Plitate

PACKAGE LEAFLET: INFORMATION FOR THE USER

Plitate 250 IU + 300 IU/10 ml Powder and solvent for solution for infusion, 500 IU + 600 IU/10 ml Powder and solvent for solution for infusion, 1000 IU + 1200 IU/10 ml Powder and solvent for solution for infusion, 1500 IU + 1800 IU/15 ml Powder and solvent for solution for infusion

Human coagulation Factor VIII and human von Willebrand Factor complex
Please read all of this 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, pharmacist, or nurse.
• 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 experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What Plitate is and what it is used for

Plitate consists of a lyophilized powder containing approximately 250 IU, 500 IU, 1000 IU, and 1500 IU of factor VIII (FVIII), and 300, 600, 1200, or 1800 IU per vial of von Willebrand factor (VWF), together with a solvent for solution for infusion (water for injectable preparations). Once reconstituted with the appropriate volume of solvent, each vial contains 25, 50, or 100 IU of FVIII/ml and 30, 60, or 120 IU of VWF/ml.

Vial:

• Active substance: FVIII 250 IU 500 IU 1000 IU 1500 IU VWF 300 IU 600 IU 1200 IU 1800 IU Specific activity FVIII:C after separation 1000 - 3000 IU/mg of protein from VWF: (Total proteins: ≤ 90 mg ≤ 135 mg)
• Excipients: Histidine, Human albumin, Arginine Pre-filled syringe with solvent: Plitate 250, 500, 1000 Water for injectable preparations 10 ml Plitate 1500 Water for injectable preparations 15 ml

Plitate belongs to the group of medicines known as haemostatics: coagulation factors: von Willebrand factor and blood coagulation factor VIII in combination.

Plitate is used for:

• Treatment and prevention of bleeding episodes in patients with haemophilia A (congenital factor VIII deficiency).
• Treatment of acquired factor VIII deficiency.
• Treatment of haemophilia A patients with antibodies against factor VIII (inhibitors).
• Treatment of patients with von Willebrand disease. Prevention and treatment of bleeding and surgical procedure-related bleeding in patients in whom treatment with desmopressin alone is ineffective or contraindicated.

2. What you should know before using Plitate

Do not use Plitate

• If you are allergic to human coagulation factor VIII and/or von Willebrand factor or to any of the other ingredients of this medicine (listed in section 6).

If you would like more information, ask your doctor.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Plitate.

• Rarely, an allergic (hypersensitivity) reaction may occur, characterized by skin rash, chest tightness, wheezing, dizziness, lightheadedness, nausea, or low blood pressure with dizziness upon standing. This reaction may progress to shock (a severe and sudden allergic reaction). If you experience these symptoms, you must stop using the product immediately and contact your doctor.

• Your doctor should perform appropriate laboratory tests to ensure that the dose of Plitate you are receiving is sufficient to achieve and maintain an adequate factor VIII level, thereby controlling any bleeding episode.

• The development of inhibitors (antibodies) is a known complication that may occur during treatment with all factor VIII-containing medicines. Inhibitors, especially at high levels, prevent the treatment from working properly, and you or your child will be closely monitored for the development of such inhibitors. If Plitate fails to control bleeding in you or your child, inform your doctor immediately.

• If you have previously developed inhibitors against FVIII and are switching to another factor VIII medicine, you must be carefully monitored for the recurrence of inhibitors.

• During treatment for von Willebrand disease, there is a risk of blood clot formation, especially if clinical risk factors are present. Therefore, your doctor should perform appropriate tests to identify any signs of thrombosis (blood clot formation) and prescribe suitable treatment if necessary.

• When using VWF products containing FVIII:C, prolonged treatment may lead to excessive increases in FVIII:C levels. Plasma levels of FVIII:C must be closely monitored to avoid persistently elevated levels, which may increase the risk of thrombotic events.

• Patients with von Willebrand disease, especially type 3, may develop neutralizing antibodies against von Willebrand factor (inhibitors). Von Willebrand factor inhibitors are antibodies in the blood that may block the von Willebrand factor you are receiving. If von Willebrand factor activity does not reach expected plasma levels, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine the presence of a von Willebrand factor inhibitor. In patients with high levels of
  inhibitor, treatment with von Willebrand factor may prove ineffective, and alternative therapeutic options should be considered.

• If a central venous access device (CVAD) is required for the administration of Plitate, your doctor should consider the risk of CVAD-related complications, including local infections, bacteria in the blood (bacteraemia), and blood clot formation in the blood vessel where the catheter is inserted (thrombosis).

