AZACITIDINE ACCORD 25 mg/mL POWDER FOR INJECTABLE SUSPENSION

Introduction

Package Leaflet: Information for the User

Azacitidina Accord25mg/ml powder for injectable suspension EFG

azacitidina

Read all of this leaflet carefully before you start usingthis 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, pharmacist, or nurse.
• If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Azacitidina Accord and what is it used for

What is Azacitidina Accord

Azacitidina Accord is an anti-cancer agent that belongs to a group of medicines called "antimetabolites". Azacitidina Accord contains the active substance "azacitidina".

What is Azacitidina Accord used for

Azacitidina Accord is used in adults who cannot receive a stem cell transplant to treat:

• High-risk myelodysplastic syndromes (MDS).
• Chronic myelomonocytic leukemia (CMML).
• Acute myeloid leukemia (AML).

These diseases affect the bone marrow and can cause problems with the normal production of blood cells.

How Azacitidina Accord works

Azacitidina Accord works by preventing the growth of cancer cells. Azacitidina is incorporated into the genetic material of cells (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]). It is believed to work by altering the way cells activate or deactivate genes by interfering with the production of new RNA and DNA. It is believed that these actions correct the problems of maturation and growth of healthy blood cells in the bone marrow that cause myelodysplastic disorders, and that kill cancer cells in leukemia.

Talk to your doctor or nurse if you have any questions about how Azacitidina Accord works or why you have been prescribed this medicine.

2. What you need to know before you use Azacitidina Accord

Do not use Azacitidina Accord

• If you are allergic to azacitidina or any of the other ingredients of this medicine (listed in section 6).
• If you have advanced liver cancer.
• During breast-feeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using Azacitidina Accord:

• If you have a low platelet count, red blood cells, or white blood cells.
• If you have kidney disease.
• If you have liver disease.
• If you have ever had heart disease or a heart attack, or have a history of lung disease.

Azacitidina may cause a severe immune reaction called "differentiation syndrome" (see section 4).

Blood tests

Before you start treatment with Azacitidina Accord and at the start of each treatment period (called a "cycle"), you will have blood tests. This is to check that you have enough blood cells and that your liver and kidneys are working properly.

Children and adolescents

Azacitidina Accord is not recommended for use in children and adolescents under 18 years of age.

Other medicines and Azacitidina Accord

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines. This is because Azacitidina Accord may affect the way other medicines work. Similarly, other medicines may affect the way Azacitidina Accord works.

Pregnancy, breast-feeding, and fertility

Pregnancy

Do not use Azacitidina Accord during pregnancy because it may harm the baby.

If you are a woman who can become pregnant, you must use an effective contraceptive method while you are taking Azacitidina Accord and for 6 months after finishing treatment with Azacitidina Accord.

Tell your doctor immediately if you become pregnant during treatment.

If you are pregnant or breast-feeding, think you may be pregnant, or plan to become pregnant, ask your doctor or pharmacist for advice before using this medicine.

Breast-feeding

Azacitidina Accord must not be used during breast-feeding. It is not known if this medicine is excreted in breast milk.

Fertility

Men must not father a child while receiving treatment with Azacitidina Accord.

Men must use an effective contraceptive method while taking Azacitidina Accord and for 3 months after finishing treatment with Azacitidina Accord.

Ask your doctor if you want to preserve your sperm before you are given this treatment.

Driving and using machines

Do not drive or use tools or machines if you experience side effects such as fatigue.

3. How to use Azacitidina Accord

Before you are given Azacitidina Accord, your doctor will give you another medicine to prevent nausea and vomiting at the start of each treatment cycle.

• The recommended dose is 75 mg/m2 of body surface area. Your doctor will decide your dose of this medicine based on your general condition, height, and weight. Your doctor will monitor your progress and, if necessary, may change your dose.
• Azacitidina Accord is given every day for a week, followed by a 3-week rest period. This "treatment cycle" is repeated every 4 weeks. You will usually receive at least 6 cycles of treatment.

A doctor or nurse will give you this medicine as an injection under the skin (subcutaneously). It can be given under the skin of the thigh, abdomen, or arm (above the elbow).

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

4. Possible side effects

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

Tell your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal swelling, and easy bruising. These can be symptoms of liver failure and can be life-threatening.
• Swelling of legs and feet, back pain, decreased urine output, increased thirst, rapid pulse, dizziness, and nausea, vomiting, or decreased appetite and feeling of confusion, restlessness, or fatigue. These can be symptoms of kidney failure and can be life-threatening.
• Fever. This could be due to an infection as a result of having low white blood cell counts, which can be life-threatening.
• Chest pain or difficulty breathing that may be accompanied by fever. This could be due to a lung infection known as "pneumonia" and can be life-threatening.
• Bleeding. For example, blood in the stool, due to bleeding in the stomach or intestines, or bleeding in the head. These can be symptoms of having low platelet counts in the blood.
• Difficulty breathing, swelling of the lips, itching, or skin rash. These can be due to an allergic reaction (hypersensitivity).

