Prospect: information for the user

Azacitidina Zentiva25mg/ml powder for injectable suspension EFG

Lead the entire prospect carefully before starting to use this medication, because it contains important information for you.

• Conserve this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor, pharmacist, or nurse.
• Si experimenta efectos adversos, consulte a su médico, farmacéutico o enfermero, incluso si se trata de efectos adversos que no aparecen en este prospecto. Ver sección 4. If you experience adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this prospect. See section 4.

Content of the prospect

1. What Azacitidina Zentiva is and for what it is used
2. What you need to know before starting to use Azacitidina Zentiva
3. How to use Azacitidina Zentiva
4. Possible adverse effects

5Storage of Azacitidina Zentiva

6.Contents of the package and additional information

What isAzacitidinaZentiva

This medication is an anticancer agent that belongs to a group of medications called “antimetabolites”. This medication contains the active ingredient “azacitidina”.

What is it used forAzacitidinaZentiva

This medication 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 in the normal production of blood cells.

How it worksAzacitidinaZentiva

Azacitidina works by preventing the growth of cancer cells. Azacitidina incorporates 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 kill cancer cells in leukemia.

Consult a doctor or nurse if you have any questions about how this medication works or why you have been prescribed this medication.

Do not use Azacitidina Zentiva

• If you are allergic to azacitidina or any of the other components of this medication (listed in section6).
• If you have advanced liver cancer.
• During lactation.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use this medication:

• If you have a decrease in platelet, red blood cell, or white blood cell count.
• If you have a kidney disease.
• If you have a liver disease.
• If you have ever had a heart disease or myocardial infarction, or have a history of lung disease
• Azacitidina may cause a severe immune reaction called “differentiation syndrome” (see section 4).

Blood tests

Before starting treatment with Azacitidina Zentiva and at the beginning of each treatment period (called “cycle”) blood tests will be performed. This is done to check that you have a sufficient number of blood cells and that your liver and kidneys are functioning correctly.

Children and adolescents

This medication is not recommended for use in children and adolescents under 18years.

Other medications and Azacitidina Zentiva

Inform your doctor or pharmacist if you are using, have used recently, or may have to use any other medication.

This is because Azacitidina Zentiva may affect the way other medications work. Similarly, other medications may affect the way Azacitidina Zentiva works.

Pregnancy, lactation, and fertility

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medication.

Pregnancy

You should not use this medication during pregnancy as it may be harmful to the baby.

If you are a woman who may become pregnant, you must use an effective contraceptive method while taking Azacitidina Zentiva and for 6 months after stopping treatment with this medication.

Inform your doctor immediately if you become pregnant during treatment.

Lactation

This medication should not be used during breastfeeding. It is unknown whether this medication is excreted in breast milk.

Fertility

Males should not conceive a child while receiving treatment with azacitidina Zentiva. Males should use an effective contraceptive method while taking Azacitidina Zentiva and for 3 months after stopping treatment with this medication.

Consult your doctor if you wish to preserve your sperm before you are administered this treatment.

Driving and operating machinery

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

Before administering azacitidina, your doctor will give you another medicine to prevent nausea and vomiting at the beginning 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 is administered every day for one week, followed by a three-week rest period. This "treatment cycle" will be repeated every four weeks. You will usually receive at least six treatment cycles.

A doctor or nurse will administer this medicine as a subcutaneous injection under the skin. It can be administered under the skin of the thigh, abdomen, or arm (above the elbow).

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor immediately if you observe any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal bloating, and bruising easily. They may be symptoms of liver failure and can be potentially fatal.
• Swelling of the 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 may be symptoms of kidney failure and can be potentially fatal.
• Fever.It could be due to an infection as a result of having low white blood cell counts, which can be potentially fatal.
• 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 fatal.
• Bleeding.For example, blood in the stool, due to bleeding in the stomach or intestines, or bleeding in the head. These may be symptoms of having low platelet counts in the blood.
• 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 10people)

• Decreased red blood cell count (anemia). You may feel tired and pale.
• Decreased white blood cell count. It may be accompanied by fever. You also have a higher probability of getting 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.
• Tiredness (fatigue).
• Reaction at the injection site, which includes redness, pain, or skin rash.
• Loss of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nasal and throat pain
• Dizziness.
• Headache.
• Difficulty falling asleep (insomnia).
• Nasal bleeding (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding in 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 may cause low red and white blood cell counts, and platelet counts.
• 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 gums, bleeding stomach or intestines, 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.
• Mouth or tongue ulcers.
• Changes in the skin, at the injection site. These may be swelling, a hard lump, bruising, bleeding into the skin (hematoma), skin rash, itching, and changes in skin color.
• Skin redness.
• Skin infection (cellulitis).
• Nasal and throat infection, or throat pain.
• Nasal or sinus pain or discharge (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Throat and larynx pain.
• Indigestion.
• Drowsiness (somnolence).
• Feeling unwell.
• Anxiety.
• Feeling confused.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside the cheeks, and sometimes the palate, gums, and tonsils (fungal infection of the mouth).
• Loss of consciousness.
• Decreased blood pressure when standing (orthostatic hypotension) that causes dizziness when standing or sitting.
• Sleep, drowsiness (somnolence).
• Bleeding due to a catheter.
• A disease that affects the intestine that can cause fever, vomiting, and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (rigors).
• Muscle spasms
• Skin rash with itching (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

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

• Reaction to an allergen (hypersensitivity).
• Tremors.
• Liver failure.
• Painful, large, and swollen purple spots on the skin and fever.
• Painful skin ulcers (pyoderma gangrenosum).
• Inflammation of the heart lining (pericarditis).