Viral safety
When medicines are manufactured from human plasma or blood, specific precautionary measures are taken to prevent transmission of infections to patients. These measures include:

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

Despite these measures, when administering medicines derived from human plasma or blood, 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 against the non-lipid-enveloped hepatitis A virus (HAV). However, these measures may have limited effectiveness against non-enveloped (non-lipid-coated) viruses such as parvovirus B19.
Parvovirus B19 infections can be serious for pregnant women (fetal infection) and for individuals with immunosuppression or certain types of anemia (e.g., sickle cell anemia or hemolytic anemia).
Your doctor may recommend vaccination against hepatitis A and B if you receive regular or repeated infusions of plasma-derived factor VIII/von Willebrand factor concentrates.
It is recommended that, each time Plitate is administered, the product name and batch number be recorded to ensure traceability of the batches used.
See also section 4.
Children and adolescents
The warnings and precautions listed above apply to both adults and children.
Other medicines and Plitate
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No interactions between FVIII/VWF and other medicines are known.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
FVIII/VWF should be used during pregnancy and breastfeeding only if clearly indicated.
Driving and using machines
No effects on the ability to drive or operate machinery have been observed.
Sodium content
This medicine contains less than 1 mmol (23 mg) of sodium in the 250 IU+300 IU/10 ml, 500 IU+600 IU/10 ml, and 1000 IU+1200 IU/10 ml vials, i.e., essentially 'sodium-free'. This medicine contains 34.5 mg of sodium (the main component of table salt) per 1500 IU+1800 IU/15 ml vial. This corresponds to 1.72% of the maximum daily dietary intake recommended for an adult. However, depending on the patient's body weight and dosage, the patient may receive more than one vial.

3. How to use Plitate

Use this medicine exactly as instructed by your doctor or healthcare staff at the haemophilia centre. If you have any doubts, consult your doctor, pharmacist, or nurse.
This product must be administered intravenously. The infusion rate must not exceed 10 ml/min.
The dose and duration of treatment with Plitate depend on several factors, such as body weight, clinical condition, type and severity of bleeding. Your doctor will calculate the required dose, frequency, administration intervals, and duration of Plitate therapy to achieve the necessary blood levels of factor VIII or von Willebrand factor.
Your doctor will determine the duration of treatment with Plitate.

To prepare the solution:
Ensure that you work under appropriate conditions throughout the entire process to avoid product contamination.

1. Warm the vial and the syringe, not exceeding 30 °C.
2. Insert the plunger into the syringe containing the solvent.
3. Remove the filter from its packaging. Remove the cap from the syringe connector and attach the syringe to the filter.
4. Remove the vial adapter from its packaging and connect it to the filter on the syringe.
5. Remove the plastic protector from the vial and clean the stopper with the disinfectant swabs provided.
6. Pierce the vial stopper with the needle of the adapter.
7. Transfer all the solvent from the syringe into the vial.
8. Gently rotate the vial without shaking until the entire product is completely dissolved. As this is a parenteral solution, do not use the product if it is not fully dissolved or if visible particles are present.
9. Quickly disconnect the syringe with the filter from the vial with the adapter to release any vacuum.
10. With the vial held upright, draw the solution into the syringe.
11. Prepare the injection site, disconnect the syringe, and inject the product using the butterfly needle set provided. The injection rate should be 3 ml/min intravenously, and in no case exceed 10 ml/min, to avoid vasomotor reactions.

Do not reuse administration sets. Any remaining product must never be reused or stored in the refrigerator.
It is important to use the infusion set supplied with the medicine. If other medical infusion systems are used, their compatibility with the pre-filled syringe must be verified. Adapters should be used when necessary to ensure proper administration of the product.

Use in children and adolescents
The safety and efficacy of Plitate in children under 6 years of age have not yet been established.
If you use more Plitate than you should
The consequences of excessive use of this product are unknown.
However, if you have taken more Plitate than you should, inform your doctor or pharmacist immediately.
If you forget to use Plitate

• Proceed immediately with the next scheduled dose and continue at regular intervals as instructed by your doctor.
• Do not use a double dose to make up for a missed dose.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Rarely, you may experience one or more of the following side effects after administration of Plitate.
Contact your doctor immediately if any of the following occur:

• itching, and local reactions at the injection site (e.g.: temporary burning sensation and redness)
• allergic reactions (e.g., chest tightness or feeling unwell, dizziness, nausea and low blood pressure, which may cause dizziness upon standing, chills, flushing, widespread hives, headache, drowsiness, restlessness, tingling, vomiting, wheezing),
• fever
• rapid heartbeat (tachycardia).

