ADVATE 1000 IU POWDER AND SOLVENT FOR INJECTABLE SOLUTION

Introduction

Package Leaflet: Information for the User

ADVATE250UI powder andsolvent for solution for injection

ADVATE500UIpowder andsolvent for solution for injection

ADVATE1000UIpowder andsolvent for solution for injection

ADVATE1500UIpowder andsolvent for solution for injection

ADVATE2000UIpowder andsolvent for solution for injection

ADVATE3000UIpowder andsolvent for solution for injection

Octocog alfa (recombinant human coagulation factor VIII)

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 further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

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

1. What is ADVATE and what is it used for

ADVATE contains the active substance octocog alfa, a recombinant human coagulation factor VIII produced by DNA technology. Factor VIII is necessary for blood to clot and to stop bleeding. In patients with hemophilia A, factor VIII is missing or does not work properly (hereditary absence of factor VIII).

ADVATE is used to treat and prevent bleeding in patients of all ages with hemophilia A (a hereditary bleeding disorder caused by the absence of factor VIII).

ADVATE is prepared without adding any human or animal-derived protein during the entire manufacturing process.

2. What you need to know before you use ADVATE

Do not use ADVATE

• if you are allergic (hypersensitive) to octocog alfa or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to mouse or hamster proteins

If you are not sure if you are allergic, consult your doctor.

Warnings and precautions

Consult your doctor before starting treatment with ADVATE. Inform your doctor if you have been previously treated with medicines containing factor VIII, especially if you developed inhibitors, as there may be a high risk that this will happen again. Inhibitors are antibodies that block factor VIII, reducing the effectiveness of ADVATE in preventing bleeding control. The development of inhibitors is a known complication in the treatment of hemophilia A. If your bleeding is not controlled with ADVATE, consult your doctor immediately.

There is a small risk that you may experience a severe allergic reaction (anaphylaxis) to ADVATE. You should be aware that the first symptoms of an allergic reaction are rash, itching, hives, generalized itching, swelling of the lips and tongue, difficulty breathing, wheezing, chest tightness, feeling of general discomfort, and dizziness. These symptoms can be a warning of anaphylactic shock, which can also cause severe dizziness, loss of consciousness, and severe breathing difficulties.

If you experience any of these symptoms, stop the administration of the medicine immediately and consult a doctor. Severe symptoms, including difficulty breathing and (near) fainting, require rapid emergency treatment.

Patients who develop factor VIII inhibitors

The formation of inhibitors (antibodies) is a known complication that can occur during treatment with all factor VIII medicines. These inhibitors, especially in large quantities, prevent the treatment from working properly, so you and your child will be carefully monitored for the development of such inhibitors. If your bleeding or your child's bleeding is not controlled with ADVATE, consult your doctor immediately.

Children and adolescents

The warnings and precautions mentioned apply to adults and children (from 0 to 18 years of age).

Using ADVATE with other medicines

Tell your doctor if you are using, have recently used, or might use any other medicines.

Pregnancy andbreast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor for advice before taking this medicine.

Driving and using machines

Treatment with ADVATE does not affect the ability to drive and use machines.

ADVATE contains sodium

This medicine contains 0.45 mmol of sodium (10 mg) per vial, which should be taken into account in patients on a low-sodium diet.

3. How to use ADVATE

Treatment with ADVATE will be started by a doctor who has experience in treating patients with hemophilia A.

Your doctor will calculate your dose of ADVATE (in international units or IU) based on your condition, body weight, and whether it is to be used for prevention or treatment of bleeding. The frequency of administration will depend on how ADVATE works for you. Replacement therapy with ADVATE is usually a lifelong treatment.

Follow the instructions for administration of this medicine exactly as told by your doctor. If you are unsure, consult your doctor again.

Prevention of bleeding

The usual dose of octocog alfa is 20 to 40 IU per kilogram of body weight, administered every 2 or 3 days. However, in some cases, especially in younger patients, more frequent administration of injections or higher doses may be required.

Treatment of bleeding

The dose of octocog alfa is calculated based on your body weight and the desired factor VIII levels. The factor VIII levels to be achieved will depend on the severity and location of the bleeding.

Dose (IU) = body weight (kg) x desired increase in factor VIII (% of normal) x 0.5

If you think the effect of ADVATE is too weak, consult your doctor.

Your doctor will perform the necessary laboratory tests to ensure you have adequate factor VIII levels. This is especially important if you are going to have major surgery.

