Fanhdı

PACKAGE LEAFLET: INFORMATION FOR THE USER

Fanhdi 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 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, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What Fanhdi is and what it is used for

Fanhdi consists of lyophilized powder and solvent for solution for infusion, containing approximately 250 IU, 500 IU, 1000 IU, and 1500 IU of factor VIII (FVIII), and 300 IU, 600 IU, 1200 IU, or 1800 IU of von Willebrand factor (VWF) per vial. Once reconstituted with the appropriate amount of solvent (water for injection), each vial contains approximately 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: Fanhdi 250, 500, 1000 Water for injection 10 ml Fanhdi 1500 Water for injection 15 ml

Fanhdi belongs to the group of medicines known as antihemorrhagics: coagulation factors: von Willebrand factor and coagulation factor VIII in combination.
Fanhdi is used for:

• Treatment and prevention of bleeding episodes in patients with hemophilia A (congenital factor VIII deficiency).
• Treatment of acquired factor VIII deficiency.
• Treatment of hemophilia A patients with antibodies against factor VIII (inhibitors).
• Treatment and prevention of bleeding episodes in patients with von Willebrand disease, when treatment with desmopressin (DDAVP) alone is ineffective or contraindicated.

2. What you should know before using Fanhdi

Do not use Fanhdi

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

If you need more information, please consult your doctor.
Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Fanhdi.

• 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; such a reaction may progress to shock (a severe and sudden allergic reaction). If these symptoms occur, you must stop using the product immediately and contact your doctor.

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

• 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, may prevent the treatment from working properly, and you or your child will be closely monitored for the development of such inhibitors. If Fanhdi does not control the bleeding in you or your child, inform your doctor immediately.

• If you have previously developed an inhibitor against FVIII and you switch to another factor VIII medicine, you may still develop an inhibitor again.

• During treatment for von Willebrand disease, there is a risk of blood clots forming, especially if clinical risk factors are known. Therefore, your doctor should perform tests to identify any signs of clotting and prescribe 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 should be carefully monitored to avoid persistently elevated levels in plasma, 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 action of the von Willebrand factor you are using. 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 inhibitor levels, effective von Willebrand factor therapy may prove ineffective, and alternative treatment options should be considered.

• If you require a central venous access device (CVAD) for administration of Fanhdi, your doctor must consider the risk of CVAD-related complications, including:

  • local infections,
  • bacteria in the blood (bacteraemia),
  • blood clot formation in the blood vessel (thrombosis) where the catheter is inserted.

• When medicines are made from human plasma or blood, precautionary measures are taken to prevent the transmission of infections to patients. These measures include:

  • careful selection of plasma and blood donors to ensure that donors at risk of carrying infections are excluded,
  • testing of each donation and plasma pools for signs of viruses/infections,
  • inclusion of manufacturing processes that can inactivate or remove viruses.

Despite these measures, when medicines derived from human plasma or blood are administered, the possibility of transmitting an infection cannot be completely ruled out. This applies to all viruses of unknown origin, emerging viruses, or other types of infections.
The measures taken are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, and the non-enveloped hepatitis A virus. However, these measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19.
Infections with parvovirus B19 may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency 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 factor VIII concentrates derived from human plasma.
It is recommended that, each time Fanhdi 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 Fanhdi
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No interactions between FVIII/FVW and other medicines are known.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning to become pregnant, 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
Fanhdi does not affect the ability to drive or operate machinery.
Sodium content
The residual sodium content in Fanhdi, originating from the manufacturing process, does not exceed 23 mg per vial (0.1 mmol/ml or 2.3 mg/ml) in the 250, 500, and 1000 IU presentations, and 34.5 mg per vial (0.1 mmol/ml or 2.3 mg/ml) in the 1500 IU presentation. This corresponds to 1.15% and 1.72%, respectively, of the maximum recommended daily intake of sodium 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 Fanhdi

This product must be administered by intravenous injection. The rate of administration must not exceed 10 ml/min.
Use this medicine exactly as directed by your doctor or the healthcare staff at the hemophilia treatment center. If you have any doubts, consult your doctor, pharmacist, or nurse.
The amount of Fanhdi you need depends on several factors, such as body weight, clinical condition, type and severity of bleeding. Your doctor will calculate the dose, frequency, and intervals of Fanhdi administration required to achieve the necessary blood level of factor VIII or von Willebrand factor.
Your doctor will determine the duration of treatment with Fanhdi.

To prepare the solution:
Ensure that you work under the most appropriate conditions throughout all steps to avoid product contamination.

1. Warm the vial and syringe, without 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 cap 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 product is completely dissolved. Since this is a solution for parenteral use, do not use the product if it is not completely dissolved or if visible particles are present.
9. Quickly disconnect the syringe with filter from the vial adapter to release the 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 must be 3 ml/min intravenously, and in any case never 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 correct administration of the product.

Use in children and adolescents
Clinical study data are insufficient to recommend the use of Fanhdi in children under 6 years of age.
If you use more Fanhdi than you should
There are no known cases of overdose with factor VIII and von Willebrand factor in combination.
However, in the event of a severe overdose, thromboembolic events may occur.
If you have administered more Fanhdi than prescribed, inform your doctor or pharmacist immediately.
If you forget to use Fanhdi

• Proceed immediately with the next scheduled dose and continue at regular intervals as directed 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 gets them.

