bleeding, the goal should be to achieve near-normal values (healthy individuals: 70%-140%).
Children and adolescents
Dosage and administration in children and adolescents are based on body weight and generally do not differ from the guidelines for adults. Dosage and/or administration frequency for each patient should always be adjusted based on clinical efficacy and FXIII activity level.
Elderly patients
Dosage and administration in elderly patients (> 65 years) have not been documented in clinical trials.
Method of administration
General instructions
The solution should be clear or slightly opalescent. After filtration/removal of the vial contents (see below), the reconstituted product before administration should be visually inspected; check for any contamination or change in color.
Do not use cloudy solutions or those that contain flakes or particles.
Reconstitution and removal from the vial must be performed under aseptic conditions.
Reconstitution
Bring the solvent to room temperature. Remove the plastic caps from the vials containing the powder and solvent, and wipe the stoppers with an aseptic solution. After drying, open the system containing the Mix2Vial connector.

1	1. Open the packaging containing the Mix2Vial by removing the cap. Do not remove the Mix2Vial from the blister.

2	2. Place the vial with the solvent on a flat, clean surface and hold it firmly. Without removing the Mix2Vial system from the blister, place the blue end of the system with the needle on the cork of the solvent vial and, pressing vertically downwards, pierce the cork of the solvent vial.
3	3. Holding the edge of the Mix2Vial system, carefully remove the blister by pulling it vertically upwards. Note that only the blister should be removed, not the entire Mix2Vial system.
4	4. Place the vial with the powder on a flat, hard surface. Invert the vial with the solvent and the attached Mix2Vial system, and insert the transparent end of the system into the cork of the vial with the powder, moving vertically downwards. The solvent will automatically be transferred to the vial with the powder.
5	5. Holding the Mix2Vial system in the vial containing the solution, with one hand, and holding the connector part from the solvent vial side, carefully unscrew the two parts of the connector. Remove the vial with the solvent from the Mix2Vial system.
6	6. Gently swirl the vial with the attached transparent end of the Mix2Vial system, containing the solution, to completely dissolve the medicine. Do not shake.
7	7. Draw air into an empty, sterile syringe. Holding the vial with the medicinal product vertically with the stopper facing upwards, attach the syringe to the Luer Lock connector of the Mix2Vial system. Inject air into the vial.

Withdrawal and administration

8	8. Holding the syringe plunger, invert the vial with the syringe and slowly withdraw the solution into the syringe.
9	9. After filling the syringe with the solution, firmly hold the syringe cylinder (holding the syringe with the plunger facing downwards) and carefully disconnect the transparent end of the Mix2Vial system from the syringe.

Caution should be exercised to prevent blood from entering the syringe filled with the medicinal product, as there is a risk that the blood may clot in the syringe and fibrin clots could be administered to the patient.
The reconstituted solution should be administered through separate infusion sets (supplied with the product), by slow intravenous injection, at a rate not exceeding 4 ml per minute.
Any unused medicinal products and their waste should be disposed of in accordance with local requirements.