Cluviat

Package leaflet: Information for the user

Cluviat 250 IU

Powder and solvent for solution for injection/infusion.
Concentrate of human coagulation Factor XIII plasma
Please read carefully all of this leaflet before you start 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.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it may be harmful.
• If you notice any side effects or any unlisted side effects not mentioned in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Cluviat is and what it is used for

What is Cluviat?
Cluviat is a white powder and solvent. The prepared solution must be administered by intravenous injection.
Cluviat is a product composed of coagulation factor XIII (FXIII) derived from human plasma (the liquid component of blood) and plays an important role in hemostasis (stopping bleeding).

What is Cluviat used for?
Cluviat is used in adult and pediatric patients

• for the prophylactic treatment of congenital factor XIII deficiency;
• for the perioperative treatment of surgical bleeding due to congenital factor XIII deficiency.

2. What you need to know before using Cluviat

The following paragraphs contain information the doctor should consider before administering Cluviat.
Do not take Cluviat:

• if you are allergic to the active substances or to any of the excipients of this medicine (see list in section 6). Inform your doctor if you are allergic to any medication or food.

Warnings and precautions

• if you have previously experienced allergic reactions to coagulation factor FXIII. You should take antihistamines and corticosteroids prophylactically, if advised by your doctor.
• in case of allergic or anaphylactic reactions (severe allergic reaction causing severe breathing difficulties or dizziness). Administration of Cluviat must be stopped immediately (e.g., stop the infusion). In case of shock, standard clinical measures for the treatment of shock must be taken.
• if you have recently experienced thrombosis (blood clot formation). Caution is required due to the fibrin-stabilizing effect of FXIII.
• the development of inhibitors (neutralizing antibodies) is a known complication of treatment, meaning that the treatment will no longer be effective. If bleeding does not stop with Cluviat administration, inform your doctor immediately. You must remain under close medical supervision for the development of inhibitors.

Your doctor will carefully evaluate the benefits of treatment with Cluviat against the risk of these complications.
Viral safety
When medicines are prepared from human blood or plasma, certain measures are taken to prevent transmission of infectious agents to patients. These measures include:

• careful selection of blood and plasma donors to ensure potentially infected donors are excluded,
• testing of each individual donation and plasma pools to detect the possible presence of viruses/infections,
• inclusion of steps in the blood or plasma manufacturing process that can inactivate or remove viruses.

Despite these measures, when medicines derived from human blood or plasma are administered, it cannot be completely ruled out that transmission of infections may occur.
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, and hepatitis C virus, as well as against non-enveloped viruses such as hepatitis A virus and parvovirus B19.
It is strongly recommended that, each time Cluviat is administered to you, your doctor records the name and batch number of the product (shown on the packaging).
Your doctor may recommend vaccination against hepatitis A and B if you regularly or repeatedly receive medicines derived from human plasma.
Taking Cluviat with other medicines

• Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
• No interactions are known between human plasma coagulation factor XIII concentrate and other medicines.
• Cluviat must not be mixed with other medicines, diluents, or solvents except those listed in section 6, and must be administered through a separate infusion line.

Pregnancy, breastfeeding, and fertility

• If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
• Limited clinical data on the use of Cluviat during pregnancy have not shown negative effects on pregnancy progression or perinatal or postnatal development. Therefore, Cluviat may be considered during pregnancy if necessary.
• There are no data on the excretion of Cluviat in human milk. However, due to its large molecular size, excretion in breast milk is unlikely, and, given its protein nature, absorption of intact molecules by the infant is also unlikely. Cluviat may therefore be used in breastfeeding women.
• There are no data available on fertility.

Driving and use of machinery
No studies on the ability to drive vehicles and use machinery have been conducted.
Cluviat contains sodium
Please note that Cluviat contains sodium. This is important if you are on a sodium-controlled diet. Cluviat contains 124.4 to 195.4 mg (5.41 to 8.50 mmol) of sodium per dose (40 IU/kg body weight – average 70 kg), when the recommended dose (2800 IU = 44.8 ml) is administered.