Other side effects include:

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

• Low red blood cell count (anemia). You may feel tired and pale.
• Low white blood cell count. This can be accompanied by fever. You are also more likely to get infections.
• Low platelet count in the blood (thrombocytopenia). You are more prone to bleeding and bruising.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, difficulty breathing.
• Fatigue (fatigue).
• Reaction at the injection site, including redness, pain, or skin rash.
• Loss of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Difficulty sleeping (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding in the head.
• Blood infection caused by bacteria (sepsis). This can be due to low white blood cell counts in the blood.
• Bone marrow failure. This can cause low red and white blood cell counts, and low platelet counts.
• A type of anemia where there is a decrease in red and white blood cells, and platelets.
• Urinary tract infection.
• A viral infection that causes herpes-like lesions.
• Bleeding from the gums, stomach, or intestine, or bleeding in the lower back due to hemorrhoidal bleeding, bleeding in the eyes, bleeding under the skin or within the skin (hematoma).
• Blood in the urine.
• Ulcers in the mouth or tongue.
• Changes in the skin at the injection site. These can be swelling, a hard lump, bruising, bleeding into the skin (hematoma), skin rash, itching, and changes in skin color.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection, or sore throat.
• Pain or discharge from the nose or sinuses (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Pain in the throat and larynx.
• Indigestion.
• Drowsiness (lethargy).
• Feeling unwell.
• Anxiety.
• Feeling confused.
• Hair loss.
• Kidney failure.
• Dehydration.
• A white coating on the tongue, inside of the cheeks, and sometimes the palate, gums, and tonsils (fungal infection in the mouth).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension) that causes dizziness when standing up or sitting.
• Sleepiness, drowsiness (somnolence).
• Bleeding due to the catheter.
• A disease that affects the intestine that can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (shivering).
• Muscle spasms.
• Itchy skin rash (urticaria).
• Fluid around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Painful, large, and swollen purple spots on the skin and fever.
• Painful ulcers on the skin (pyoderma gangrenosum).
• Inflammation of the lining around the heart (pericarditis).

Rare side effects(may affect up to 1 in 1,000 people)

• Dry cough.
• Painless swelling of the fingertips (drumstick fingers).
• Tumor lysis syndrome - metabolic complications can occur during cancer treatment and sometimes even without treatment. These complications occur as a result of the product of dying tumor cells and can include: changes in blood biochemistry, high levels of potassium, phosphorus, uric acid, and low levels of calcium, which can cause changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known(cannot be estimated from the available data)

• Infection of the deep layers of the skin that spreads quickly, damaging the skin and tissue, which can be life-threatening (necrotizing fasciitis).
• Severe immune reaction (differentiation syndrome) that can cause fever, cough, difficulty breathing, skin rash, decreased urine output, low blood pressure (hypotension), swelling of the arms or legs, and rapid weight gain.
• Inflammation of blood vessels in the skin that can cause skin rash (cutaneous vasculitis).

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidina Accord

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 vial label and carton. The expiry date is the last day of the month stated.

Your doctor, pharmacist, or nurse is responsible for the storage of Azacitidina Accord. They are also responsible for the proper preparation and disposal of unused Azacitidina Accord.

Unopened vials of this medicine do not require special storage conditions.

If used later

If the Azacitidina Accord suspension is prepared using non-refrigerated water for injections, the suspension should be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and stored in the refrigerator for a maximum of 8 hours.

If the Azacitidina Accord suspension is prepared using refrigerated water for injections (between 2°C and 8°C), the suspension should be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and stored in the refrigerator for a maximum of 22 hours.

The suspension should be allowed to reach room temperature (20°C to 25°C) for a maximum of 30 minutes before administration.

The suspension should be discarded if it contains large particles.

6. Container Content and Additional Information

Azacitidina Accord Composition

• The active ingredient is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution with 4 ml of water for injectable preparations, the reconstituted suspension contains 25 mg/ml of azacitidine.
• The other component is mannitol (E421).

Product Appearance and Container Content

Azacitidina Accord is a white powder for injectable suspension and is supplied in a glass vial containing 100 mg of azacitidine. Each container contains one vial of Azacitidina Accord.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n,

Edifici Est 6ª planta,

08039 Barcelona, Spain

Manufacturer

O

Accord Healthcare Polska Sp.z o.o.

ul. Lutomierska 50,

95-200 Pabianice

Poland

O

Laboratori Fundació Dau

C/ C, 12-14 Pol. Ind.

Zona Franca, Barcelona, 08040,

Spain

Ó

Accord Healthcare B.V.

Winthontlaan, 200

3526 KV Utrecht

Netherlands

Date of Last Revision of this Leaflet:{MM/AAAA}.

Detailed information on this medicinal product is available on the European Medicines Agency website:

http://www.ema.europa.eu/. There are also links to other websites on rare diseases and orphan medicines.