Anaphylactic shock may rarely occur. If you experience any of the following symptoms during administration:

• chest tightness or feeling unwell
• dizziness
• mild hypotension (slight drop in blood pressure with dizziness upon standing)
• chills
• flushing, widespread hives
• headache, drowsiness, restlessness
• tingling
• wheezing
• nausea, vomiting

be aware that these may be early signs of hypersensitivity and anaphylactic reaction. In case of an anaphylactic or allergic reaction, stop the administration immediately and contact your doctor right away.

Haemophilia A
Allergic reactions to the excipients of the product cannot be ruled out. For previously untreated children receiving factor VIII-containing medicines, the development of inhibitory antibodies (see section 2) may be very common (more than 1 in 10 patients); however, in patients who have previously received factor VIII treatment (more than 150 exposure days), the risk is uncommon (less than 1 in 100 patients). If this occurs, the medicine may become less effective and you or your child may experience persistent bleeding. If this happens, contact your doctor immediately.

von Willebrand Disease
When using a VWF-containing product with FVIII for the treatment of VWD (von Willebrand disease), prolonged treatment may lead to excessive increase of FVIII in the blood, thereby increasing the risk of thrombotic events.
If you are a patient with known risk factors for thrombotic disorders (either clinically or laboratory-confirmed), you should be closely monitored for early signs of thrombosis. Your doctor should implement preventive measures (prophylaxis) against venous thromboembolism in accordance with current guidelines.
If you are a patient with type 3 von Willebrand disease, in rare cases you may develop neutralizing antibodies (inhibitors) against von Willebrand factor. If such inhibitors develop, von Willebrand factor becomes less effective in controlling bleeding. If your bleeding does not stop, testing for the presence of inhibitors in your blood should be performed. These antibodies may be associated with anaphylactic reactions. Therefore, in patients who develop anaphylactic reactions, the presence of inhibitors should be evaluated. In such cases, contact your doctor immediately.

List of adverse reactions
The following table is organized according to the MedDRA system organ class (SOC) and preferred term level.
Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data).
Within each frequency group, adverse reactions are listed in decreasing order of severity.

Description of selected adverse reactions
The most frequently reported adverse reactions after marketing since the product's registration have been the development of factor VIII inhibitors, urticaria, hypersensitivity, dizziness, nausea, vomiting, chills, anaphylactic reaction, hypotension, skin rashes, and tachycardia.
Paediatric population
The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.
For information on viral safety, see section 2.
Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. You can also report adverse reactions directly via [relevant national reporting system]. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. How to store Plitate

Keep this medicine out of the sight and reach of children.
Do not store above 30 °C.
Do not freeze. Protect from light.
Do not use this medicine after the expiry date stated on the label and carton after "Exp.".
Do not use this medicine if you notice that the solution is cloudy or contains deposits. The solution
should be clear or slightly opalescent. If the solution is cloudy or shows changes in colour, discard it.
After reconstitution, the product is stable for 4 hours when stored at 25 °C.
From a microbiological point of view, the product should be used immediately; if not used immediately,
the duration and conditions of storage prior to use are the responsibility of the user.
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. Package Contents and Other Information

What Plitate Contains
The active substance is human blood coagulation factor VIII and von Willebrand factor in combination.
Plitate consists of lyophilized powder and solvent for solution for infusion, containing approximately
250 IU, 500 IU, 1000 IU, or 1500 IU of human coagulation factor VIII, and 300 IU, 600 IU,
1200 IU, or 1800 IU of von Willebrand factor per vial. The product is reconstituted with 10 ml
(for the 250 IU, 500 IU, and 1000 IU presentations) or 15 ml (for the 1500 IU presentation) of water for
injection.
The other components are histidine, human albumin, and arginine.

Description of the Appearance of Plitate and Contents of the Package
Powder and solvent for solution for infusion.
Plitate is supplied as a vial containing hygroscopic powder or friable solid, white or pale yellow in color, and a pre-filled syringe containing water for injection (solvent).
Each package of Plitate contains: 1 vial of lyophilized powder, 1 pre-filled syringe of solvent (water for injection), and accessories (a vial adapter, a filter, 2 antiseptic wipes, and an infusion set).

