Emowil

Package leaflet: Information for the user

EMOWIL 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, 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 others, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor or pharmacist.

Contents of this leaflet:

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

1. What EMOWIL is and what it is used for

EMOWIL is a plasma-derived coagulation factor VIII solution. Factor VIII is a protein with antihemorrhagic activity.
EMOWIL is used in the treatment of:
bleeding episodes in patients with hereditary deficiency of factor VIII coagulation activity (haemophilia A);
bleeding episodes in patients with acquired deficiency of factor VIII coagulation activity secondary to other diseases;
patients with von Willebrand disease;
haemophilic patients who have developed antibodies against factor VIII (inhibitors).

2. What you should know before using EMOWIL

Do not use EMOWIL

• if you are allergic to human coagulation 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 EMOWIL.
Allergic reaction
Allergic-type hypersensitivity reactions may occur with EMOWIL.
EMOWIL contains traces of human proteins other than factor VIII. If during administration you notice any of the symptoms listed below, stop administration of EMOWIL immediately and contact your doctor, as these symptoms could be the first signs of an allergic reaction. Symptoms may include: generalized hives, chest tightness, wheezing, low blood pressure, and severe allergic reaction (anaphylactic shock).
In case of shock, standard medical treatments for shock should be initiated.
Inhibitors
The development of inhibitors (antibodies) is a known complication that may occur during treatment with any factor VIII medicine. 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 EMOWIL does not control bleeding effectively in you or your child, 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 you require a central venous access device, the risk of device-related complications should be considered, including local infections, bacteremia, and thrombosis at the catheter site.
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 viruses/infections;
• inclusion in the manufacturing process of blood and plasma of steps capable of inactivating or removing viruses.

Despite these measures, when administering medicinal products prepared from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to emerging or unknown viruses or other types of 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 the non-lipid-enveloped hepatitis A virus (HAV). The measures taken may have limited effect against non-lipid-enveloped viruses such as parvovirus B19.
Infection with parvovirus B19 may be severe during pregnancy (fetal infection) and in individuals with weakened 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 EMOWIL, the product name and batch number are recorded to ensure traceability of the batch used.
Your doctor may advise you to consider vaccination against hepatitis A and B if you receive human plasma-derived coagulation factor VIII regularly or repeatedly.
Children
Specific data in the pediatric population are not available.
Other medicines and EMOWIL
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 medicinal products.
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine.
Animal reproduction studies have not been conducted with factor VIII. Due to the rarity of hemophilia A in women, there are no data available on the use of factor VIII during pregnancy and breastfeeding. Therefore, factor VIII should be used during pregnancy and breastfeeding only if clearly indicated.
Driving and using machines
EMOWIL has no effect on the ability to drive or use machinery.
EMOWIL 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 EMOWIL

Use this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.

The recommended dose and duration of replacement therapy depend on the severity of factor VIII deficiency, the location and extent of bleeding, and your clinical condition. The product must be administered intravenously, either by injection or slow infusion. The infusion rate should be adjusted according to your individual characteristics.

EMOWIL must not be mixed with other medicinal products.

On-demand treatment
The amount of medicine and frequency of administrations should be determined based on your clinical response.

Prophylactic treatment
If you have severe haemophilia A and require long-term prophylactic treatment to prevent bleeding, the usual dose is 20 to 40 IU (International Units) of factor VIII per kg of body weight, administered every 2–3 days. In some cases, particularly if you are young, shorter intervals or higher doses may be required.

You must be carefully monitored for the possible development of factor VIII inhibitors through appropriate clinical observations and laboratory tests.

During treatment, appropriate assessment 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 therapy be monitored by performing coagulation tests (factor VIII plasma activity assays).

Only the injection/infusion devices supplied in the package must be used, as treatment failure may occur due to adsorption of factor VIII onto the surfaces of certain devices.

For intravenous injection, a recommended administration time of 3 to 5 minutes is advised. Monitor your pulse and interrupt or reduce the infusion rate if your pulse rate increases.

Use in children
The safety and efficacy of EMOWIL in children under 6 years of age have not yet been established.

Reconstitution of powder with solvent:

1. Bring the vial of powder and the solvent vial to room temperature;
2. Maintain this temperature throughout the entire reconstitution process (within a maximum of 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 package 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 package and pull it away to release the device without touching it (Fig. C);
9. Ensure the vial containing the powder is securely placed on a stable surface. Invert the system so that the solvent vial is positioned above the device. Press the transparent adapter onto the stopper of the powder vial so that the plastic spike pierces the powder vial stopper; 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).

