Azacitidine Zentiva

Leaflet accompanying the packaging: information for the user

Azacitidine Zentiva, 25 mg/ml, powder for suspension for injection

Azacitidine

You should carefully read the contents of the leaflet before using the medicine, as it contains

important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, you should ask your doctor, pharmacist, or nurse.
• If the patient experiences any side effects, including those not listed in this leaflet, they should inform their doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Azacitidine Zentiva and what is it used for
• 2. Important information before using Azacitidine Zentiva
• 3. How to use Azacitidine Zentiva
• 4. Possible side effects
• 5. How to store Azacitidine Zentiva
• 6. Contents of the packaging and other information

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

What is Azacitidine Zentiva

Azacitidine Zentiva is an anti-cancer medicine that belongs to a group of medicines called "antimetabolites". Azacitidine Zentiva contains the active substance azacitidine.

What is Azacitidine Zentiva used for

Azacitidine Zentiva is used in adult patients who cannot receive a stem cell transplant, for the treatment of:

• high-risk myelodysplastic syndromes (MDS);
• chronic myelomonocytic leukemia (CMML);
• acute myeloid leukemia (AML).

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

How Azacitidine Zentiva works

Azacitidine Zentiva works by preventing the growth of cancer cells. Azacitidine is incorporated into the genetic material of cells (RNA and DNA). It is thought to work by changing the way genes are activated and deactivated, and by disrupting the production of RNA and DNA. It is believed that these actions correct the disturbances in the maturation and growth of young blood cells in the bone marrow, causing myelodysplastic syndromes, and that they kill cancer cells in leukemia. If you have any questions about how Azacitidine Zentiva works or why it has been prescribed, you should ask your doctor or nurse.

2. Important information before using Azacitidine Zentiva

When not to use Azacitidine Zentiva

Warnings and precautions

Before starting treatment with Azacitidine Zentiva, you should discuss it with your doctor, pharmacist, or nurse if you:

• have a low platelet count, red blood cell count, or white blood cell count;
• have kidney disease;
• have liver disease;
• have a history of heart disease or heart attack, or any lung disease.

Azacitidine Zentiva may cause a severe immune reaction called "differentiation syndrome" (see section 4). Blood tests will be performed before starting treatment with Azacitidine Zentiva and at the beginning of each treatment period (called a cycle). This is to check that you have a sufficient number of blood cells and that your liver and kidneys are working properly.

Children and adolescents

Azacitidine Zentiva should not be used in children and adolescents under 18 years of age.

Azacitidine Zentiva and other medicines

You should tell your doctor or pharmacist about all medicines you are taking, or have recently taken, and about any medicines you plan to take. Azacitidine may affect the way some other medicines work, and some other medicines may affect the way azacitidine works.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child, you should ask your doctor or pharmacist for advice before using this medicine. Pregnancy You should not use Azacitidine Zentiva during pregnancy, as it may harm the baby. Women who can become pregnant should use effective contraception during treatment with Azacitidine Zentiva and for 6 months after stopping treatment with this medicine. If you become pregnant during treatment, you should inform your doctor immediately. Breastfeeding You should not breastfeed while using Azacitidine Zentiva. It is not known whether this medicine passes into breast milk. Fertility Men should not father a child during treatment with Azacitidine Zentiva. Men should use effective contraception during treatment with Azacitidine Zentiva and for 3 months after stopping treatment with Azacitidine Zentiva. You should ask your doctor for advice before starting treatment if you want to store sperm.

Driving and using machines

If you experience side effects such as fatigue, you should not drive or operate machinery.

3. How to use Azacitidine Zentiva

Before administering Azacitidine Zentiva to the patient, the doctor will give another medicine to prevent nausea and vomiting at the start of each treatment cycle.

