Azacitidine TilloMed

PACKAGE LEAFLET

Package leaflet: Information for the user

Azacitidine Tillomed 25 mg/mL powder for injectable suspension

Generic medicine
Please read this entire leaflet carefully before using this medicine, as 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 experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

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

Azacitidina Tillomed is an anticancer agent belonging to a group of medicines called
"antimetabolites". Azacitidina Tillomed contains the active substance "azacitidine".
What Azacitidina Tillomed is used for
Azacitidina Tillomed is used in adults who are not eligible for stem cell transplantation for the treatment of:

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

These diseases affect the bone marrow and can cause problems with the normal production of
blood cells.
How Azacitidina Tillomed works
Azacitidina Tillomed works by preventing cancer cells from growing. 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 and off, and also by interfering with the production of new RNA and DNA.
These actions are thought to correct the abnormalities in maturation and growth of young blood cells in the bone marrow that cause myelodysplastic disorders, and to kill cancer cells in leukaemia.
If you have any questions about how Azacitidina Tillomed works or why it has been prescribed for you, please consult your doctor or nurse.

2. What you need to know before using Azacitidine Tillomed

Do not use Azacitidine Tillomed

• 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.
• if you are breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Azacitidine Tillomed:

• if you have a reduced platelet count, red blood cells, or white blood cells;
• if you have kidney disease;
• if you have liver disease;
• if you have previously had heart disease, a heart attack, or a history of lung disease.

Blood tests
Before starting treatment with Azacitidine Tillomed and at the beginning of each treatment period
(called a "cycle"), blood tests will be performed to check whether you have an adequate number of blood cells and to assess whether your liver and kidneys are functioning normally.

Children and adolescents
The use of Azacitidine Tillomed is not recommended in children and adolescents under 18 years of age.

Other medicines and Azacitidine Tillomed
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Azacitidine Tillomed may affect how other medicines work. Conversely, other medicines may affect how Azacitidine Tillomed works.

Pregnancy, breastfeeding, and fertility

Pregnancy
You must not use Azacitidine Tillomed during pregnancy, as it may harm the unborn child.
If you are a woman of childbearing age, you must use an effective method of contraception during treatment with Azacitidine Tillomed and for 6 months after stopping treatment with Azacitidine Tillomed.
Inform your doctor immediately if you become pregnant during treatment.

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

Breastfeeding
You must not breastfeed while using Azacitidine Tillomed. It is not known whether this medicine passes into breast milk.

Fertility
During treatment with Azacitidine Tillomed, male patients must not father a child. Men should use an effective method of contraception while taking Azacitidine Tillomed and for 3 months after stopping treatment with this medicine.
Consult your doctor if you wish to preserve 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 Tillomed

Before administering Azacitidina Tillomed, 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 per m² of body surface area. Your doctor will determine the dose of this medicine based on your general condition, height, and body weight. Your doctor will monitor your progress and, if necessary, adjust the dose.
• Azacitidina Tillomed is administered daily for one week, followed by a 3-week break. This “treatment cycle” will be repeated every 4 weeks. Generally, at least 6 treatment cycles are administered.

This medicine will be administered by a doctor or nurse via subcutaneous injection (under the skin). The injection can be given under the skin of the thigh, abdomen, or upper arm.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Immediately inform your doctor if you notice any of the following side effects:

