Prospect: information for the user

Cluvot 250 UI

Powder and solvent for injectable solution or infusion.

Concentrate of human plasma-derived coagulation factor XIII

1. What is Cluvot and how it is used

2. What you need to know before starting to use Cluvot

3. How to use Cluvot

4. Possible adverse effects

5. Storage of Cluvot

6. Contents of the package and additional information

What is Cluvot

Cluvot is presented as a white powder and a solvent. The resulting solution must be administered via injection into a vein.

Cluvot is a product composed of coagulation factor XIII (FXIII) derived from human plasma (the liquid part of blood), and has important functions in hemostasis (interruption of bleeding).

What is Cluvot used for

Cluvot is used in adult and pediatric patients

• for the preventive treatment of hereditary factor XIII deficiency and
• for perioperative treatment of surgical bleeding with congenital FXIII deficiency

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The following sections contain information that your doctor should consider before administering Cluvot to you.

Do not use Cluvot:

• if you are allergic to the active ingredient or to any of the other components of this medication (listed in section 6).

Inform your doctor if you are allergic to any medication or food.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Cluvot.

• Ifyou have experienced allergic reactionsto coagulation factor XIII in the past. You should take antihistamines and corticosteroids for prophylactic purposes if your doctor advises you to do so.
• Whenallergic or anaphylactic reactions(a severe allergic reaction that causes severe breathing difficulties or dizziness),the administration of Cluvot should be interrupted immediately (e.g., stop the infusion). In case of shock, follow the current medical guidelines for its treatment.
• If you have experienced arecent thrombosis (blood clot), you should act with caution due to the stabilizing effect of fibrin on FXIII.
• Theformation of inhibitors (neutralizing antibodies)is a known complication of treatment and implies that the treatment has stopped working. If your bleeding cannot be controlled with Cluvot, inform your doctor immediately. You should be closely monitored for the development of any inhibitors.

Your doctor will carefully consider the benefit of treatment with Cluvot compared to the risk of these complications.

Viral safety

When medications are prepared from blood or human plasma, certain measures are taken to prevent the transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure that potential carriers of infections are excluded;
• analysis of each donation and plasma mixture to detect signs of viruses/infections;
• the inclusion of measures during the processing of blood or plasma to inactivate or eliminate viruses.

Despite these measures, when administering medications prepared from human blood or plasma, it cannot be entirely ruled out that infections may be transmitted. This also applies to any unknown or emerging viruses or other types of infections.

The measures adopted are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus, and for non-enveloped hepatitis A virus and parvovirus B19.

It is strongly recommended that, each time Cluvot is administered to you, your doctor notes the name and batch number of the medication (found on the carton box).

Your doctor may recommend that you consider the possibility of vaccinating against hepatitis A and B if you regularly or repeatedly receive products derived from human plasma.

Use of Cluvot with other medications

• Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.
• Up to now, no interactions have been known between human coagulation factor XIII concentrate and other medications.
• Cluvot should not be mixed with other medications, diluents, or solvents, except those indicated in section 6, and should be administered through a separate infusion line.

Pregnancy, breastfeeding, and fertility

• If you are pregnant or breastfeeding, think you may be pregnant, or intend to become pregnant, consult your doctor or pharmacist before this medication is administered to you.

• The limited data on the clinical use of Cluvot during pregnancy did not show any negative effects on the course of pregnancy and perinatal or postnatal development. Therefore, if necessary, Cluvot can be considered for use during pregnancy.
• No data are available on the excretion of Cluvot in human milk. However, based on its large molecular size, excretion in milk is unlikely, and due to its protein nature, the absorption of intact molecules by the infant is also unlikely. Therefore, Cluvot can be used during breastfeeding.
• No fertility data are available.

Driving and operating machinery

No studies have been conducted on the effects on the ability to drive and operate machinery.

Cluvot contains sodium

Take note that Cluvot contains sodium. This is important if you are following a low-sodium diet. Cluvot contains 124.4 to 195.4 mg (5.41 to 8.50 mmol) of sodium per dose (40 UI/weight: for an average of 70 kg), if the recommended dose (2,800 UI = 44.8 ml) is applied.

• Your doctor will typically be the one to administer Cluvot to you.
• Cluvot is intended solely for intravenous injection.

Dosage

Your doctor will calculate the correct dose and decide how often Cluvot should be administered to you, taking into account how the treatment is progressing.

For more information, see the section “This information is intended solely for healthcare professionals”.

Overdose

No cases of overdose have been reported and none are anticipated, as the medication is administered by healthcare professionals.

Like all medications, this medication may produce adverse effects, although not all people will experience them.

The following adverse effects have been observed inrare occasions(affecting more than 1 user in every 10,000 and fewer than 1 user in every 1,000):

• Allergic Reactions, such as generalized urticaria (hives with itching on the skin), skin rash, decreased blood pressure (which may cause dizziness or lightheadedness) and difficulty breathing.
• Increased Temperature

The following adverse effects have been observed invery rare occasions(affecting fewer than 1 user in every 10,000):

• Development of FXIII Inhibitors.

If allergic reactions occur, discontinue Cluvot administration immediately and initiate appropriate treatment. For shock treatment, follow current medical standards.