3. How to use Cluviat

• Cluviat is normally administered by a doctor.
• Cluviat is intended for intravenous injection only.

Dosage
Your doctor will calculate the correct dose and decide how often Cluviat should be administered,
taking into account the beneficial effects of the treatment.
For further information, see the section “The following information is intended exclusively for doctors or healthcare professionals”.

Overdose
Cases of overdose have not been reported and are not expected, as the medicine is administered by healthcare professionals.

4. Possible side effects

Like all medicines, this medicinal product can cause side effects, although not everyone experiences them.
The following side effects have been observed rarely (affect more than 1 in 10,000
patients and less than 1 in 1,000 patients):

• Allergic reactions, such as systemic urticaria (itchy skin swellings), skin rashes, drop in blood pressure (accompanied by possible feeling of weakness or dizziness), and breathing difficulties.
• Increase in body temperature.

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

• Development of FXIII inhibitors.

In case of allergic reactions, administration of Cluviat must be stopped immediately and appropriate therapy initiated. Standard clinical measures for the treatment of shock should be taken.
Side effects in children and adolescents
In children, the same side effects expected as those observed in adults.
Reporting of side effects
If you experience any side effects, inform your doctor, nurse, or pharmacist, even if the side effect is not listed in this leaflet. You may also report side effects directly through the Italian Medicines Agency's national reporting system, Website: http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting side effects, you help provide further information on the safety of this medicine.

5. How to store Cluviat

• Store in a refrigerator (+2°C - +8°C).
• Do not freeze.
• Keep the vial in the outer packaging to protect it from light.
• Cluviat does not contain preservatives. The product must be used immediately after reconstitution. If not administered immediately, the solution may be kept for a maximum of 4 hours at room temperature. Do not refrigerate or freeze the reconstituted solution.
• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date stated on the label and the carton.

6. Package contents and other information

What Cluviat contains
Active substance:
Human plasma coagulation Factor XIII concentrate containing 250 IU per
vial.
Excipients:
Human albumin, glucose monohydrate, sodium chloride, sodium hydroxide (in small quantities
for pH adjustment)
Solvent: Water for Injections
What Cluviat looks like and contents of the pack
Cluviat is a white powder supplied with a solvent (Water for Injections).
The reconstituted solution must be colourless and clear to slightly opalescent. When examined against the light, it must not appear cloudy or contain residues (deposits/particulate matter).
Presentation
One pack containing 250 IU:

• 1 vial with powder
• 1 vial with 4 ml of Water for Injections
• 1 filter transfer device 20/20 (Mix2Vial)
• Administration set (inner box):
• 1 single-use 5 ml syringe
• 1 intravenous injection set
• 2 alcohol swabs
• 1 non-sterile plaster

Marketing Authorisation Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
The following information is intended for healthcare professionals only:
Dosage and method of administration
Dosage
1 ml corresponds to approximately 62.5 IU and 100 IU correspond to 1.6 ml, respectively.
Important:
The amount to be administered and the frequency of administration must always be adjusted according to the clinical efficacy in each individual case.
Dosing regimen
The dosing regimen should be individualized based on body weight, laboratory values, and the patient's clinical condition.
Dosing Schedule for Routine Prophylaxis
Initial dose

• 40 International Units (IU) per kg of body weight.
• The infusion rate must not exceed 4 ml per minute.

Subsequent dosing

• The dose should be selected based on the most recent minimum FXIII activity level, administered every 28 days (4 weeks) to maintain a minimum FXIII activity level of approximately 5–20%.
• Dose adjustments of ±5 IU/kg from the recommended dose should be evaluated based on minimum FXIII activity levels (as shown in Table 1) and the patient's clinical condition.
• Dose adjustments should be based on a specific sensitive assay used to determine FXIII levels. An example of dose adjustment using the Berichrom® standard activity assay is provided below in Table 1.

Table 1: Dose Adjustment using the Berichrom® Activity Assay

The activity expressed in units is determined by the Berichrom activity test, according to the current International Standard for Coagulation Factor XIII, Plasma. Therefore, in this case, one unit corresponds to one International Unit.

