AZACITIDINE ZENTIVA 25 mg/mL POWDER FOR INJECTABLE SUSPENSION

Introduction

Package Leaflet: Information for the User

Azacitidine Zentiva25mg/ml powder for injectable suspension EFG

L.

• Keep this package 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 package leaflet. See section 4.

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1. What is Azacitidine Zentiva and what is it used for
2. What you need to know before taking Azacitidine Zentiva
3. How to take Azacitidine Zentiva
4. Possible side effects

5 Conservation of Azacitidine Zentiva

1. Contents of the pack and further information

1. What is Azacitidine Zentiva and what is it used for

QzacitidineZ

This medicine is an anticancer agent that belongs to a group of medicines called "antimetabolites". This medicine contains the active substance "azacitidine".

PzacitidineZ

This medicine 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.

CzacitidineZ

Azacitidine works by preventing the growth of cancer cells. Azacitidine is incorporated into the genetic material of cells (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]). It is believed to act 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 they kill cancer cells in leukemia.

Ask your doctor or nurse if you have any questions about how this medicine works or why you have been prescribed this medicine.

2. What you need to know before taking Azacitidine Zentiva

Do not take Azacitidine Zentiva

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

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before taking this medicine:

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

Blood tests

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

Children and adolescents

The use of this medicine is not recommended in children and adolescents under 18 years of age.

Other medicines and Azacitidine Zentiva

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

This is because Azacitidine Zentiva may affect the way other medicines work. Similarly, other medicines may affect the way Azacitidine Zentiva works.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before taking this medicine.

Pregnancy

You should not take this medicine 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 taking Azacitidine Zentiva and for 6 months after stopping treatment with this medicine.

Tell your doctor immediately if you become pregnant during treatment.

Breastfeeding

This medicine should not be used during breastfeeding. It is not known if this medicine is excreted in breast milk.

Fertility

Men should not father a child while receiving treatment with azacitidine Zentiva. Men should use an effective contraceptive method while taking Azacitidine Zentiva and for 3 months after stopping treatment with this medicine.

Consult your doctor if you wish to preserve your sperm before receiving 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 take Azacitidine Zentiva

Before administering azacitidine, 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.
• Azacitidine is given every day for a week, followed by a three-week rest period. This "treatment cycle" is repeated every four weeks. You will usually receive at least six 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. They can be symptoms of liver failure and can be potentially 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.They can be symptoms of kidney failure and can be potentially life-threatening.
• Fever.It could be due to an infection as a result of having low white blood cell counts, which can be potentially life-threatening.
• Chest pain or difficulty breathing that may be accompanied by fever.It may be due to a lung infection known as "pneumonia" and can be potentially life-threatening.
• Bleeding.For example, blood in the stool, due to bleeding in the stomach or intestines, or bleeding in the lower back due to hemorrhoidal bleeding, bleeding in the eyes, bleeding under the skin, or inside the skin (hematoma).
• Difficulty breathing, swelling of the lips, itching, or skin rash.They may 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. It may 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 reaction.
• Lack of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain
• Dizziness.
• Headache.
• Sleeping problems (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 inside the head.
• Blood infection caused by bacteria (sepsis). It may be due to low white blood cell counts in the blood.
• Bone marrow failure. It can cause low red and white blood cell counts and platelets.
• A type of anemia in which 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, bleeding from the stomach or intestine, bleeding in the lower back due to hemorrhoidal bleeding, bleeding in the eyes, bleeding under the skin, or inside 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 excessive 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, the inside of the cheeks, and sometimes the palate, gums, and tonsils (fungal infection in the mouth).
• Fainting.
• Decreased blood pressure when standing up (orthostatic hypotension) that causes dizziness when standing up or sitting.
• Sleepiness, drowsiness (somnolence).
• Bleeding due to the catheter route.
• A disease that affects the intestine that can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms
• Skin rash with itching (urticaria).
• Fluid accumulation 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 that surrounds 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 cancer cells and may include: changes in blood biochemistry, high levels of potassium, phosphorus, uric acid, and low levels of calcium, which in turn generate 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, which spreads rapidly damaging the skin and tissue, which can be potentially 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 package leaflet. You can also report side effects directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Conservation of Azacitidine Zentiva

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

Do not use this medicine after the expiration date that appears on the vial label and on the carton after EXP. The expiration date is the last day of the month indicated.