Adverse Effects in Children and Adolescents

It is expected that adverse effects in children will be the same as in adults.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is an adverse effect not listed in this prospectus. You can also report them directly through the Spanish System for Pharmacovigilance of Medicinal Products for Human Use: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

• Store in refrigerator (between + 2 °C and + 8 °C).

• Do not freeze.
• Store the vial in the outer packaging to protect it from light.
• Cluvot does not contain preservatives. The product must be used immediately after reconstitution. In case it is not used immediately, it should not be stored for more than 4 hours at room temperature. Do not refrigerate or freeze the reconstituted solution.
• Keep this medication out of the sight and reach of children.
• Do not use this medication after the expiration date that appears on the label and on the carton packaging. The expiration date is the last day of the month indicated.
• Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. In this way, you will help protect the environment.

Composition of Cluvot

The active principle is:

Concentrated human plasma-derived factor XIII coagulation factor containing 250 UI per vial.

The other components are:

Human albumin, glucose monohydrate, sodium chloride, sodium hydroxide (in small quantities for pH adjustment)

Disolvent:Water for injection

Appearance of the product and contents of the package

Cluvot is presented as a white powder and is supplied with a solvent (water for injection).

The resulting solution must be colorless, transparent or slightly opalescent. When exposed to light, it should not be turbid or contain residues (deposits/particles).

Presentation

One package of 250 UI containing:

• 1 vial with powder
• 1 vial with 4 ml of water for injection
• 1 transfer set with filter 20/20 (Mix2Vial)
• Administration equipment (inner box):

- 1 disposable 5 ml syringe

- 1 venipuncture set

- 2 alcohol-impregnated wipes

- 1 non-sterile dressing

Marketing authorization holder and responsible manufacturer

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg (Germany)

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

CSL Behring, S.A.

c/ Tarragona 157, 18th floor

08014 Barcelona (Spain)

This medication is authorized in the member states of the European Economic Area with the following names:Cluvot

Last review date of this leaflet: October 2018.

Detailed and updated information about this medication is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es

_____________________________________________________________________________________

This information is intended solely for healthcare professionals:

Dosage and administration

Dosage

1 ml is approximately equivalent to 62.5 UI, and 100 UI is equivalent to 1.6 ml, respectively.

Important:

The amount to be administered and the frequency of administration must always be guided by clinical efficacy in each individual case.

Dosing

The dosing regimen must be individualized based on body weight, analytical values, and the patient's clinical status.

Usual prophylactic dosing regimen

Initial dose

• 40 units international (UI) per kilogram of body weight
• The injection speed should not exceed 4 ml per minute.

Subsequent dosing

• Dosing should be guided by the most recent minimum activity level of FXIII, with administration every 28 days (4 weeks) to maintain a minimum activity level of FXIII between 5 and 20%, approximately.
• Dose adjustments of ± 5 UI per kilogram should be based on FXIII minimum activity levels as shown in Table 1 and the patient's clinical status.
• Dose adjustments should be made based on a specific and sensitive analysis to determine FXIII levels. Table 1 below describes an example of dose adjustment using the Berichrom standard activity test.

Table 1: dose adjustment using the Berichrom standard activity test

The potency expressed in units is determined by the Berichrom activity test, referred to the current international standard for blood coagulation factor XIII in plasma.

Therefore, one unit in this document is equivalent to one international unit.

Preoperative prophylaxis

After the last usual prophylactic dose of the patient, if surgery is scheduled:

• Between 21 and 28 days later: administer the total prophylactic dose to the patient immediately before surgery and the next prophylactic dose should be administered 28 days later.
• Between 8 and 21 days later: a supplemental dose (total or partial) may be administered before surgery. The dose should be guided by FXIII activity levels and the patient's clinical status and should be adjusted based on the half-life of Cluvot.
• Within 7 days after the last dose: no additional dose may be necessary.

Dose adjustments may differ from these recommendations and should be individualized based on FXIII activity levels and the patient's clinical status. Precise monitoring of all patients during and after surgery is recommended.

Therefore, it is recommended to monitor the increase in FXIII activity with an FXIII test. In the case of major surgery and severe bleeding, the goal is to achieve almost normal values (healthy individuals: 70% - 140%).

Pediatric population

The dosage and administration in children and adolescents are based on body weight and, therefore, generally follow the same guidelines as for adults. The dose and administration frequency for each individual should always be guided by clinical efficacy and FXIII activity levels.

Geriatric population

The dosage and administration in individuals over 65 years old have not yet been documented in clinical studies.

Administration

General instructions

• The solution must be transparent or slightly opalescent. After extracting and filtering the reconstituted product (see below), it must be visually inspected for the presence of foreign particles and discoloration before administration.
• Visibly turbid solutions or solutions still containing flakes or particles should not be used.
• Reconstitution and extraction must be performed in aseptic conditions.

Reconstitution

Warm the solvent to room temperature. Ensure that the product and solvent vials have been removed from their capsules and that the stoppers have been treated with an asptic solution and allowed to dry before opening the Mix2Vial package.

Transfer and administration

Care must be taken to prevent blood from entering the syringe filled with product, as there is a risk that the blood will clot in the syringe and therefore, fibrin clots will be administered to the patient.

The reconstituted solution must be administered intravenouslyin a separate injection/infusion line (provided with the product) via a slow injection, at a rate not exceeding 4 ml per minute.

Elimination of unused medication and all materials that have come into contact with it will be carried out in accordance with local regulations.