Preoperative Prophylaxis
After the patient's last routine prophylactic dose, if surgery is planned:

• Between 21 and 28 days after – administer the full prophylactic dose to the patient immediately before surgery; the next prophylactic dose should then be administered after 28 days.
• Between 8 and 21 days after – an additional dose (full or partial) may be administered before surgery. The dose should be determined based on FXIII activity levels and the patient's clinical condition and adjusted according to Cluviat's half-life.
• Within 7 days of the last dose – an additional dose may not be necessary.

Dosage adjustments may differ from these recommendations and must be individualized based on FXIII activity levels and the patient's clinical condition. All patients must be closely monitored during and after surgical procedures.
Therefore, it is recommended to monitor the increase in FXIII activity using a specific assay. In the case of major surgical procedures or severe bleeding, the goal is to achieve levels close to normal (healthy subjects: 70% - 140%).

Paediatric population
The dosage and route of administration in children and adolescents are based on body weight and generally follow the same guidelines as those used in adults. The dose and/or frequency of administration for each patient must always take into account clinical efficacy and FXIII activity levels.

Elderly population
Dosage and route of administration in elderly subjects (> 65 years) have not been documented in clinical studies.

Method of administration
General instructions

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

Reconstitution
Allow the solvent to reach room temperature. Ensure that the removable caps of both the product and the solvent are removed and that the stoppers are disinfected with an antiseptic solution and allowed to dry before opening the Mix2Vial pack.

Withdrawal and administration

Care should be taken to avoid allowing blood to enter the syringe filled with the product, as there is a risk that blood may coagulate in the syringe, resulting in the administration of fibrin clots to the patient.
The reconstituted solution must be administered intravenously through a separate injection/infusion line (provided with the product) by slow injection at a rate not exceeding 4 ml per minute.
Any unused medicinal product or waste material must be disposed of in accordance with local regulations.

Package leaflet: Information for the user

Cluviat 1250 IU

Powder and solvent for solution for injection/infusion.
Concentrate of human coagulation Factor XIII from plasma
Please read this instruction leaflet carefully before you start 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.
• 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 notice any side effects, or any side effects not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Cluviat is and what it is used for

What is Cluviat?
Cluviat is presented as a white powder and solvent. The prepared solution must be administered by intravenous injection.
Cluviat is a product composed of coagulation factor XIII (FXIII) derived from human plasma (the liquid part of blood) and plays an important role in hemostasis (stopping bleeding).

What is Cluviat used for?
Cluviat is used in adult and pediatric patients:

• for the preventive treatment of congenital factor XIII deficiency;
• for the perioperative treatment of surgical bleeding due to congenital factor XIII deficiency.

2. What you need to know before using Cluviat

The following paragraphs contain information that the physician should consider before
administering Cluviat.
Do not take Cluviat:

• if you are allergic to the active substances or to any of the excipients of this medicine (see list in section 6). Inform your doctor if you are allergic to any medication or food.

Warnings and precautions

• if you have previously experienced allergic reactions to coagulation factor FXIII. You should take antihistamines and corticosteroids prophylactically if advised by your doctor.
• in case of allergic or anaphylactic reactions (severe allergic reaction causing serious breathing difficulties or dizziness). Administration of Cluviat must be immediately discontinued (e.g., stop the infusion). In case of shock, standard clinical measures for the treatment of shock must be implemented.
• if you have recently experienced thrombosis (formation of blood clots). Caution is required due to the fibrin-stabilizing effect of FXIII.
• the development of inhibitors (neutralizing antibodies) is a known complication of treatment, meaning that treatment becomes ineffective. If bleeding does not stop after taking Cluviat, inform your doctor immediately. You must remain under close medical supervision for the development of inhibitors.

Your doctor will carefully evaluate the benefits of treatment with Cluviat against the risk of these
complications.
Viral safety
When medicines are prepared from human blood or plasma, certain measures are taken to prevent the transmission of infectious agents to patients. These measures include:

• careful selection of blood and plasma donors to ensure that potentially infected donors are excluded,
• testing of each individual donation and plasma pools for the presence of viruses/infections,
• inclusion of steps in the blood or plasma manufacturing process that can inactivate or remove viruses.

