Azacitidine Zentiva 25 mg/ml powder for injectable suspension EFG

Patient Information Leaflet

Introduction

Patient Information Leaflet

Azacitidine Zentiva 25 mg/ml powder for injectable suspension EFG

Read the entire leaflet carefully before you start using this medicine, as it contains important information for you.

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

Package leaflet

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

2. What you need to know before using Azacitidina Zentiva

3. How to use Azacitidina Zentiva

4. Possible side effects

5. Storage of Azacitidina Zentiva

6. Contents of the pack and other information

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

Azacitidine Zentiva contains the active substance azacitidine, which belongs to a group of medicines called antineoplastics. It is used to treat certain types of cancer. Specifically, it is indicated for the treatment of adult patients with:

• Myelodysplastic syndromes (MDS), including patients with refractory anemia with excess blasts (RAEB), refractory anemia with ringed sideroblasts (RARS) if accompanied by neutropenia and/or thrombocytopenia, and refractory cytopenia with multilineage dysplasia (RCMD);
• Chronic myelomonocytic leukemia (CMML);
• Acute myeloid leukemia (AML) with 20–30% blasts and multi-lineage dysplasia.

Azacitidine Zentiva works by interfering with the growth of cancer cells, ultimately leading to their destruction. It may also help normalize blood cell production in the bone marrow.

What is Azacitidina Zentiva

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

What Azacitidine Zentiva is used for

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

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

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

How Azacitidine Zentiva works

Azacitidine works by inhibiting 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 switch genes on or off, through interference with the production of new RNA and DNA. These actions are thought to correct the defects in maturation and growth of healthy blood cells in the bone marrow caused by myelodysplastic disorders, and to kill cancer cells in leukemia.

Consult 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 using Azacitidina Zentiva

Do not use Azacitidina Zentiva

• If you are allergic to azacitidine or to 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 starting to use this medicine:

• If you have low platelet counts, red blood cells, or white blood cells.
• If you have kidney disease.
• If you have liver disease.
• If you have ever had heart disease, myocardial infarction, or have a history of lung disease.
• Azacitidine may cause a serious 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 a “cycle”), you will have blood tests. These are performed to ensure that you have an adequate number of blood cells and that your liver and kidneys are functioning properly.

Children and adolescents

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

Other medicines and Azacitidina Zentiva

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

This is because Azacitidina Zentiva may affect how other medicines work. Likewise, other medicines may affect how Azacitidina Zentiva works.

Pregnancy, breastfeeding, and fertility

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

Pregnancy

You must not use this medicine during pregnancy because it may harm the unborn baby.

If you are a woman of childbearing potential, you must use an effective method of contraception while taking Azacitidina Zentiva and for 6 months after stopping treatment with this medicine.

Inform your doctor immediately if you become pregnant during treatment.

Breastfeeding

This medicine must not be used during breastfeeding. It is unknown whether this medicine is excreted in human milk.

Fertility

Men must not father a child while receiving treatment with Azacitidina Zentiva. Men must use an effective method of contraception while taking Azacitidina Zentiva and for 3 months after stopping treatment with this medicine.

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

Driving and using machines

Do not drive or operate tools or machinery if you experience side effects such as fatigue.

3. How to use Azacitidina Zentiva

Before administering azacitidine, 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 determine your dose of this medicine based on your general condition, height, and weight. Your doctor will monitor your progress and, if necessary, may adjust your dose.
• Azacitidine is administered daily for one week, followed by a rest period of three weeks. 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 an injection under the skin (subcutaneous route). 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 adverse effects

Like all medicines, this medicine may cause adverse effects, although not everyone experiences them.

Immediately inform your doctor if you experience any of the following adverse effects:

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

Other adverse effects include:

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

• Decreased red blood cell count (anemia). You may feel tired and look pale.
• Decreased white blood cell count. This may be accompanied by fever. You are also at higher risk of 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).
• Injection site reaction, 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.
• Nasal and throat pain.
• Dizziness.
• Headache.
• Trouble sleeping (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding inside the head.
• Blood infection caused by bacteria (sepsis). This may result from low white blood cell counts.
• Bone marrow failure. This may cause low levels of red and white blood cells and platelets.
• A type of anemia characterized by reduced red and white blood cells and platelets.
• Urinary tract infection.
• A viral infection causing herpes-like lesions.
• Bleeding from gums, stomach or intestinal bleeding, bleeding in the lower back due to hemorrhoidal bleeding, eye bleeding, or bleeding under or into the skin (hematoma).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site, such as swelling, hard lump, bruising, bleeding into the skin (hematoma), rash, itching, or skin discoloration.
• Skin redness.
• Skin infection (cellulitis).
• Nose and throat infection, or sore throat.
• Pain or excessive nasal or sinus discharge (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing during physical activity.
• Throat and larynx pain.
• Indigestion.
• Drowsiness (lethargy).
• Feeling unwell.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating covering the tongue, inside of cheeks, and sometimes the palate, gums, and tonsils (fungal infection in the mouth).
• Fainting.
• Drop in blood pressure upon standing (orthostatic hypotension), causing dizziness when standing or sitting up.
• Sleepiness, drowsiness (somnolence).
• Bleeding due to a catheter site.
• A condition affecting the intestine that may cause fever, vomiting, and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Shivering (chills).
• Muscle spasms.
• Itchy skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

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

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

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

• Dry cough.
• Painless swelling of fingertips (drumstick fingers).
• Tumor lysis syndrome – metabolic complications may occur during cancer treatment and sometimes even without treatment. These complications arise from the breakdown products of dying tumor cells and may include: changes in blood biochemistry, high levels of potassium, phosphate, and uric acid, and low calcium levels, leading to changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known (cannot be estimated from available data)

• Deep skin layer infection that spreads rapidly, damaging skin and tissue, which may 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 arms or legs, and rapid weight gain.
• Inflammation of blood vessels in the skin, which may cause a skin rash (cutaneous vasculitis).