Rarely, you may experience one or more of the following side effects after administration of Fanhdi. Call your doctor immediately if you notice:

• itching, local reactions at the injection site (e.g.: temporary burning 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).

Rarely, anaphylactic shock may occur. If you experience any of the following symptoms during administration:

• chest tightness or feeling unwell,
• dizziness,
• drop in blood pressure that may cause dizziness upon standing,
• chills,
• flushing, widespread hives,
• headache, drowsiness, restlessness,
• tingling,
• wheezing,
• nausea, vomiting,

this may be an early sign of hypersensitivity or anaphylactic reaction. In case of anaphylactic or allergic reaction, stop administration immediately and call your doctor right away.

Haemophilia A
Allergic reactions to the excipients of the product cannot be ruled out. In previously untreated children receiving factor VIII medicines, the development of inhibitory antibodies (see section 2) may be very common (more than 1 in 10 patients); however, in patients who have received prior treatment with factor VIII (more than 150 days of treatment), the risk is uncommon (less than 1 in 100). If this occurs, the medicine may no longer work properly and you or your child may experience persistent bleeding. If this happens, contact your doctor immediately.

Von Willebrand’s disease
When using a VWF-containing product with FVIII for the treatment of VWD (von Willebrand’s disease), prolonged treatment may lead to excessive increase of FVIII in the blood. This may increase the risk of thrombotic events.
If you are a patient with clinically or laboratory-confirmed risk factors, you should be monitored for early signs of thrombosis. Your doctor should implement preventive measures (prophylaxis) against venous thromboembolism according to current recommendations.
Especially if you are a patient with type 3 von Willebrand’s disease, in rare cases you may develop neutralizing antibodies (inhibitors) against von Willebrand factor. If these inhibitors develop, von Willebrand factor becomes less effective in controlling bleeding. If your bleeding does not stop, testing should be performed to check for the presence of inhibitors in your blood. 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.

For information on viral safety, see section 2.

Paediatric population
The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Fanhdi

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 the solution is cloudy or contains deposits. The solution should be clear or slightly opalescent. If the solution is cloudy or shows colour changes, discard it.
After reconstitution, the product is stable for 4 hours when stored at 25 °C.
From a microbiological standpoint, the product should be used immediately; if not used immediately, the duration and conditions of storage prior to use are under the user's responsibility.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package Contents and Other Information

What Fanhdi Contains
The active substance is human blood coagulation factor VIII and von Willebrand factor in combination.
Fanhdi 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 injections.
The other components are histidine, human albumin, and arginine.

Description of the Appearance of Fanhdi and Contents of the Package
Vial containing a white or pale yellow powder and a pre-filled syringe with water for injections (solvent).
Pack: 1 vial, 1 pre-filled syringe with solvent, and accessories (one vial adapter, one filter, two disinfectant swabs, and one infusion set).

Marketing Authorization Holder and Manufacturer
Instituto Grifols, S.A.
Can Guasc, 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 correlate with the current WHO standards 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).
One International Unit (IU) of factor VIII corresponds to the amount of factor VIII present in 1 ml of normal human plasma.

Treatment on Demand
Dose calculation for factor VIII 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:
Required Units = Body Weight × Desired Increase in Factor VIII × 0.5
(IU) (kg) (%) (IU/dl)
The amount to be administered and the frequency of administration should always aim to achieve clinical efficacy in each individual case.

In the case of the following bleeding events, factor VIII activity must not fall below the indicated plasma activity levels (in % of normal or IU/dl) for the specified time.
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 bleeding, or oral cavity bleeding | 20 – 40 | Repeat every 12–24 hours. At least 1 day, until pain resolves or healing is evident. | | More extensive hemarthrosis, intramuscular bleeding, or hematoma | 30 – 60 | Repeat infusion every 12–24 hours for 3–4 days or more, until pain and acute disability resolve. | | Life-threatening bleeding | 60 – 100 | Repeat infusion every 8–24 hours until the threat is resolved. | | Surgery | | | | Minor surgery (including dental extractions) | 30 – 60 | Every 24 hours, at least 1 day, until wound healing. | | 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 30–60% (IU/dl). |

Prophylaxis
For long-term prophylaxis of bleeding in patients with severe haemophilia A, the usual dose range is 20 to 40 IU of factor VIII per kg of body weight, administered every 2–3 days. In some cases, especially in younger patients, it may be necessary to shorten the interval between doses or administer higher doses.

During treatment, it is recommended to accurately monitor factor VIII levels to adjust the dose and frequency of infusions. Individual patients may show different responses to factor VIII, with varying half-lives and recovery rates. Since dosing is based on body weight, dose adjustments may be necessary in underweight or overweight patients.

In the case of 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 haemostasis, it is recommended to administer 40–80 IU/kg of von Willebrand factor (VWF:RCo) and 20–40 IU/kg of FVIII:C.

An initial dose of 80 IU/kg of von Willebrand factor may be required, 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 then 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, physicians should be aware that prolonged treatment may lead to excessive increases in FVIII:C levels. After 24–48 hours of treatment, it may be 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 Fanhdi in children under 6 years of age have not been established.