Use in children and adolescents (from0to18years of age)

For the treatment of bleeding, the dose in children does not differ from that in adult patients. To prevent bleeding in children under 6 years of age, doses of 20 to 50 IU per kilogram of body weight are recommended 3 to 4 times a week. Administration of ADVATE in children (intravenously) does not differ from administration in adults. A central venous access device (CVAD) may be necessary to allow for frequent infusions of factor VIII products.

How ADVATE is administered

ADVATE is usually injected into a vein (intravenously) by your doctor or nurse. You or another person can also administer the injection of ADVATE, but only after receiving proper training. Detailed instructions for administration are described at the end of this leaflet.

If you use more ADVATE than you should

Follow the instructions for administration of ADVATE exactly as told by your doctor. Consult your doctor if you are unsure. If you inject a higher dose of ADVATE than recommended, consult your doctor as soon as possible.

If you forget to use ADVATE

Do not inject a double dose to make up for forgotten doses. Administer the next injection as scheduled and continue as instructed by your doctor.

If you stop treatment with ADVATE

Do not stop using ADVATE without consulting your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience sudden and severe allergic reactions(anaphylaxis), stop the injection immediately. Contact your doctor immediately if you have any of the following initial symptoms of allergic reactions:

• rash, itching, hives, and generalized itching,
• swelling of the lips and tongue,
• difficulty breathing, wheezing, chest tightness,
• feeling of general discomfort,
• dizziness and loss of consciousness.

Severe symptoms, such as difficulty breathing and (near) fainting, require early emergency treatment.

In children who have not received prior treatment with factor VIII medicines, inhibitor antibodies (see section 2) may occur very frequently (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 infrequent (less than 1 in 100 patients). If this happens, the medicines you or your child are taking may stop working properly, and you or your child may experience persistent bleeding. In this case, contact your doctor immediately.

Very common side effects(may affect more than 1 in 10 patients)

Factor VIII inhibitors (in children who have not received prior treatment with factor VIII medicines).

Common side effects(may affect up to 1 in 10 patients)

Headache and fever

Uncommon side effects(may affect up to 1 in 100 patients)

Factor VIII inhibitors (in patients who have received prior treatment with factor VIII [more than 150 days of treatment]), dizziness, flu-like symptoms, fainting, abnormal heart rhythms, red spots associated with itching, chest discomfort, bruising at the injection site, injection site reaction, itching, increased sweating, unusual taste in the mouth, hot flashes, migraines, memory loss, chills, diarrhea, nausea, vomiting, difficulty breathing, sore throat, infection of the lymph vessels, paleness, eye inflammation, rash, excessive sweating, swelling of feet and legs, decreased red blood cell count, increased monocytes (a type of white blood cell), and pain in the upper abdomen or lower chest.

Related to surgery

catheter-related infection, decreased red blood cell count, swelling of the limbs and joints, prolonged bleeding after drain removal, decreased factor VIII levels, and postoperative hematoma

Related to central venous access devices (CVAD)

Catheter-related infection, systemic infection, and local blood clot at the catheter site.

Side effects with unknown frequency(cannot be estimated from the available data)

Potentially life-threatening reactions (anaphylaxis) and other allergic reactions (hypersensitivity), general disorders (fatigue, lack of energy).

Additional side effects in children

In addition to the development of inhibitors in pediatric patients without prior treatment and catheter-related complications, no age-specific differences in side effects were observed in clinical trials.

Reporting of side effects

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

5. Storage of ADVATE

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of the month stated.

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Until the expiry date, the powder vial can be stored at room temperature (up to 25°C) for a single period not exceeding 6 months. In this case, the medicine expires at the end of this 6-month period or on the expiry date printed on the product vial, whichever comes first. Please note the end date of the 6-month storage period at room temperature on the carton. The medicine cannot be refrigerated again after storage at room temperature.

Keep the vial in the outer carton in order to protect from light.

This medicine is for single use only. Dispose of any unused solution properly.

Use the medicine immediately after complete dissolution of the powder.

Do not refrigerate the medicine after preparation.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Container Contents and Additional Information

Composition of ADVATE

• The active substance is octocog alfa (human coagulation factor VIII produced by recombinant DNA technology). Each vial of powder contains nominally 250, 500, 1000, 1500, 2000, or 3000 IU of octocog alfa.
• The other components are mannitol, sodium chloride, histidine, trehalose, calcium chloride, tromethamine, polysorbate 80, and glutathione (reduced)

Solvent vial: 5 ml of sterile water for injectable preparations

Appearance of the Product andContainer Contents

ADVATE is a white to off-white friable powder.

