Klott

Package leaflet: Information for the user

KLOTT 500 IU/10 ml Powder and solvent for solution for infusion, 1000 IU/10 ml Powder and solvent for solution for infusion

Coagulation factor VIII 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, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What KLOTT is and what it is used for

KLOTT is a solution of factor VIII of blood coagulation derived from human plasma.
Factor VIII is a protein with antihemorrhagic activity.
KLOTT is used in the following treatments:
for the treatment and prevention of bleeding in patients with an inherited deficiency of factor VIII activity (haemophilia A);
for the treatment of bleeding in patients with acquired factor VIII deficiency due to other diseases;
for the treatment of haemophilic patients who have developed antibodies against factor VIII (inhibitors).

2. What you need to know before using KLOTT

Do not use KLOTT

• if you are allergic to human factor VIII or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor before using KLOTT.
Allergic reaction
Allergic-type hypersensitivity reactions may occur with KLOTT.
KLOTT contains traces of human proteins other than factor VIII. If during administration you notice any of the symptoms listed below, stop the infusion immediately and contact your doctor, as these symptoms could be the first signs of an allergic reaction. Possible symptoms include: hives, generalized urticaria, tightness in the chest, wheezing, drop in blood pressure, and even severe allergic reaction.
In case of shock, standard shock management guidelines must be followed.
Inhibitors
The development of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII medicines. Inhibitors, especially at high levels, may prevent the treatment from working properly, and you or your child will be closely monitored for the development of such inhibitors. If bleeding in you or your child is not controlled by KLOTT, inform your doctor immediately.
Cardiovascular events
In patients with cardiovascular risk factors, replacement therapy with FVIII may increase cardiovascular risk.
Complications related to catheter use
If a central venous access device is required, the risk of device-related complications, including local infections, bacteremia, and catheter site thrombosis, should be considered.
Viral safety
When medicines are prepared from human blood or plasma, specific measures are taken to prevent transmission of infections to patients. These measures include:

• careful selection of blood and plasma donors to ensure potentially infected donors are excluded;
• testing of each donation and plasma pool (a mixture of multiple donations) for the presence of infections/viruses;
• inclusion of manufacturing steps capable of inactivating or removing viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of transmitting infectious agents 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 hepatitis A virus (HAV), which lacks a lipid envelope. The measures taken may have limited effect against non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection can be severe during pregnancy (fetal infection) and in individuals with suppressed immune systems or certain types of anemia (e.g., sickle cell anemia or hemolytic anemia).

It is strongly recommended that each time you receive a dose of KLOTT, both the product name and the batch number are recorded, in order to maintain traceability of the batch used.
Your doctor may advise you to consider vaccination against hepatitis A and B if you receive factor VIII derived from human plasma regularly or repeatedly.
Children
Specific data in the pediatric population are not available.
Further information is provided at the end of the package leaflet in the section intended for
doctors or healthcare professionals.
Other medicines and KLOTT
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No interactions have been reported between human coagulation factor VIII products and other medicines.
Specific data in the pediatric population are not available.
Pregnancy, breastfeeding and fertility

• If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
• Animal reproductive studies have not been conducted with factor VIII. Due to the rarity of hemophilia A in women, data on the use of factor VIII during pregnancy and breastfeeding are not available. Therefore, factor VIII should be used during pregnancy and breastfeeding only if clearly indicated.

Driving and using machines
KLOTT has no effect on the ability to drive or operate machinery.
KLOTT contains sodium
This medicine contains up to a maximum of 41 mg of sodium (a main component of table salt) per 10 ml vial.
This corresponds to 2.05% of the maximum daily dietary intake recommended for an adult.