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder:
Grifols Italia S.p.A.
Via Torino, 15
56010 Vicopisano
Pisa – ITALY

Manufacturer:
Instituto Grifols, S.A.
Can Guasch, 2 – Parets del Vallès
08150 Barcelona - SPAIN
……………………....................................................................................................................................

The following information is intended exclusively for physicians or healthcare professionals:

Dosage and Administration

Haemophilia A
The doses 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 units of factor VIII administered is expressed in International Units (IU), which are referenced to the current WHO standards for factor VIII-containing 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).
One International Unit (IU) of factor VIII activity corresponds to the amount of factor VIII present in 1 ml of normal human plasma.

Treatment on Demand
Dose calculation is based on empirical evidence showing that 1 International Unit (IU) of factor VIII per kg of body weight increases plasma factor VIII activity by 2.1 ± 0.4% of normal activity.
The required dose can be determined using the following formula:
Units required = Body weight x Desired increase in factor VIII x 0.5
(IU) (kg) (%) (IU/dl)

The amount administered and the frequency of administration should always aim to achieve clinical efficacy in each individual case.
For the following bleeding events, factor VIII activity must not fall below the indicated plasma activity levels (in % of normal or IU/dl) during the corresponding time period.
The following table may be used to guide dosing during bleeding episodes and surgery:

| Bleeding Grade / Surgical Procedure | Required Factor VIII Levels (%) (IU/dl) | Frequency of Administrations (hours) / Duration of Therapy (days) | |----------------------------------------|---------------------------------------------|----------------------------------------------------------------------| | Bleeding | | Recent hemarthrosis, intramuscular or oral cavity bleeding | 20 – 40 | Repeat every 12–24 hours. At least 1 day, until the bleeding episode, indicated by pain, has resolved or healing is evident. | | More extensive hemarthrosis, intramuscular bleeding, or hematoma | 30 – 60 | Repeat administration every 12–24 hours for 3–4 days or longer, until pain and acute disability resolve. | | Life-threatening bleeding | 60 – 100 | Repeat administration every 8–24 hours until the life-threatening risk has passed. | | Surgery | | Minor surgery, including dental extractions | 30 – 60 | Every 24 hours, at least 1 day, until wound healing is complete. | | Major surgery (pre- and postoperative) | 80 – 100 | Repeat administration every 8–24 hours until adequate wound healing is achieved, followed by therapy for at least another 7 days to maintain factor VIII activity between 30 and 60% (IU/dl). |

Prophylaxis
For long-term prophylaxis of bleeding in patients with severe haemophilia A, usual doses range from 20 to 40 IU of factor VIII per kg of body weight, administered at intervals of 2–3 days. In some cases, especially in younger patients, shorter intervals between doses or higher doses may be required.

During treatment, it is recommended to accurately monitor factor VIII levels to adjust the administered dose and the frequency of infusions. Individual patients may exhibit different responses to factor VIII, with varying half-lives and recovery rates. Since dosing is based on body weight, dose adjustment may be necessary in underweight or overweight patients. In particular, during major surgical procedures, precise monitoring of replacement therapy using coagulation tests (plasma factor VIII activity) is essential.

von Willebrand Disease
Generally, 1 IU/kg of VWF:RCo increases circulating VWF:RCo levels by 0.02 IU/ml (2%).
Target levels should be VWF:RCo > 0.6 IU/ml (60%) and FVIII:C > 0.4 IU/ml (40%).
Typically, to achieve hemostasis, administration of 40–80 IU/kg of von Willebrand factor (VWF:RCo) and 20–40 IU/kg of FVIII:C is recommended.
An initial dose of 80 IU/kg of von Willebrand factor may be necessary, especially in patients with type 3 von Willebrand disease, where maintaining adequate levels may require higher doses compared to other types of von Willebrand disease.

Appropriate doses should subsequently be administered every 12–24 hours. The dose and duration of treatment depend on the patient's clinical condition, the type and severity of bleeding, and the levels of VWF:RCo and FVIII:C.

When using von Willebrand factor preparations containing FVIII, the physician should consider that prolonged treatment may lead to excessive increases in FVIII:C levels. After 24–48 hours of treatment, it is advisable to reduce the dose and/or increase the interval between administrations, or to use a VWF product with a low FVIII content, to avoid excessive elevation of FVIII:C levels.

Paediatric Population
The safety and efficacy of Plitate in children under 6 years of age have not been established.
Since dosage is adjusted according to the clinical outcome of the conditions mentioned above, it is considered that the dosage per kg of body weight in children is not different from that in adults.