• The recommended dose is 75 mg per square meter of body surface area. The doctor will decide on the dose of the medicine based on the patient's overall condition, height, and weight. The doctor will monitor progress and may change the dose if necessary.
• Azacitidine Zentiva is given daily for one week, followed by a break of three weeks. This treatment cycle is repeated every 4 weeks. Patients usually receive at least 6 cycles of treatment.

This medicine is given by a doctor or nurse as an injection under the skin. It can be injected under the skin of the thigh, abdomen, or arm. If you have any further questions about using this medicine, you should ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Azacitidine Zentiva can cause side effects, although not everybody gets them.

You should immediately inform your doctor if you experience any of the following side effects:

• Drowsiness, trembling, jaundice, abdominal swelling, and easy bruising.These may be symptoms of liver failure and can be life-threatening.
• Swelling of the feet and ankles, back pain, decreased urine output, increased thirst, rapid heartbeat, dizziness, and nausea, vomiting, or loss of appetite, as well as feelings of disorientation, anxiety, or fatigue.These may be symptoms of kidney failure and can be life-threatening.
• Fever.This may be due to an infection caused by a low white blood cell count, which can be life-threatening.
• Chest pain or shortness of breath, which may be accompanied by fever.This may be due to a lung infection called "pneumonia" and can be life-threatening.
• Bleeding.Such as blood in the stool due to bleeding in the stomach or intestine, or bleeding in the head. These may be symptoms of a low platelet count.
• Difficulty breathing, swelling of the lips, itching, or rash.This 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. This may be accompanied by fever. You are also more susceptible to infections.
• Low platelet count (thrombocytopenia). You are more susceptible to bleeding and bruising.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue.
• Reaction at the injection site, including redness, pain, or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Purple or red spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Sleep disturbances (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness.
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding in the brain.
• Blood infection caused by bacteria (sepsis). This may be due to a low white blood cell count in the blood.
• Bone marrow failure. This may lead to a low number of red and white blood cells and platelets.
• A type of anemia where the number of red and white blood cells and platelets is decreased.
• Urinary tract infection.
• Viral infection causing cold sores.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anus due to hemorrhoids (hemorrhoidal bleeding), eye bleeding, bleeding under the skin or in the skin (hematomas).
• Blood in the urine.
• Ulcers in the mouth or tongue.
• Skin changes at the injection site. These include: swelling, hard lumps, bruising, bleeding in the skin (hematomas), rash, itching, and skin color changes.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection or sore throat.
• Nose or sinus pain, or sinusitis (sinus infection).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath when moving.
• Throat and larynx pain.
• Nausea.
• Apathy
• General feeling of being unwell.
• Anxiety.
• Disorientation.
• Excessive hair loss.
• Kidney failure.
• Dehydration.
• White patches on the tongue, inside the cheeks, and sometimes on the palate, gums, and tonsils (oral thrush).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension), leading to dizziness when changing position to standing or sitting.
• Drowsiness, lethargy.
• Bleeding at the injection site.
• A disease of the intestines that can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• A raised, itchy rash on the skin (hives).
• Fluid around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, raised, painful spots of a plum color on the skin, with fever.
• Inflammation of the sac surrounding the heart (pericarditis).

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

• Dry cough
• Painful swelling of the fingertips (digital clubbing).
• Tumor lysis syndrome - a complication of metabolism that can occur during cancer treatment, as well as sometimes without treatment. These complications are caused by the breakdown of dying cancer cells and can include: changes in blood chemistry; high levels of potassium, phosphorus, uric acid, and low levels of calcium, leading to kidney problems, heart rhythm problems, seizures, and sometimes death.

Frequency not known(cannot be estimated from the available data):

• A skin infection that spreads quickly, causing skin and tissue damage, which can be life-threatening (necrotizing fasciitis).
• A severe immune reaction (differentiation syndrome), which can cause fever, cough, difficulty breathing, rash, decreased urine output, low blood pressure (hypotension), swelling of the hands or feet, and sudden weight gain.
• Inflammation of the blood vessels in the skin, which can cause a rash (cutaneous vasculitis).