3. How to use KLOTT

Use this medicine exactly as instructed by your doctor or pharmacist. If you have
any doubts, consult your doctor or pharmacist.
Dosage
The dose and duration of replacement therapy depend on the severity of factor VIII deficiency,
the location and extent of bleeding, and your clinical condition.
On-demand treatment
The amount of medicine and frequency of administrations you should receive must be
determined based on your clinical response.
Prophylaxis
For long-term prevention of bleeding in patients with severe haemophilia A, the usual doses
are 20 to 40 IU (International Units) of factor VIII per kg body weight, administered every 2–3
days. In some cases, especially in younger patients, shorter treatment intervals or higher doses may be required.
You should be carefully monitored for the possible development of factor VIII inhibitors through appropriate clinical observations and laboratory tests.
During treatment, appropriate monitoring of factor VIII levels is required to adjust the dose and frequency of repeated infusions. In particular, during major surgical procedures, it is essential that your replacement therapy is closely monitored using coagulation tests (plasma factor VIII activity).
Use in children and adolescents
The safety and efficacy of KLOTT in children under 12 years of age have not yet been established. For adolescents (12–18 years), the dose for each indication will be adjusted according to body weight.
Further information regarding dosage and duration of therapy is provided at the end
of this leaflet in the section intended for doctors or healthcare professionals.
Instructions for correct use
This product must be administered intravenously, either by injection or slow infusion.
For intravenous injection, a recommended administration time of 3 to 5 minutes is advised. Monitor the pulse and discontinue or reduce the injection rate if pulse rate increases.
The infusion rate should be individually assessed for each patient.
Only the injection/infusion devices supplied in the package must be used, as treatment failure may occur because part of the factor VIII may adhere to the walls of certain devices.
Incompatibilities: in the absence of compatibility studies, KLOTT must not be mixed with other
medicines.
Reconstitution of the powder with the solvent:

1. Bring the vial of powder and the solvent vial to room temperature;
2. Maintain this temperature 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 part; 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 to release 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 is positioned above the device; push the transparent/white adapter onto the stopper of the powder vial so that the plastic spike penetrates 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 foaming (fig. F). Ensure that the powder is fully dissolved, otherwise there will be a loss of product activity.

Administration of the solution
After reconstitution, the solution may contain a few fine filaments or particles.
The reconstituted medicine should be visually inspected before administration for the presence of particulate matter or discoloration. The solution should be clear or slightly opalescent. Do not use cloudy solutions or those with visible deposits.

1. Fill the syringe with air 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 draw the concentrate into the syringe by slowly pulling back the plunger (fig. H);
3. Detach the syringe by rotating it counterclockwise;
4. Visually inspect the solution in the syringe, which should appear clear or slightly opalescent and free of particles;
5. Attach the butterfly needle to the syringe and administer slowly by intravenous infusion or injection.

If you use more KLOTT than you should
The consequences of excessive use of this product are unknown.
In case of accidental ingestion/overdose of KLOTT, contact your doctor immediately or go to the nearest hospital.
If you have any doubts about how to use KLOTT, consult your doctor.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences
them.
If you experience any of the following adverse reactions, contact your doctor immediately or go to the
nearest hospital:

• Severe allergic reactions (hypersensitivity): rapid swelling of the skin and mucous membranes around the mouth and face (angioedema). This adverse reaction has been observed rarely and in some cases may lead to severe acute allergic reactions (anaphylaxis), including shock.
• Patients with haemophilia A may develop neutralising antibodies against factor VIII (inhibitors). The presence of these inhibitors is manifested by an inadequate clinical response. In such cases, it is advisable to contact a specialised haemophilia treatment centre.

Other adverse reactions:
Other allergic reactions (hypersensitivity) may include:
a burning sensation and stinging pain at the infusion site;
chills, flushing, generalized skin rash (generalized urticaria), wheals;
headache (cephalalgia);
lowering of blood pressure (hypotension), restlessness, rapid heartbeat (tachycardia), chest tightness, wheezing;
drowsiness (lethargy);
nausea, vomiting;
tingling (paraesthesia).
These adverse reactions have been observed rarely and in some cases may lead to severe
acute allergic reactions (anaphylaxis), including shock.

• Fever has been observed.

In previously untreated children receiving factor VIII-containing medicines, the development of
inhibitor antibodies (see section 2) may be very common (more than 1 patient in 10); however, in
patients who have previously received treatment with factor VIII (more than 150 days of
treatment), the risk is uncommon (less than 1 patient in 100). If this occurs, the medicine may cease to work effectively, and you or your child may experience persistent bleeding. If this happens, you must contact your doctor immediately.
Additional adverse reactions in children
Although specific data in the paediatric population are limited, the few published data from efficacy and safety studies have not shown significant differences between adults and children affected by the same disease.
Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report adverse reactions directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-
avverse .
By reporting adverse reactions, you can help provide more information on the safety of this medicine.
For safety information regarding transmissible agents, see section 2 "What you need to know before
using KLOTT".

5. How to store KLOTT

Keep this medicine out of the sight and reach of children. Do not use KLOTT after the expiry date which is stated on the label and on the outer packaging after "Exp.". The expiry date refers to the last day of that month.
Store in a refrigerator (2 °C - 8 °C). Do not freeze. Keep the vial in the outer packaging to protect the medicine from light.
Before use and within the expiry date, the vial containing the powder may be stored at room temperature, not exceeding 25°C, for up to 6 consecutive months. After this period, the vial containing the powder must be discarded. In any case, this vial must not be returned to the refrigerator once it has been stored at room temperature.
Record the date of starting room temperature storage on the outer carton.
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 dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What KLOTT contains
The active substance is human coagulation factor VIII.