• Drowsiness, tremor, jaundice, abdominal swelling and easy bruising. These may be symptoms of liver failure and can be life-threatening.
• Swollen legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness, nausea, vomiting or reduced appetite, confusion, restlessness 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 number of white blood cells, which can be life-threatening.
• Chest pain or shortness of breath, possibly accompanied by fever. This may be due to a lung infection called "pneumonia" and can be life-threatening.
• Bleeding. For example, blood in the stools due to bleeding in the stomach or intestine, or bleeding inside the head. These may be symptoms of low platelet levels in the blood.
• Difficulty breathing, swollen lips, itching or rash. These may 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 (anaemia). You may feel tired and weak.
• Low white blood cell count. This may be accompanied by fever. Also, you may be more likely to get infections.
• Low platelet count in the blood (thrombocytopenia). You may be more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue.
• Reaction at the injection site, with redness, pain or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Small red or purple spots under the skin.
• Abdominal pain (abdominal pain).
• Itching.
• Fever.
• Irritation of the nose and throat.
• Dizziness.
• Difficulty sleeping (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 inside the head.
• Blood infection due to bacteria (sepsis), which may be caused by low white blood cell counts.
• Bone marrow failure, which may cause low levels of red blood cells, white blood cells and platelets.
• A type of anaemia with reduced red blood cells, white blood cells and platelets.
• Urinary tract infection.
• Viral infection causing sores (herpes).
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anus due to haemorrhoids (haemorrhoidal bleeding), bleeding in the eye, bleeding under or into the skin (haematoma).
• Mouth and tongue ulcers.
• Skin changes at the injection site, including swelling, hard lump, bruising, bleeding into the skin (haematoma), rash, itching and skin colour changes.
• Skin redness.
• Skin infection (cellulitis).
• Infection of the nose and throat, or sore throat.
• Irritated or runny nose or sinuses (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Throat and larynx pain.
• Indigestion.
• Lethargy.
• General feeling of being unwell.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating covering the tongue, inside of the cheeks, and sometimes the palate, gums and tonsils (fungal infection of the mouth).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension), causing dizziness when moving to a standing or sitting position.
• Drowsiness, numbness.
• Bleeding due to the catheter.
• Illness affecting the intestine that may cause fever, vomiting and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• Raised, itchy rash on the skin (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremor.
• Liver failure.
• Appearance of large, painful, raised plum-coloured skin patches with fever.
• Painful skin ulcers (pyoderma gangrenosum).
• Inflammation of the inner lining of the heart (pericarditis).

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

• Dry cough.
• Painless swelling of the fingertips (drumstick fingers).
• Tumour lysis syndrome – metabolic complications that may occur during cancer treatment and sometimes even without treatment. These complications are caused by the breakdown products of dying tumour cells and may include the following: changes in haematological parameters; high levels of potassium, phosphate and uric acid; and low calcium levels, leading consequently to changes in kidney function, heart rhythm, seizures and sometimes death.

Not known (frequency cannot be estimated from the available data)

• Infection of the deeper layers of the skin, spreading rapidly and damaging skin and tissues, which may be fatal (necrotising fasciitis).
• Severe immune reaction (differentiation syndrome) that may cause fever, cough, difficulty breathing, rash, reduced 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 rash (cutaneous vasculitis).

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse.
You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidine Tillomed

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 or on the
packaging. The expiry date refers to the last day of that month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Tillomed, its preparation, and the proper disposal of unused medicine.
For unopened vials of this medicine – store below 30°C.
For immediate use
Once prepared, the suspension must be administered within 45 minutes.
For subsequent use
If the Azacitidine Tillomed suspension is reconstituted with non-refrigerated water for injections, the suspension must be placed in a refrigerator (2 °C–8 °C) immediately after preparation and stored in the refrigerator for a maximum of 8 hours.
If the Azacitidine Tillomed suspension is reconstituted with refrigerated water for injections (2 °C–8 °C), the reconstituted suspension must be placed in a refrigerator (2 °C–8 °C) immediately after preparation and stored in the refrigerator for a maximum of 22 hours.
Before administration, allow up to 30 minutes for the suspension to reach room temperature (20 °C–25 °C).
The suspension must be discarded if large particles are present.

6. Package contents and other information

What Azacitidina Tillomed contains

• 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.

Description of the appearance of Azacitidina Tillomed and contents of the pack
Azacitidina Tillomed is a white lyophilized powder for injectable suspension, supplied in a glass vial containing 100 mg of azacitidine.
Azacitidina Tillomed is available in a clear type I glass vial with flanged rubber stoppers and aluminium flip-off seals. The filled vials are labelled and may be individually wrapped in transparent pre-formed heat-shrinkable sleeves with a plastic base at the bottom, or the vials may be placed in a vial protector (with lower and upper parts and grooves aligned), or they may be directly packaged in a cardboard box.
Each pack contains one vial of Azacitidina Tillomed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Tillomed Italia S.r.l.
Viale G. Richard 1, Tower A
20143 Milan (MI)
Italy

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

This medicinal product is authorised in the Member States of the European Economic Area under the following names:

| Country | Product Name | |---------------|--------------| | Germany | Azacitidin Tillomed 25 mg/ml Pulver zur Herstellung einer Injektionssuspension | | Italy | Azacitidina Tillomed | | France | Azacitidine Tillomed 25 mg/mL poudre pour suspension injectable | | Spain | Azacitidina Zentiva 25 mg/ml polvo para suspensión inyectable EFG |

This Patient Information Leaflet was last revised on: 09/2025

The following information is intended exclusively for healthcare professionals:

Safe handling recommendations
Azacitidine Tillomed is a cytotoxic medicinal product and, therefore, appropriate caution should be exercised when handling and preparing azacitidine suspensions, as with other potentially toxic compounds. Appropriate procedures for handling and disposal of antineoplastic medicinal products must be followed.
In case of skin contact with reconstituted azacitidine, wash immediately and thoroughly with soap and water. In case of mucous membrane contact, rinse thoroughly with water.