Your doctor, pharmacist, or nurse is responsible for the conservation of Azacitidine Zentiva. They are also responsible for the correct preparation and disposal of unused Azacitidine Zentiva.

Unopened vials: this medicine does not require special storage conditions.

If used immediately

The suspension must be administered within 60 minutes of preparation.

If used later

If the Azacitidine Zentiva suspension is prepared using non-refrigerated water for injectable preparations, the suspension must be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and must be kept in the refrigerator for a maximum of 8 hours.

If the Azacitidine Zentiva suspension is prepared using refrigerated water for injectable preparations (between 2°C and 8°C), the suspension must be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and must be kept in the refrigerator for a maximum of 22 hours.

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

The suspension should be discarded if it contains large particles.

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

6. Contents of the pack and further information

Composition of Azacitidine Zentiva

• The active substance 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).

Appearance of the product and pack contents

Azacitidine Zentiva is a white powder for injectable suspension and is supplied in a type I glass vial sealed with a gray dark butyl rubber stopper with one slit coated with FluroTec or a lyo butyl rubber stopper with one slit coated with bromo butyl omniflex gray dark and a tear-off aluminum cap containing 100 mg of azacitidine.

Each pack contains one vial of Azacitidine Zentiva.

Marketing authorization holder

Zentiva k.s.

U Kabelovny 130

102 37 Prague 10

Czech Republic

Manufacturer

APIS Labor GmbH

Resslstraße 9,

9065 Ebenthal

Austria

or

LABORATORI FUNDACIÓ DAU

C/ De la letra C, 12-14, Polígono Industrial de la Zona Franca

08040 Barcelona

Spain

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Zentiva Spain S.L.U.

Avenida de Europa, 19, Edificio 3, Planta 1.

28224 Pozuelo de Alarcón, Madrid

Spain

This medicine is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Date of last revision of this package leaflet:January 2024

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/.

This information is intended solely for healthcare professionals:

Recommendations for safe handling

Azacitidine is a cytotoxic medication and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Proper procedures for handling and disposing of cancer medications should be applied.

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 medication should not be mixed with others, except as mentioned below (see "Reconstitution Procedure").

Reconstitution Procedure

Azacitidine should be reconstituted with water for injectable preparations. The validity period of the reconstituted medication 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 medication.

1. The following elements should be assembled:

Vials of azacitidine; vials of water for injectable preparations; non-sterile surgical gloves; alcohol-soaked swabs; 5-ml syringes with needles.

1. 4 ml of water for injectable preparations should be drawn into the syringe, ensuring that any trapped air is purged from the syringe.
2. The needle of the syringe containing the 4 ml of water for injectable preparations should be inserted through the rubber stopper of the azacitidine vial; then, the water for injectable preparations should 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 azacitidine (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 administering the medication after reconstitution.
4. The rubber stopper should be cleaned, and a new syringe with a needle should be inserted into the vial. Then, the vial should be inverted, ensuring that the tip of the needle is below the level of the liquid. The plunger should then be pulled back to withdraw the required amount of medication for the correct dose, ensuring that any trapped air is purged from the syringe. The syringe with the needle should then be removed from the vial, and the needle should be 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 to reduce the incidence of local reactions at the injection site.
6. If more than 1 vial is required, all the previous steps should be repeated for preparing the suspension. For doses requiring more than 1 vial, the dose should be divided into equal parts, for example, a dose of 150 mg = 6 ml; 2 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, vigorously roll the syringe 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 Medication

For Immediate Use

The azacitidine suspension can be prepared immediately before use, and the reconstituted suspension should be administered within 60 minutes. If more than 60 minutes have passed, the reconstituted suspension should be properly discarded, and a new dose should be prepared.

For Later 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 should be kept in the refrigerator for a maximum of 8 hours. If the time spent in the refrigerator exceeds 8 hours, the suspension should be properly discarded, and a new dose should be 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 should be kept in the refrigerator for a maximum of 22 hours. If the time spent in the refrigerator exceeds 22 hours, the suspension should be properly discarded, and a new dose should be 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 more than 30 minutes have passed, the suspension should be properly discarded, and a new dose should be prepared.

Calculation of an Individual Dose

The total dose, based on 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 azacitidine 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, bruised, red, or hardened areas.

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