Despite these measures, when medicines derived from human blood or plasma are administered, the possibility of transmitting infections 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, and hepatitis C virus, as well as non-enveloped viruses such as hepatitis A virus and parvovirus B19.
It is strongly recommended that, each time you are administered Cluviat, your doctor records the product name and batch number (shown on the packaging).
Your doctor may recommend vaccination against hepatitis A and B if you regularly or repeatedly receive medicines derived from human plasma.
Taking Cluviat with other medicines

• Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
• No interactions are known between human plasma coagulation factor XIII concentrate and other medicines.
• Cluviat must not be mixed with other medicines, diluents, or solvents except those listed in section 6, and should be administered via a separate infusion line.

Pregnancy, breastfeeding, and fertility

• If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
• Limited clinical data on the use of Cluviat during pregnancy have not shown negative effects on pregnancy progression or perinatal or postnatal development. Therefore, Cluviat may be considered during pregnancy if necessary.
• There are no data on the excretion of Cluviat in breast milk. However, due to its large molecular size, excretion in breast milk is unlikely, and given its protein nature, absorption of intact molecules by the infant is also unlikely. Cluviat may therefore be used in breastfeeding women.
• There are no data available on fertility.

Driving and using machines
No studies have been conducted on the ability to drive vehicles or operate machinery.
Cluviat contains sodium
Please be aware that Cluviat contains sodium. This is important if you are on a sodium-controlled diet. Cluviat contains between 124.4 and 195.4 mg (5.41 to 8.50 mmol) of sodium per dose (40 IU/kg body weight – average 70 kg), when the recommended dose is administered (2800 IU = 44.8 ml).

3. How to use Cluviat

• Cluviat is normally administered by a doctor.
• Cluviat is intended for intravenous injection only.

Dosage
Your doctor will calculate the correct dose and decide how often Cluviat should be administered,
taking into account the positive effects of the treatment.
For further information, see the section "The following information is intended exclusively for doctors or healthcare professionals."

Overdose
Cases of overdose have not been reported and are not expected, as the medicine is administered by healthcare professionals.

4. Possible adverse reactions

Like all medicines, this medicinal product may cause adverse reactions, although not everyone experiences them.
The following adverse reactions have been observed rarely (affecting more than 1 in 10,000 patients and less than 1 in 1,000 patients):

• Allergic reactions, such as systemic urticaria (itchy, swollen skin rashes), skin rashes, drop in blood pressure (accompanied by possible weakness or dizziness), and breathing difficulties.
• Increase in body temperature.

The following adverse reactions have been observed very rarely (affecting less than 1 in 10,000 patients):

• Development of FXIII inhibitors.

In case of allergic reactions, administration of Cluviat must be discontinued immediately and appropriate therapy initiated. Standard clinical measures for the treatment of shock should be implemented.
Adverse reactions in children and adolescents
In children, the same adverse reactions expected as those observed in adults.
Reporting of adverse reactions
If you experience any adverse reactions, inform your doctor, nurse, or pharmacist, even if they are not listed in this leaflet. You may also report adverse reactions directly via the Italian Medicines Agency's national reporting system at the following website: http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting adverse reactions, you help provide further information on the safety of this medicine.

5. How to store Cluviat

• Store in the refrigerator (+2°C - +8°C).
• Do not freeze.
• Keep the vial in the outer packaging to protect it from light.
• Cluviat does not contain preservatives. The product must be used immediately after reconstitution. If not administered immediately, the storage time must not exceed 4 hours at room temperature. Do not cool or freeze the reconstituted solution.
• Keep the medicine out of the sight and reach of children.
• Do not use the medicine after the expiry date stated on the label and the carton.