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned below (see section “Reconstitution procedure”).

Reconstitution procedure
Azacitidine Tillomed must be reconstituted with water for injections. The shelf life of the reconstituted medicinal product may be extended if reconstitution is performed using refrigerated water for injections (2 °C–8 °C). Details on the storage of the reconstituted medicinal product are provided below.

1. Prepare the following items: vial(s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol swabs; 5 mL syringe(s) with needle(s).
2. Draw up 4 mL of water for injections into the syringe, ensuring that any air bubbles in the syringe are removed.
3. Insert the needle of the syringe containing 4 mL of water for injections through the rubber stopper of the azacitidine vial and then inject the water for injections into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a uniform, opaque suspension is formed. After reconstitution, each mL of suspension contains 25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, opaque suspension free from aggregates. The suspension must be discarded if large particles or aggregates are present. Do not filter the suspension after reconstitution, as this may remove the active substance. Note that some adapters, 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 attached needle into the vial. Invert the vial, ensuring that the tip of the needle is below the liquid level. Pull back the plunger to withdraw the required amount of medicinal product for the correct dose, ensuring that any remaining air bubbles in the syringe are eliminated. Then remove the syringe with needle from the vial and dispose of the needle.
6. At this point, securely attach a new subcutaneous-use needle to the syringe (use of 25-gauge needles is recommended). The suspension should not be pushed into the needle prior to injection in order to reduce the incidence of local reactions at the injection site.
7. When more than one vial is required, repeat the steps described for suspension preparation. For doses requiring more than one vial, divide the dose equally; e.g., a 150 mg dose = 6 mL, 2 syringes with 3 mL each. Due to retention in the vial and needle, it may not be possible to aspirate all of the suspension from the vial.
8. The contents of the dosing syringe must be resuspended immediately before administration. The suspension temperature at the time of injection should be approximately 20 °C–25 °C. To resuspend, roll the syringe vigorously between the palms of the hands until a uniform, opaque suspension is obtained. The suspension must be discarded if large particles or aggregates are present.

Storage of the reconstituted medicinal product
For immediate use
The Azacitidine Tillomed suspension may be prepared immediately before use, and the reconstituted suspension must be administered within 45 minutes. If the elapsed time exceeds 45 minutes, the reconstituted suspension must be properly discarded and a new dose prepared.
For subsequent use
When reconstitution is performed using non-refrigerated water for injections, the reconstituted suspension must be stored immediately in a refrigerator (2 °C–8 °C) after reconstitution and kept refrigerated for a maximum of 8 hours. If the storage time in the refrigerator exceeds 8 hours, the suspension must be properly discarded and a new dose prepared.
When reconstitution is performed using refrigerated water for injections (2 °C–8 °C), the reconstituted suspension must be stored immediately in a refrigerator (2 °C–8 °C) after reconstitution and kept refrigerated for a maximum of 22 hours. If the storage time in the refrigerator exceeds 22 hours, the suspension must be properly discarded and a new dose prepared.
Before administration, allow up to 30 minutes for the filled syringe containing the reconstituted suspension to reach a temperature of approximately 20 °C–25 °C. If the elapsed time exceeds 30 minutes, the suspension must be discarded and properly disposed of, and a new dose must be prepared.

Individual dose calculation
The total dose based on body surface area (BSA) can be calculated as follows:
Total dose (mg) = Dose (mg/m²) × BSA (m²)
The table below is only an example of how to calculate individual azacitidine doses based on an average BSA of 1.8 m².

Method of administration
Do not filter the suspension after reconstitution.
The reconstituted solution of Azacitidina Tillomed must be administered by subcutaneous injection (insert the needle at an angle of 45–90°) into the upper arm, thigh, or abdomen, using a 25-gauge needle.
Doses exceeding 4 mL must be administered at two different injection sites.
Rotate injection sites with each administration. Subsequent injections should be given at least 2.5 cm away from the previous site and never into tender, bruised, erythematous, or hardened areas.
Any unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.