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

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Azacitidina 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 questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

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

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

What Azacitida 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 leukaemia (CMML).
• Acute myeloid leukaemia (AML).

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

How Azacitidina Zentiva ks works

Azacitidina Zentiva ks 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, by interfering with the production of new RNA and DNA.

These actions are thought to correct the problems in maturation and growth of healthy blood cells in the bone marrow caused by myelodysplastic disorders, and to kill cancer cells in leukaemia.

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

2. What you need to know before starting to use Azacitidina Zentiva ks

Do not use Azacitidina Zentiva ks

• 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

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

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

Blood tests

Before starting treatment with azacitidine and at the beginning of each treatment cycle, you will have blood tests. These are performed to ensure that you have adequate blood cell counts and that your liver and kidneys are functioning properly.

Children and adolescents

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

Other medicines and Azacitidina Zentiva ks

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines. This is because azacitidine may affect how other medicines work. Likewise, other medicines may affect how azacitidine works.

Pregnancy, breastfeeding, and fertility

Pregnancy

You must not use azacitidine 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 azacitidine and for 6 months after stopping treatment with azacitidine.

Inform your doctor immediately if you become pregnant during treatment.

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

Breastfeeding

Azacitidine 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 azacitidine. Men should use an effective method of contraception while taking azacitidine 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 use of machines

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

3. How to use Azacitidina Zentiva ks

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 upper arm.

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 can cause adverse effects, although not everyone will experience them.

Immediately report to 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 and nausea, vomiting or loss of appetite, and feeling confused, restless, or fatigued. These may be symptoms of kidney failure and can be potentially fatal.
• Fever. This could be due to an infection resulting from low white blood cell counts, which can be potentially fatal.
• Chest pain or difficulty breathing, possibly accompanied by fever. This 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 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 more likely to develop 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, 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.
• Trouble sleeping (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low blood potassium levels.

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

• Bleeding inside the head.
• Blood infection caused by bacteria (sepsis). This may be due to 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 from the lower back due to hemorrhoidal bleeding, eye bleeding, 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), skin rash, itching, and skin color changes.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection, or sore throat.
• Pain or excessive discharge from the nose or sinuses (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 up or sitting down.
• Sleepiness, drowsiness (somnolence).
• Bleeding from 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, raised plum-colored 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 (digital clubbing).
• Tumor lysis syndrome – metabolic complications may occur during cancer treatment and sometimes even without treatment. These complications arise from the products of dying tumor cells and may include: changes in blood chemistry, 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 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 arms or legs, and rapid weight gain.
• Inflammation of blood vessels in the skin, which may cause 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 Medicines: 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 ks

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 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. They are also responsible for the correct preparation and disposal of any unused medicine.

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

If used immediately

The suspension should be administered within 45 minutes of preparation.

If used subsequently

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 stored 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 stored 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 container and additional 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 component is mannitol (E-421).

Appearance of the medicinal product and contents of the container

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

Azacitidina Zentiva ks is available in a clear type I glass vial with a flanged rubber stopper and an aluminum flip-off seal. The product may be supplied with or without a vial protector (with upper and lower components and aligned openings).

Each pack contains one vial of Azacitidina Zentiva ks.

Marketing Authorization Holder and Manufacturing Responsible Person

Marketing Authorization Holder

Zentiva k.s.,

U kabelovny 130,

Dolní Mecholupy,

102 37 Prague 10

Czech Republic

Responsible for Manufacturing

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 regarding this medicinal product, please contact the local representative of the Marketing Authorization Holder:

Zentiva Spain S.L.U.

Avenida de Europa, 19, Building 3, 1st Floor

28224 Pozuelo de Alarcón, Madrid

Spain

This medicinal product is authorized in the European Economic Area and the United Kingdom (Northern Ireland) under the following names:

Date of last review of this leaflet: June 2023

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

This information is 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 and preparing azacitidine suspensions. Appropriate procedures for the handling and disposal of anticancer drugs should be followed.

If reconstituted azacitidine comes into contact with the skin, the affected area should be washed immediately and thoroughly with water and soap. In case of contact with mucous membranes, rinse thoroughly with water.

Incompatibilities

This medicinal product 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 medicinal product can be extended by reconstituting it with refrigerated water for injections (between 2°C and 8°C). Information on the storage of the reconstituted medicinal product is provided below.

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.

2. Withdraw 4 ml of water for injections into the syringe, ensuring that any trapped air is purged from the syringe.
3. 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.
4. After removing the syringe and needle, the vial should be shaken vigorously until a uniform cloudy suspension is obtained. After reconstitution, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a cloudy, homogeneous suspension without agglomerates. The suspension should be discarded if large particles or agglomerates are present. Do not filter the suspension after reconstitution, as this may remove the active substance. Note that some adapters, infusion needles, and closed systems contain filters; therefore, such systems must not be used for administration of the medicinal product after reconstitution.
5. 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 medicinal product for the correct dose, ensuring that any trapped air in the syringe is purged. Then remove the syringe with the needle from the vial and discard the needle.
6. A new subcutaneous injection needle (25 gauge is recommended) should then 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.
7. When more than one vial is required, all the above steps should be repeated for the preparation of the suspension. For doses requiring more than one vial, the dose should be divided into equal parts; for example, a 150 mg dose = 6 ml; two syringes with 3 ml in each. Due to retention in the vial and needle, it may not be possible to withdraw all the suspension from the vial.
8. 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, roll the syringe vigorously between the palms of the hands until a uniform cloudy suspension is obtained. The suspension should be discarded if large particles or agglomerates are present.

Storage of the reconstituted medicinal product

For immediate use

The azacitidine suspension may be prepared immediately before use, and the reconstituted suspension should be administered within 45 minutes. If more than 45 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 (2°C to 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 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 injected subcutaneously (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 must be administered at least 2.5 cm away from the previous site and never into sensitive, bruised, red, or hardened areas.

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