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, you should inform your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products Al. Jerozolimskie 181C 02-222 Warsaw Tel.: +48 22 49 21 301 Fax: +48 22 49 21 309 Website: https://smz.ezdrowie.gov.pl Side effects can also be reported to the marketing authorization holder or its representative. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidine Zentiva

Medicines should be kept out of the sight and reach of children. Do not use this medicine after the expiry date stated on the carton or label on the vial after EXP. The expiry date refers to the last day of the month. The doctor, pharmacist, or nurse is responsible for storing Azacitidine Zentiva. They are also responsible for preparing Azacitidine Zentiva and disposing of any unused remains properly. Unopened vials of this medicine - no special storage instructions. For immediate useAfter preparation, the suspension should be administered within 60 minutes. For later useIf the suspension of Azacitidine Zentiva was prepared using unrefrigerated water for injections, the prepared suspension should be placed in the refrigerator (2°C - 8°C) immediately after preparation and stored in the refrigerator for no longer than 8 hours. If the suspension of Azacitidine Zentiva was prepared using refrigerated (2°C - 8°C) water for injections, the prepared suspension should be placed in the refrigerator (2°C - 8°C) immediately after preparation and stored in the refrigerator for no longer than 22 hours. Before administration, the suspension should be allowed to reach room temperature (20°C - 25°C) for a maximum of 30 minutes. Do not use the medicine if the suspension contains large particles. Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging and other information

What Azacitidine Zentiva contains

The active substance is azacitidine. 1 vial contains 100 mg of azacitidine. After preparation with 4 ml of water for injections, the suspension contains 25 mg/ml of azacitidine. The other ingredient is mannitol (E 421).

What Azacitidine Zentiva looks like and contents of the pack

Azacitidine Zentiva is a white powder for suspension for injection and is provided in a vial made of colorless glass type I closed with a dark grey rubber stopper with one hole and an aluminum flip-off cap, containing 100 mg of azacitidine. Each pack of Azacitidine Zentiva contains 1 vial.

Marketing authorization holder

Zentiva k.s. U kabelovny 130 Dolni Měcholupy 102 37 Prague 10 Czech Republic

Importer

APIS Labor GmbH Resslstraße 9 9065 Ebenthal Austria LABORATORI FUNDACIÓ DAU C/ De la letra C 12-14, Polígono Industrial de la Zona Franca 08040 Barcelona Spain

This medicine is authorized in the Member States of the European Economic Area under the following names:

Netherlands, Poland, Czech Republic, Slovakia: Azacitidine Zentiva Portugal: Azacitidina Zentiva

For further information about this medicine, you should contact the representative of the marketing authorization holder in Poland:

Zentiva Polska Sp. z o.o. ul. Bonifraterska 17 00-203 Warsaw tel: +48 22 375 92 00 Date of last revision of the leaflet:December 2023

Information intended for healthcare professionals only:

Recommendations for safe handling Azacitidine is a cytotoxic medicinal product, and as with other potentially toxic compounds, caution should be exercised when handling the azacitidine suspension. You should follow the procedures for the proper handling of anti-cancer medicinal products and their disposal. If the prepared Azacitidine Zentiva comes into contact with the skin, it should be washed immediately with soap and water. If it comes into contact with the mucous membranes, they should be rinsed with water. Incompatibilities This medicinal product should not be mixed with other medicinal products, except for those mentioned below (see "Preparation procedure"). Preparation procedure Azacitidine Zentiva should be prepared using water for injections. The shelf-life of the prepared medicinal product can be extended by preparing the product with refrigerated (2°C-8°C) water for injections. Details on the storage of the prepared product are given above.