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

• Dry cough.
• Painless swelling of the fingertips (finger drumsticks).
• Tumor lysis syndrome – complications may occur during cancer treatment and sometimes even without treatment. These complications occur as a result of the product of dying tumor cells and may include: changes in blood biochemistry, high potassium, phosphorus, and uric acid levels, and low calcium levels that, therefore, generate changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known(cannot be estimated from available data)

• Deep skin infection that spreads quickly, damaging the skin and tissue, which can be potentially fatal (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.
• Skin blood vessel inflammation that can cause skin rash (cutaneous vasculitis).

Reporting of side effects

If you experience any type of side effect,consult your doctor,pharmacist, or nurse, even if it is a possible side effect that does not appear in this prospectus.You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use: https://www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the vial label and on the box after CAD/EXP. The expiration date is the last day of the month indicated.

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

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

If used immediately

The suspension must be administered within 60 minutes of its preparation.

If used later

If the Azacitidina Zentiva suspension is prepared using non-refrigerated injectable water, 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 Azacitidina Zentiva suspension is prepared using refrigerated injectable water (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 must be allowed to reach an ambient temperature of 20°C to 25°C for up to 30 minutes before administration.

The suspension must be discarded if it contains large particles.

Medicines should not be thrown away through the drains or in the trash. Ask your pharmacist how to dispose of the containers and medicines that you no longer need. This will help protect the environment.

CompositionofAzacitidina Zentiva

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

Aspect of the product and content of the package

Azacitidina Zentiva is a white powder for injectable suspension and is delivered in a transparent glass vial of typeI sealed with a grey-brown chlorobutyl rubber stopper with a single orifice covered with FluroTec or a grey-brown lyo rubber stopper with a single orifice covered with bromobutyl omniflex and an aluminium flip-off cap containing 100mg of azacitidina.

Each package contains a vial of Azacitidina Zentiva.

Marketing Authorization Holder

Zentiva k.s.

U Kabelovny 130

102 37 Prague 10

Czech Republic

Responsible for manufacturing

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

Further information about this medicinal product can be obtained 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 medicinal product is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Last update of this leaflet:January 2024

Further detailed and updated information about this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/.

This information is intended solely for healthcare professionals:

Recommendations for safe handling

Azacitidineis a cytotoxic drug and, like other potentially toxic compounds, caution should be exercised when handling and preparing azacitidina suspensions. The procedures for correct handling and disposal of cancer drugs should be applied.

If azacitidine reconstituted 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 washed thoroughly with water.

Incompatibilities

This medicinal product should not be mixed with others, except as mentioned below (see “Reconstitution procedure”).

Reconstitution procedure

Azacitidineshould be reconstituted with water for injection. The shelf-life of the reconstituted medicinal product can be extended by reconstituting it with refrigerated water for injection (between 2°C and 8°C). The following information is provided on the storage of the reconstituted medicinal product.

1. The following items should be mounted:

Vial(s) of azacitidine; vial(s) of water for injection; non-sterile surgical gloves; alcohol-moistened wipes; 5ml injection syringes with needles.

1. 4ml of water for injection should be withdrawn from the syringe, ensuring that the air trapped in the syringe is purged.
2. The needle of the syringe containing the 4ml of water for injection should be inserted through the rubber stopper of the azacitidine vial; the water for injection should then be injected into the vial.
3. After withdrawing 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 25mg of azacitidine (100mg/4ml). The reconstituted product is a turbid and homogeneous suspension, without aggregates.The suspension should be discarded if it contains large particles or aggregates.
4. The rubber stopper should be cleaned and a new syringe with a needle should be introduced into the vial. The vial should then be inverted, ensuring that the tip of the needle is below the liquid level. The plunger should then be pulled back to withdraw the required amount of medicinal product for the correct dose, ensuring that the air trapped in the syringe is purged. The vial should then be withdrawn from the syringe and the needle should be discarded.
5. A new subcutaneous needle (a calibre 25 needle is recommended for injectables) should 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 1vial is required, all the above steps should be repeated for the preparation of the suspension. In the case of doses requiring more than 1vial, the dose should be divided into equal parts, for example, a dose of 150mg=6ml; two syringes with 3ml in each syringe. Due to retention in the vial and needle, it may not be possible to withdraw all the suspension from the vial.
7. The dose in the 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 vigorously rolled between the palms of the hands until a uniform turbid suspension is obtained.The suspension should be discarded if it contains large particles or aggregates.

Storage of the reconstituted medicinal product

For immediate use

The azacitidine suspension can be prepared immediately before use and the reconstituted suspension should be administered within the following 60minutes. If the time elapsed is greater than 60minutes, the reconstituted suspension should be discarded correctly and a new dose should be prepared.

For later use

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

When reconstituted with refrigerated water for injection (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 stored in the refrigerator for a maximum of 22hours. If the time elapsed in the refrigerator is greater than 22hours, the suspension should be discarded correctly and a new dose should be prepared.

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

Calculation of an individual dose

The total dose, according to the body surface area (SC), can be calculated as follows: Total dose (mg) = dose (mg/m2) × SC (m2)

The following table is presented only as an example to calculate individual doses of azacitidine, based on an average SC value of 1.8m2.

Administration form

Do not filter the suspension after reconstitution.

Azacitidinereconstituted should be injected subcutaneously (insert the needle at an angle of 45 to 90°), with a calibre 25 needle, in the arm, thigh or abdomen.

Doses greater than 4ml should be injected in two separate locations.

The injection sites should be rotated. New injections should be administered at least 2.5cm from the previous site and never in sensitive areas, with ecchymosis, redness or hardening.

The elimination of unused medicinal product and all materials that have come into contact with it will be carried out in accordance with local regulations.