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This information is intended for healthcare professionals only:

Recommendations for Safe Handling

Azacitidina Accord is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Procedures for the handling and disposal of anticancer medicinal products should be followed.

If reconstituted azacitidine comes into contact with the skin, the area should be washed immediately and thoroughly with water and soap. If it comes into contact with mucous membranes, it should be rinsed thoroughly with water.

Incompatibilities

This medicinal product should not be mixed with other medicinal products except those mentioned below (see "Reconstitution Procedure").

Reconstitution Procedure

Azacitidina Accord should be reconstituted with water for injectable preparations. The validity period of the reconstituted medicinal product can be extended by reconstituting it with refrigerated water for injectable preparations (between 2 °C and 8 °C). The following information is provided on the storage of the reconstituted medicinal product.

1. The following elements should be assembled:

Vial(s) of azacitidina; vial(s) of water for injectable preparations; non-sterile surgical gloves; alcohol-impregnated swabs; 5 ml syringes with needles.

1. 4 ml of water for injectable preparations should be drawn into the syringe, ensuring that any air trapped in the syringe is purged.
2. The needle of the syringe containing the 4 ml of water for injectable preparations should be inserted through the rubber stopper of the azacitidina vial; the water for injectable preparations should then be injected into the vial.
3. After removing the syringe and needle, the vial should be shaken vigorously until a uniform, turbid suspension is obtained. After reconstitution, each ml of suspension will contain 25 mg of azacitidina (100 mg/4 ml). The reconstituted product is a turbid, homogeneous suspension without agglomerates. The suspension should be discarded if it contains large particles or agglomerates. The suspension should not be filtered after reconstitution, as this could remove the active ingredient. It should be noted that some adapters, infusion needles, and closed systems contain filters; therefore, such systems should not be used for the administration of the medicinal product after reconstitution.
4. The rubber stopper should be cleaned and a new syringe with a needle inserted into the vial. The vial should then be inverted, ensuring that the needle tip is below the level of the liquid. The plunger should then be pulled back to withdraw the required amount of medicinal product for the correct dose, ensuring that any air trapped in the syringe is purged. The syringe with the needle should then be removed from the vial and the needle discarded.
5. A new subcutaneous needle (25 gauge recommended) for injectables should then be firmly attached to the syringe. The needle should not be purged before injection, in order to reduce the incidence of local reactions at the injection site.
6. If more than one vial is required, all the above steps should be repeated for the preparation of the suspension. In the case of doses requiring more than one vial, the dose should be divided into equal parts, for example, a dose of 150 mg = 6 ml; two syringes with 3 ml in each syringe. Due to retention in the vial and needle, it may not be possible to withdraw the entire suspension from the vial.
7. The contents of the dosing syringe should be resuspended immediately before administration. The temperature of the suspension at the time of injection should be approximately 20 °C to 25 °C. To resuspend, the syringe should be rolled vigorously between the palms of the hands until a uniform, turbid suspension is obtained. The suspension should be discarded if it contains large particles or agglomerates.

Storage of the Reconstituted Medicinal Product

For Immediate Use

. If the time elapsed is more than 60 minutes, the reconstituted suspension should be discarded correctly and a new dose prepared.

For Subsequent Use

When reconstituted with non-refrigerated water for injectable preparations, the reconstituted suspension should be placed in a refrigerator (temperature between 2 °C and 8 °C) immediately after reconstitution and stored in the refrigerator for a maximum of 8 hours. If the time elapsed in the refrigerator is more than 8 hours, the suspension should be discarded correctly and a new dose prepared.

When reconstituted with refrigerated water for injectable preparations (between 2 °C and 8 °C), the reconstituted suspension should be placed in a refrigerator (between 2 °C and 8 °C) immediately after reconstitution and stored in the refrigerator for a maximum of 22 hours. If the time elapsed in the refrigerator is more than 22 hours, the suspension should be discarded correctly and a new dose prepared.

The loaded syringe with the reconstituted suspension should be allowed to reach a temperature of approximately 20 °C to 25 °C for a maximum of 30 minutes before administration. If the time elapsed is more than 30 minutes, the suspension should be discarded correctly and a new dose prepared.

Calculation of an Individual Dose

The total dose, according to body surface area (BSA), can be calculated as follows:

Total dose (mg) = dose (mg/m2) × BSA (m2)

The following table is presented only as an example for calculating individual doses of azacitidine, based on an average BSA value of 1.8 m2.

Method of Administration

Do not filter the suspension after reconstitution.

Reconstituted Azacitidina Accord should be injected subcutaneously (insert the needle at an angle of 45 to 90°), with a 25-gauge needle, in the arm, thigh, or abdomen.

Doses greater than 4 ml should be injected at two separate sites.

Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous site and never in sensitive areas, with bruising, redness, or induration.

Disposal

Disposal of the unused medicinal product and all materials that have come into contact with it should be carried out in accordance with local regulations.