AZACITIDINE ZENTIVA KS 25 mg/mL POWDER FOR INJECTABLE SUSPENSION

Introduction

Package Leaflet: Information for the User

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

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, 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 package leaflet

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

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

This medicine is an anti-cancer agent that belongs to a group of medicines called “anti-metabolites”. This medicine contains the active substance “azacitidine”.

What Azacitidine Zentiva ks is used for

Azacitidine 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 Azacitidine Zentiva ks works

Azacitidine Zentiva ks works by stopping 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 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 they kill cancer cells in leukemia.

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

2. What you need to know before you use Azacitidine Zentiva ks

Do not use Azacitidine Zentiva ks

• 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 breast-feeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with azacitidine:

• 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.

Blood tests

Before starting treatment with azacitidine 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

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

Other medicines and Azacitidine Zentiva ks

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

Pregnancy, breast-feeding, and fertility

Pregnancy

Do not use azacitidine 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 and for 6 months after finishing treatment with azacitidine.

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

Azacitidine 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 azacitidine. Men must use an effective contraceptive method while taking azacitidine and for 3 months after finishing treatment with this medicine.

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 Azacitidine Zentiva ks

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 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 upper arm.

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 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.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 reaction.
• 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.
• Sleep 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 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.
• Gum bleeding, stomach or intestinal bleeding, bleeding in the lower back due to hemorrhoidal bleeding, eye bleeding, or bleeding under the skin or within the skin (hematoma).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site, including swelling, a hard lump, bruising, bleeding into the skin (hematoma), skin rash, itching, and changes in skin color.
• Skin redness.
• Skin infection (cellulitis).
• Nose and throat infection or sore throat.
• Sinusitis (infection of the nasal passages and sinuses).
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Throat and larynx pain.
• 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.
• Decrease 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 stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (shivering).
• Muscle spasms.
• Itchy skin rash (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.
• Pain-free 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 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 rapidly, 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 Spanish Medicines and Healthcare Products Agency (AEMPS) website: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidine Zentiva ks

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 after EXP. The expiry date is the last day of the month stated.

Your doctor, pharmacist, or nurse is responsible for the storage of azacitidine. They are also responsible for the correct preparation and disposal of the medicine that is not used.

Unopened vials of this medicine – store below 30°C.

If used immediately

The suspension must be administered within 45 minutes of preparation.

If used later

If the azacitidine suspension is prepared using non-refrigerated water for injections, 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 suspension is prepared using refrigerated water for injections (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.

Allow up to 30 minutes for the suspension to reach room temperature (20°C to 25°C) before administration.

The suspension must be discarded if it contains large particles.

6. Contents of the pack and other information

Composition of Azacitidine Zentiva ks

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

Appearance and pack contents

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

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

Each pack contains one vial of Azacitidine Zentiva ks.

Marketing authorization holder and manufacturer

Marketing authorization holder

Zentiva k.s.,

U kabelovny 130,

Dolní Mecholupy,

102 37 Prague 10

Czech Republic

Manufacturer

Pharmadox Healthcare Limited

KW20A Kordin Industrial Park,

Paola PLA 3000, Malta

Tillomed Malta Limited,

Malta Life Sciences Park,

LS2.01.06 Industrial Estate,

San Gwann, SGN 3000, Malta

For further information about this medicine, please contact 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 leaflet: June 2023

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency for Medicines and Healthcare Products (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, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Procedures for the handling and disposal of cancer drugs 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

Azacitidineshould be reconstituted with water for injectable preparations. The validity period of the reconstituted drug 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 drug.

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 is 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. Do not filter the suspension 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 drug administration after reconstitution.
4. The rubber stopper should be cleaned, and a new syringe with a needle is 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 required amount of medication for the correct dose, ensuring that any trapped air is purged from the syringe. Then, the syringe with the needle should be removed from the vial, and the needle should be discarded.
5. A new subcutaneous needle (25-gauge recommended) for injectables should 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 needed, all the previous 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 of 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, 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 drug

For immediate use

The azacitidine suspension can be prepared immediately before use, and the reconstituted suspension should be administered within the next 45 minutes. If the time elapsed is more than 45 minutes, the reconstituted suspension should be discarded properly, 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 elapsed in the refrigerator is more than 8 hours, the suspension should be discarded properly, 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 elapsed in the refrigerator is more than 22 hours, the suspension should be discarded properly, 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 the time elapsed is more than 30 minutes, the suspension should be discarded properly, and a new dose should be 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 to calculate individual doses of azacitidine, based on an average BSA value of 1.8 m2.

Method of administration

Do not filter the suspension after reconstitution.

Azacitidinereconstituted 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 ecchymosis, redness, or hardening.

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