After reconstitution, the solution is clear, colorless, and free of foreign particles.

Each container also includes a reconstitution device (BAXJECT II).

Marketing Authorization Holder

Takeda Manufacturing Austria AG

Industriestrasse 67

A-1221 Vienna

Tel: +800 66838470

E-mail: medinfoEMEA@shire.com

Manufacturers

Baxalta Belgium Manufacturing SA

Boulevard René Branquart 80

B-7860 Lessines

Belgium

Date of Last Revision of this Leaflet

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/.

--------------------------------------------------------------------------------------------------------------------

Instructions for Preparation andAdministration

An aseptic technique is required for the preparation of the solution and its administration.

Use only the sterile water for injectable preparations and the reconstitution device included in each ADVATE container. ADVATE must not be mixed with other medicines or solvents.

It is strongly recommended to record the name and batch number of the product each time ADVATE is administered.

Instructions for Reconstitution

• Do not use after the expiration date stated on the labels and on the container.
• Do not use if the BAXJECT II device, the sterile protective system, or its container is damaged or shows signs of deterioration, as indicated by the symbol: .
• Do not refrigerate the preparation after reconstitution.

1. If the medicine is in the refrigerator, remove the ADVATE powder and solvent vials from the refrigerator and let them reach room temperature (between 15°C and 25°C).
2. Wash your hands with soap and warm water.
3. Remove the protectors from the powder and solvent vials.
4. Clean the stoppers with alcohol-impregnated swabs. Place the vials on a flat, clean surface.
5. Open the BAXJECT II device wrapper by removing the paper cover without touching the inside (Fig. a). Do not remove the device from the wrapper. Do not use if the BAXJECT II device, its sterile barrier system, or its packaging is damaged or shows signs of deterioration.
6. Turn the wrapper over and insert the plastic tip through the solvent stopper. Hold the wrapper by its end and pull out the BAXJECT II device from its wrapper (Fig. b). Do not remove the blue protector from the BAXJECT II device.
7. For reconstitution, use only the sterile water for injectable preparations and the reconstitution device included in the container. With the BAXJECT II device attached to the solvent vial, invert the system so that the solvent vial is on top of the device. Insert the white plastic tip into the ADVATE powder vial stopper. The vacuum will draw the solvent into the ADVATE powder vial (Fig. c).
8. Gently swirl until all material is dissolved. Ensure that the ADVATE powder is completely dissolved; if not, the reconstituted solution will not pass through the filter of the device. The medicine dissolves rapidly (usually in less than 1 minute). After reconstitution, the solution must be clear, colorless, and free of foreign particles.

Fig. aFig. bFig. c

Instructions for Injection

A luer-lock syringe is required for administration.

Important Note:

• Do not attempt to administer the injection unless you have received special training from your doctor or nurse.
• Inspect the prepared solution for particles or discoloration before administration (the solution must be clear, colorless, and free of foreign particles).

Do not use ADVATE if the solution is not totally clear or not completely dissolved.

1. Remove the blue protector from the BAXJECT II device. Do not introduce air into the syringe. Connect the syringe to the BAXJECT II device (Fig. d).
2. Invert the system (the vial with the reconstituted solution on top). Draw the reconstituted solution into the syringe by slowly pulling back the plunger (Fig. e).
3. Disconnect the syringe.
4. Connect a winged infusion needle to the syringe. Inject intravenously. The solution should be administered slowly, at a rate determined by the patient's comfort level, not exceeding 10 ml per minute. The pulse should be taken before and during the administration of ADVATE. If a significant increase in pulse is observed, the administration rate should be reduced or temporarily interrupted, which usually allows the symptoms to disappear (see section 4 "Possible Side Effects").
5. Dispose of the unused solution properly.

Fig. dFig. e

--------------------------------------------------------------------------------------------------------------------

This information is intended only for healthcare professionals:

On-demand Treatment

In the case of subsequent hemorrhagic episodes, the factor VIII activity should not be lower than the given plasma activity level (in % of normal or IU/dl) during the corresponding period. The following table can be used as a dosage guide for hemorrhagic episodes and surgery.

The dose and frequency of administration should be adapted to the individual clinical response. In certain circumstances (e.g., presence of a low inhibitor titre), higher doses than those calculated using the formula may be necessary.