• 1. You should gather the following equipment: Vial(s) of Azacitidine Zentiva; vial(s) of water for injections; non-sterile surgical gloves; alcohol swabs; 5 ml syringe(s) for injection with needle(s)
• 2. 4 ml of water for injections should be drawn into the syringe, ensuring that the syringe does not contain air bubbles.
• 3. The needle of the syringe containing 4 ml of water for injections should be inserted through the rubber stopper of the vial of Azacitidine Zentiva, and the water for injections should be injected into the vial.
• 4. After removing the syringe and needle, the vial should be shaken vigorously until a uniform, cloudy suspension is obtained. After preparation, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml). The prepared product is a uniform, cloudy suspension without agglomerates. You should discard the product if it contains large particles or agglomerates. Do not filter the suspension after preparation, as this may remove the active substance. Note that some adapters, needles, and closed systems contain filters. Therefore, such components should not be used to administer the prepared medicinal product.
• 5. The rubber stopper should be cleaned and a new syringe with a needle inserted into the vial. Then, the vial should be turned upside down, ensuring that the needle tip is below the level of the liquid. The plunger should be pulled back to draw the required amount of medicinal product for the correct dose. Ensure that the air has been removed from the syringe. Then, the needle should be withdrawn from the vial and discarded.
• 6. A new injection needle (25G is recommended) should be firmly attached to the syringe. The needle should not be flushed before injection to reduce the frequency of local reactions at the injection site.
• 7. If more than 1 vial is needed, all the above steps should be repeated. For doses requiring more than 1 vial, the dose should be evenly divided, e.g., 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.

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.

• 8. The contents of the syringe with the dose must be resuspended immediately before administration. For up to 30 minutes before administration, the syringe filled with the prepared suspension should be allowed to reach a temperature of approximately 20°C–25°C. If more than 30 minutes have passed, the suspension should be discarded and a new dose prepared. To resuspend, the syringe should be vigorously shaken between the hands until a uniform, cloudy suspension is obtained. You should discard the suspension if it contains large particles or agglomerates.

Storage of the prepared product For immediate useAzacitidine Zentiva can be prepared immediately before administration and administered within 60 minutes. If more than 60 minutes have passed, the prepared suspension should be discarded and a new dose prepared. For later useIf the product was prepared using unrefrigerated water for injections, the prepared suspension should be placed in the refrigerator (2°C - 8°C) immediately after preparation and stored in the refrigerator for no longer than 8 hours. If more than 8 hours have passed, the suspension should be discarded and a new dose prepared. If the product was prepared using refrigerated (2°C - 8°C) water for injections, the prepared suspension should be placed in the refrigerator (2°C - 8°C) immediately after preparation and stored in the refrigerator for no longer than 22 hours. If more than 22 hours have passed, the suspension should be discarded and a new dose prepared. Before administration, the syringe filled with the prepared suspension should be allowed to reach a temperature of approximately 20°C–25°C for up to 30 minutes. If more than 30 minutes have passed, the suspension should be discarded and a new dose prepared. Calculation of the individual dose The total dose can be calculated based on the body surface area (BSA) as follows: Total dose (mg) = dose (mg/m2) x BSA (m2) The following table is an example of how to calculate the individual dose of azacitidine based on a body surface area of 1.8 m2. Dose mg/m2 BSA (% of recommended starting dose) Required total volume of prepared suspension 75 mg/m2 BSA (100%) 135 mg 2 vials 5.4 ml 37.5 mg/m2 BSA (50%) 67.5 mg 1 vial 2.7 ml 25 mg/m2 BSA (33%) 45 mg 1 vial 1.8 ml Administration method Do not filter the suspension after reconstitution. The prepared Azacitidine Zentiva should be administered subcutaneously (the needle should be inserted at an angle of 45-90°) using a 25G needle in the arm, thigh, or abdomen. Doses greater than 4 ml should be administered in two different sites. Total dose based on BSA 1.8 m2 Number of vials required You should change the injection site. New injections should be administered at a distance of at least 2.5 cm from the previous injection site and never in sensitive, bruised, red, or hard areas. Unused medicinal product and its remains should be disposed of in accordance with local regulations.