6. Package contents and other information

What Cluviat contains
Active substance:
Human plasma-derived Coagulation Factor XIII Concentrate containing 1250 IU per
vial.
Excipients:
Human albumin, monohydrate glucose, sodium chloride, sodium hydroxide (in small quantities
for pH adjustment)
Solvent: Water for Injections
What Cluviat looks like and contents of the pack
Cluviat is a white powder and is supplied with a solvent (Water for Injections).
The reconstituted solution should be colourless and clear to slightly opalescent. When examined
against a bright light, it should not appear cloudy or contain residues (deposits/particulate matter).
Presentation
One pack containing 1250 IU comprising:

• 1 vial containing the powder
• 1 vial containing 20 ml of Water for Injections
• 1 transfer device with filter 20/20 (Mix2Vial)
• Administration set (inner box):
• 1 single-use 20 ml syringe
• 1 intravenous injection set
• 2 alcohol swabs
• 1 non-sterile plaster

Marketing Authorisation Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Strasse 76
35041 Marburg
Germany
The following information is intended for healthcare professionals only:
Dosage and administration
Dosage
1 ml corresponds to approximately 62.5 IU and 100 IU correspond to 1.6 ml, respectively.
Important:
The amount to be administered and the frequency of administration must always be adjusted according to clinical efficacy in each individual case.
Dosing regimen
The dosing regimen should be individualized based on body weight, laboratory values, and the patient's clinical condition.
Dosing Schedule for Routine Prophylaxis
Initial dose

• 40 International Units (IU) per kg of body weight.
• The injection rate must not exceed 4 ml per minute.

Subsequent dosing

• The dose should be selected based on the most recent trough FXIII activity level, with administration every 28 days (4 weeks) to maintain a trough FXIII activity level of approximately 5–20%.
• Dose adjustments of ±5 IU/kg from the recommended dose should be considered based on trough FXIII activity levels (as shown in Table 1) and the patient's clinical condition.
• Dose adjustments should be based on a specific sensitive assay used to determine FXIII levels. An example of dose adjustment using the Berichrom® standard activity assay is provided below in Table 1.

Table 1: Dose Adjustment using the Berichrom® Activity Assay

The activity expressed in units is determined by the Berichrom activity test, according to the current International Standard for Coagulation Factor XIII, Plasma. Therefore, in this case, one unit corresponds to one International Unit.

Preoperative Prophylaxis
After the patient's last routine prophylactic dose, if surgery is planned:

• Between 21 and 28 days later – administer the full prophylactic dose to the patient immediately before surgery, while the next prophylactic dose should be administered 28 days later.
• Between 8 and 21 days later – an additional dose (full or partial) may be administered before surgery. The dose should be determined based on FXIII activity levels and the patient's clinical condition and adjusted according to Cluviat's half-life.
• Within 7 days of the last dose – an additional dose may not be necessary.

Dosage adjustments may differ from these recommendations and should be individualized based on FXIII activity levels and the patient's clinical condition. All patients must be closely monitored during and after surgical procedures.
Therefore, it is recommended to monitor the increase in FXIII activity using a specific assay. In the case of major surgical procedures and severe bleeding, the goal is to achieve levels close to normal (healthy subjects: 70%–140%).

Paediatric population
Dosage and administration in children and adolescents are based on body weight and generally follow the same guidelines as those used for adults. The dose and/or frequency of administration for each patient must always take into account clinical efficacy and FXIII activity levels.

Elderly population
Dosage and administration in elderly subjects (>65 years) have not been documented in clinical studies.

Method of administration
General instructions

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

Reconstitution
Allow the solvent to reach room temperature. Ensure that the removable caps of both the product and the solvent are removed and that the stoppers are treated with an antiseptic solution and allowed to dry before opening the Mix2Vial pack.

Withdrawal and administration

Care must be taken to avoid allowing blood to enter the syringe filled with the product, as there is a risk that blood may coagulate in the syringe, leading to the administration of fibrin clots to the patient.
The reconstituted solution must be administered intravenously through a separate injection/infusion line (provided with the product) by slow injection at a rate not exceeding 4 ml per minute.
Any unused medicinal product or waste material must be disposed of in accordance with local requirements.