Reporting of adverse reactions

If you experience any type of adverse reaction, consult your doctor, pharmacist, or nurse, even if it is a possible adverse reaction not listed in this leaflet. You may also report them directly through the Spanish Pharmacovigilance System for Human Medicinal Products: https://www.notificaRAM.es. By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidine Zentiva

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

Do not use this medicine after the expiry date stated on the vial label and the carton after CAD/EXP. The expiry date refers to the last day of the month indicated.

Your doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Zentiva. They are also responsible for the correct preparation and disposal of any 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 injections, the suspension must be placed immediately in the refrigerator (between 2 °C and 8 °C) after preparation and may be stored in the refrigerator for up to 8 hours.

If the Azacitidine Zentiva suspension is prepared using refrigerated water for injections (between 2 °C and 8 °C), the suspension must be placed immediately in the refrigerator (between 2 °C and 8 °C) after preparation and may be stored in the refrigerator for up to 22 hours.

The suspension should be allowed to reach room temperature (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 disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers that you no longer need. This will help protect the environment.

6. Contents of the pack and other 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 injections, the reconstituted suspension contains 25 mg/ml of azacitidine.
• The other component is mannitol (E421).

Nature of the product and pack contents

Azacitidine Zentiva is a white powder for injectable suspension and is supplied in a clear type I glass vial sealed with a grey chlorobutyl rubber stopper with a single groove, coated with FluroTec, or a single-groove lyo rubber stopper coated with grey bromobutyl omniflex, and an aluminum flip-off seal 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 responsible for production

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 on this medicinal product is available upon request 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:

Date of the most recent review of this leaflet: January 2024

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/.

This information is intended for healthcare professionals only:

Recommendations for safe handling

Azacitidine is a cytotoxic medicine and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Appropriate procedures for handling and disposal of anticancer drugs should be followed.

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

Incompatibilities

This medicine must not be mixed with other medicinal products except those mentioned below (see "Reconstitution procedure").

Reconstitution procedure

Azacitidine must be reconstituted with water for injections. The shelf life of the reconstituted product can be extended by reconstituting it with refrigerated water for injections (between 2 °C and 8 °C). Below is information on storage of the reconstituted medicine.

1. Assemble the following items:

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

1. Draw up 4 ml of water for injections into the syringe, ensuring that any trapped air is purged from the syringe.
2. Insert the needle of the syringe containing 4 ml of water for injections through the rubber stopper of the azacitidine vial; then inject the water for injections into the vial.
3. After removing the syringe and needle, the vial should be shaken vigorously until a uniformly turbid suspension is obtained. After reconstitution, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a homogeneous, turbid suspension without clumps. The suspension should be discarded if large particles or clumps are present. Do not filter the suspension after reconstitution, as this may remove the active ingredient. Note that some adapters, infusion needles, and closed systems contain filters; therefore, such systems must not be used for administering the medicine after reconstitution.
4. Clean the rubber stopper and insert a new syringe with a needle into the vial. Invert the vial, ensuring that the tip of the needle is below the liquid level. Then pull back the plunger to withdraw the required amount of medicine for the correct dose, ensuring that any trapped air in the syringe is purged. Then remove the syringe with needle from the vial and discard the needle.
5. Firmly attach a new subcutaneous injection needle (25 gauge is recommended) to the syringe. The needle should not be purged before injection to reduce the incidence of local reactions at the injection site.
6. When more than 1 vial is required, repeat all the above steps for suspension preparation. For doses requiring more than 1 vial, the dose should be divided into equal parts; for example, a 150 mg dose = 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 all the suspension from the vial.
7. The contents of the dosing syringe must 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, roll the syringe vigorously between the palms of the hands until a uniformly turbid suspension is obtained. The suspension should be discarded if large particles or clumps are present.

Storage of the reconstituted medicine

For immediate use

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

For later use

When reconstituted with unrefrigerated water for injections, the reconstituted suspension must be placed in a refrigerator (between 2 °C and 8 °C) immediately after reconstitution and stored in the refrigerator for a maximum of 8 hours. If the time in the refrigerator exceeds 8 hours, the suspension must be properly discarded and a new dose prepared.

When reconstituted with refrigerated water for injections (between 2 °C and 8 °C), the reconstituted suspension must 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 in the refrigerator exceeds 22 hours, the suspension must be properly discarded and a new dose prepared.

The loaded syringe containing 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 elapsed, the suspension must be properly discarded and a new dose 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 provided only as an example for calculating individual azacitidine doses, based on an average BSA of 1.8 m².

Route of administration

Do not filter the suspension after reconstitution.

Reconstituted azacitidine must be administered by subcutaneous injection (insert the needle at an angle of 45 to 90°) using a 25-gauge needle into the arm, thigh, or abdomen.

Doses exceeding 4 ml must be administered at two separate injection sites.

Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous injection site and never into sensitive, bruised, red, or hardened areas.

Any unused medicinal product and materials that have come into contact with it must be disposed of in accordance with local requirements.