Label: information for the user

Azacitidina Zentiva ks 25 mg/ml powder for injectable suspension EFG

Read this label carefully before starting to use this medicine, as it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this label. See section 4.

Contentsof the label

1. What Azacitidina Zentiva ks is and for what it is used
2. What you need to know before starting to use Azacitidina Zentiva ks
3. How to use Azacitidina Zentiva ks
4. Possible adverse effects
5. Storage of Azacitidina Zentiva ks
6. Contents of the package and additional information

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

What is Azacitidina Zentiva ks used for

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

• High-risk myelodysplastic syndromes (SMD).
• Chronic myelomonocytic leukemia (LMMC).
• Acute myeloid leukemia (LMA).

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

How Azacitidina Zentiva ks worksks

Azacitidina Zentiva ks works by inhibiting 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 azacitidina works or why you have been prescribed this medication.

No use Azacitidina Zentiva ks

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

Warnings and Precautions

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

• 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 a myocardial infarction, or have a history of lung disease

Blood Tests

Before starting treatment with azacitidine 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

The use of azacitidine is not recommended in children and adolescents under 18 years old.

Other Medications and Azacitidina Zentiva ks

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication. This is because azacitidine may affect the way other medications work. Similarly, other medications may affect the way azacitidine works.

Pregnancy, Lactation, and Fertility

Pregnancy

You should not use azacitidine during pregnancy because it may be harmful to the baby.

If you are a woman and may become pregnant, you should use an effective contraceptive method while taking azacitidine and for 6 months after completing treatment with azacitidine.

Inform your doctor immediately if you become pregnant during treatment.

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

Lactation

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

Fertility

Males should not conceive a child while receiving treatment with azacitidine. Men should use an effective contraceptive method while taking azacitidine and for 3 months after completing treatment with this medication.

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

Driving and Operating Machines

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 generally 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 upper arm.

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

Like all medications, this medication may 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 swelling, 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 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 10 people)

• 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.
• Fatigue (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.
• Sore throat and nasal congestion.
• Dizziness.
• Headache.
• Insomnia (difficulty sleeping).
• Nosebleed (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). 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 from the gums, bleeding from the 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.
• Ulcers in the mouth or tongue.
• 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).
• Throat and nasal congestion, or sore throat.
• Chest or sinus congestion.
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Sore throat and laryngeal pain.
• Indigestion.
• Drowsiness (somnolence).
• Discomfort.
• Anxiety.
• Confusion.
• 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 of the mouth).
• Fainting.
• Low 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 may 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 100 people)

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, painful, and 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 1,000 people)

• Dry cough.
• Swelling without pain of the fingertips (fingers like 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 renal function and heart rhythm, seizures, and sometimes death.

Unknown frequency(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 may cause fever, cough, difficulty breathing, skin rash, decreased urine output, low blood pressure (hypotension), swelling of the arms or legs, and rapid weight gain.
• Deep skin blood vessel inflammation that may cause skin rash (cutaneous vasculitis).

Reporting 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 medication.

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. The expiration date is the last day of the month indicated.

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

Unopened vials of this medication – store below30°C.

If used immediately

The suspension must be administered within 45 minutes of its preparation.

If used later

If the azacitidina 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 stored in the refrigerator for a maximum of 8 hours.

If the azacitidina 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 stored in the refrigerator for a maximum of 22 hours.

Allow up to 30 minutes to permit the suspension to reach an ambient temperature of 20°C to 25°C before administration.

The suspension must be discarded if it contains large particles.

Composition of Azacitidine Zentiva ks

• The active ingredient is azacitidine. A vial contains 100 mg of azacitidine. After reconstitution with 4 ml of water for injection, the reconstituted suspension contains 25 mg/ml of azacitidine..
• The other component is mannitol (E-421).

Aspect of the product and content of the package

Azacitidine Zentiva ksis a white powder for injectable suspension and is delivered in a glass vial containing 100 mg of azacitidine.

Azacitidine Zentiva ksis available in a transparent type I glass vial with rubber stoppers and aluminum flip-off caps.The product may be supplied with or without a vial protector (with lower and upper components and the holes are aligned).

Each package contains a vial ofAzacitidine Zentiva ks.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

Zentiva k.s.,

U kabelovny 130,

Dolní Mecholupy,

102 37 Prague 10

Republic of Czech

Responsible for manufacturing

MIAS Pharma Limited

Suite 2, Stafford House, Strand Road

Portmarnock, Co. Dublin

Ireland

Tillomed Malta Limited,

Malta Life Sciences Park,

LS2.01.06 Industrial Estate,

San Gwann, SGN 3000, Malta

You can request more information about this medication 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 medication is authorized in the member states of the European Economic Area and in the United Kingdom (Northern Ireland) with the following names:

Last review date of this leaflet: June 2023

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

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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 azacitidine suspensions. The procedures for correct handling and disposal of cancer medications 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 medication 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 medication may 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 medication.

1. The following elements should be mounted:

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

1. 4 ml of water for injection should be withdrawn from the syringe, ensuring that the air trapped inside the syringe is purged.
2. The needle of the syringe containing the 4 ml of water for injection should be inserted through the rubber stopper of the azacitidine vial; then, the water for injection should 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 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a turbid and homogeneous suspension, without aggregates.The suspension should be discarded if it contains large particles or aggregates.The suspension should not be filtered after reconstitution, as this may eliminate the active ingredient.It should be noted that some adapters, perfusion needles, and closed systems contain filters; therefore, these systems should not be used for the administration of 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 liquid level. Next, the plunger should be pulled back to withdraw the amount of medication needed for the correct dose, ensuring that the air trapped inside the syringe is purged. Then, the syringe with the needle should be withdrawn from the vial and the needle should be discarded.
5. Next, a new subcutaneous needle (a gauge 25 needle is recommended) should be securely 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 needed, all the above steps should be repeated for the preparation of the suspension. In the case of doses that require 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 all the 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 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 medication

For immediate use

The azacitidine suspension can be prepared immediately before use and the reconstituted suspension should be administered within 45 minutes. If the time elapsed is greater than 45 minutes, 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 8 hours. If the time elapsed in the refrigerator is greater than 8 hours, 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 22 hours. If the time elapsed in the refrigerator is greater than 22 hours, 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 30 minutes before administration. If the time elapsed is greater than 30 minutes, the suspension should be discarded correctly and a new dose should be prepared.

Calculation of an individual dose

The total dose, based on body surface area (SC), can be calculated as follows:

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

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

Administration form

The suspension should not be filtered after reconstitution.

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

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

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

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