Check that the powder is completely dissolved; incomplete dissolution may result in loss of product activity.

fig. A	fig. B
fig. C	fig. D
fig. E	fig. F

.
Administration of the solution
The reconstituted medicinal product must be inspected visually before administration for the presence of
particulate matter or discoloration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or contain 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. while keeping the plunger steady, invert the system so that the vial with the reconstituted solution is positioned above the device, and slowly draw 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 appear clear or slightly opalescent and free from particulate matter;
5. attach the butterfly needle to the syringe and administer the solution by slow intravenous infusion or injection.

fig. G

fig. H

Once the vials have been opened, the contents must be used immediately.
The reconstituted solution transferred into the syringe must be administered immediately.
The contents of the vial must be used for a single administration only.
Do not use after the expiry date stated on the label.
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.
If you use more EMOWIL than you should
The consequences of an overdose are unknown.
In case of accidental ingestion/overdose of EMOWIL, inform your doctor immediately or go to the nearest hospital.
If you have any questions about the use of EMOWIL, consult your doctor or pharmacist.
Further information regarding dosage and duration of treatment is provided at the end of the
package leaflet in the section intended for healthcare professionals.

4. Possible side effects

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

• Severe allergic reactions (hypersensitivity): rapid onset of swelling of mucous membranes and the face and mouth area (angioedema). This side effect has been observed rarely and in some cases may lead to severe acute allergic reactions (up to anaphylactic shock).
• Development of neutralizing antibodies directed against factor VIII (inhibitors). The presence of these inhibitors manifests as an inadequate response to treatment. In such cases, it is advisable to contact a specialized haemophilia treatment centre.

Other side effects:

• Other allergic reactions (hypersensitivity) may include: burning sensation and stinging pain at the infusion site; chills, flushing, generalized skin rash (generalized urticaria), hives; headache (cephalalgia); drop in blood pressure (hypotension), restlessness, rapid heartbeat (tachycardia), feeling of tightness in the chest, wheezing; drowsiness (lethargy); nausea, vomiting; tingling (paresthesia). These side effects have been observed rarely and in some cases may lead to severe acute allergic reactions (up to anaphylactic shock).
• Fever has also been reported.

In previously untreated children receiving factor VIII-containing medicines, the formation of inhibitory
antibodies (see section 2) can be very common (more than 1 in 10 patients); however, in patients who
have previously received factor VIII treatment (more than 150 days of treatment), the risk is uncommon (less
than 1 in 100 patients). If this occurs, the medicine may no longer work properly and you or your child may
experience persistent bleeding. If this happens, you must contact your doctor immediately.
Additional side effects 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 with the same condition.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, 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 taking EMOWIL".

5. How to store EMOWIL

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 outer packaging following “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 it 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 dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

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

The specific activity of EMOWIL is approximately 80 IU/mg of protein.
Produced from human donor plasma.
This preparation contains von Willebrand factor 400 IU/1000 IU of human factor VIII.
Other components are: sodium chloride, trisodium citrate, glycine, calcium chloride (excipients).
The solvent vial contains water for injections.
Description of the appearance of EMOWIL and contents of the pack
Powder and solvent for solution for infusion.
After reconstitution, the solution may contain a few small filaments or particles.
The reconstituted medicinal product (dissolved solution) must be visually inspected before administration for the presence of suspended particles or abnormal colour. The solution should be clear or slightly opalescent. Do not use EMOWIL if you notice that the solution is cloudy or has deposits.
The EMOWIL 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 healthcare professionals:

Monitoring of treatment
During the course of treatment, appropriate determination of factor VIII levels is required to adjust the dose to be administered and the frequency of repeat infusions. Response to factor VIII may vary among individual patients, showing different half-lives and recovery rates. Dosing calculated based on body weight may require adjustment in underweight or overweight patients.
Particularly during major surgical procedures, it is essential to closely monitor replacement therapy through coagulation analyses (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, there may be significant discrepancies between results obtained with an aPTT-based "one-stage" coagulation assay and those obtained with the chromogenic assay according to the European Pharmacopoeia. This is particularly important when changing laboratories and/or reagents used in testing.

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), which are 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 present in one milliliter 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 increases plasma factor VIII activity by 1.5% to 2% of normal activity. The required dose is determined using the following formula:
Required units = body weight (kg) × desired increase in factor VIII (%) (IU/dL) × reciprocal of observed recovery

The amount to administer and the frequency of infusions 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 relevant period must not fall below the indicated plasma activity level (in % of normal). The following table can be used as a reference in bleeding episodes and surgical procedures:

Prophylaxis
For long-term prophylaxis of bleeding episodes in patients with severe hemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg 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 EMOWIL in children under 6 years of age have not yet been established.

Method of administration
For intravenous use, by injection or slow infusion.
When administering by intravenous injection, a duration of administration between 3 and 5 minutes is recommended. The patient's pulse should be monitored, and the injection rate should be slowed down or stopped if an increase in pulse rate occurs.
The infusion rate should be adjusted according to the individual patient.
Reconstitute the powder as described in section “3. How to use EMOWIL”, subsection “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, factor VIII therapy may be ineffective and alternative therapeutic options should be considered. The management of such patients should be supervised by a physician experienced in the treatment of hemophilia and factor VIII inhibitors.