The activity (IU) is determined using the chromogenic method of the European Pharmacopoeia.
The specific activity of KLOTT is approximately 80 IU/mg of protein.
Produced from plasma of human donors.
This preparation contains human von Willebrand factor.
The vial of powder contains human coagulation factor VIII (active substance),
sodium chloride, trisodium citrate, glycine, calcium chloride (excipients).
The solvent vial contains water for injections.

Description of the appearance of KLOTT and contents of the pack
Powder and solvent for solution for infusion.
After reconstitution, the solution may contain a few fine filaments or particles.
The reconstituted medicinal product (dissolved solution) must be inspected visually before administration for the presence of suspended particles or abnormal discoloration. The solution should be clear or slightly opalescent. Do not use KLOTT if the solution appears cloudy or contains deposits.
The KLOTT pack contains one vial of powder, one vial of solvent for preparing the solution to be administered, and a sterile, pyrogen-free, single-use set consisting of a reconstitution device, an injection syringe, and a butterfly needle with PVC tubing.

Marketing Authorization 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:

Monitoring of treatment
During treatment, appropriate monitoring of factor VIII levels is required to adjust the dose and frequency of infusions. The response to factor VIII may vary between individual patients, with differing half-lives and recovery rates. Dosing calculated according to body weight may require adjustment in underweight or overweight patients.
In particular, during major surgical procedures, it is essential to closely monitor replacement therapy through coagulation assays (plasma factor VIII activity).
When using an in vitro “one-stage” coagulation assay based on activated partial thromboplastin time (aPTT) to determine factor VIII activity in patient blood samples, the results of plasma factor VIII activity may be significantly influenced by both the type of aPTT reagent and the reference standard used in the assay. Furthermore, significant discrepancies may occur between results obtained with an aPTT-based “one-stage” assay and those obtained with the chromogenic assay according to Ph. Eur. This is particularly important when changing laboratory and/or reagents used in the assay.

Dosage
The dosage and duration of replacement therapy depend on the severity of factor VIII deficiency, the location and extent of bleeding, and the patient's clinical condition.
The number of factor VIII units administered is expressed in International Units (IU), referenced to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for plasma factor VIII).
The activity of one International Unit of factor VIII is equivalent to the amount of factor VIII contained in one millilitre of normal human plasma.

On-demand treatment
The calculation of the required factor VIII dose is based on the empirical observation that 1 International Unit (IU) of factor VIII per kg of body weight raises plasma factor VIII activity by 1.5% to 2% of normal activity. The required dose can be calculated using the following formula:
Required units = body weight (kg) × desired increase in factor VIII activity (%) (IU/dL) × 0.4
The amount to be administered and the frequency of administration should always be guided by the clinical efficacy observed in the individual case.

In the case of the following bleeding events, factor VIII activity during the corresponding period should not fall below the indicated plasma activity level (as % of normal). The following table may be used as a reference guide for bleeding episodes and surgical procedures:

Prophylaxis
For long-term prophylaxis of bleeding episodes in patients with severe haemophilia A, the usual dose is
20 to 40 IU of factor VIII per kg of body weight, administered every 2–3 days. In some cases,
particularly in younger patients, shorter treatment intervals or higher doses may be required.

Paediatric population
The safety and efficacy of KLOTT in children under 12 years of age have not yet been established. For adolescents (12–18 years), the dosage for each indication is based on body weight.

Method of administration
For intravenous use, by injection or slow infusion.
When administering by intravenous injection, a delivery time of 3 to 5 minutes is recommended, monitoring the patient's pulse and interrupting or reducing the injection rate if pulse rate increases.
The infusion rate should be individually adjusted for each patient.
Reconstitute the powder as described in section “ 3. How to use KLOTT ” under the paragraph “ Instructions
for correct use ”.

Inhibitors
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors through appropriate clinical observation and laboratory tests. If expected plasma factor VIII activity levels are not achieved, or if bleeding is not controlled with an appropriate dose, testing for the presence of factor VIII inhibitors should be performed. In patients with high inhibitor levels, treatment with factor VIII may not be effective and alternative therapeutic options should be considered. The management of such patients should be directed by a physician experienced in the treatment of haemophilia and factor VIII inhibitors.