Azacitidine eugia

Package leaflet: Information for the user

Azacitidine Eugia, 25 mg/mL, powder for suspension for injection
Azacitidinum
Please read all of this leaflet carefully before using this medicine because it contains
important information for you.
Keep this leaflet as you may need to read it again.
If you have any further questions, please ask your doctor, pharmacist, or nurse.
This medicine has been prescribed for a specific individual. Do not pass it on to others. It may
harm someone else, even if their symptoms are the same.
If you experience any side effects, including any not listed in this leaflet, tell your doctor,
pharmacist, or nurse. See section 4.
Contents of the leaflet:

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

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

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

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

These are diseases that affect the bone marrow and may cause difficulties in the proper production of blood cells.

How Azacitidine Eugia works
Azacitidine Eugia works by preventing 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 genes are switched on and off, as well as by interfering with the production of new RNA and DNA. These actions are thought to correct the impaired maturation and growth of young blood cells in the bone marrow seen in myelodysplastic disorders, and to kill cancer cells in leukaemia.
If you have any questions about how Azacitidine Eugia works or why this medicine has been prescribed for you, please consult your doctor or nurse.

2. Important information before using Azacitidine Eugia

When not to use Azacitidine Eugia

• if the patient is allergic to azacitidine or any of the other ingredients of this medicine (listed in section 6).
• if the patient has advanced liver cancer.
• if the patient is breastfeeding.

Warnings and precautions
Before starting treatment with Azacitidine Eugia, discuss with your doctor, pharmacist, or
nurse if the patient:

• has low platelet count, red blood cells, or white blood cells.
• has kidney disease.
• has liver disease.
• has previously had heart disease, heart attack, or any lung disease.

Azacitidine Eugia may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Before starting treatment with Azacitidine Eugia and at the beginning of each treatment cycle, the patient will undergo blood tests. The purpose of these tests is to check whether the patient has an adequate number of blood cells and whether the liver and kidneys are functioning properly.
Children and adolescents
Azacitidine Eugia is not recommended for use in children and adolescents under 18 years of age.
Azacitidine Eugia and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take. Azacitidine Eugia may affect the action of certain other medicines. Likewise, certain other medicines may affect the action of Azacitidine Eugia.
Pregnancy, breastfeeding, and fertility
Pregnancy
Do not use Azacitidine Eugia during pregnancy, as it may be harmful to the unborn child.
If the patient can become pregnant, she should use an effective method of contraception during treatment with Azacitidine Eugia and for 6 months after completion of treatment with Azacitidine Eugia. Inform the doctor immediately if the patient becomes pregnant during treatment.
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a baby, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding
Do not breastfeed while taking Azacitidine Eugia. It is not known whether this medicine passes into human milk.
Effect on fertility
Men should not father a child during treatment with Azacitidine Eugia. Men should use an effective method of contraception during treatment and for 3 months after completion of treatment with Azacitidine Eugia.
The patient should consult his doctor if he wishes to store sperm before starting this treatment.
Driving and using machines
If adverse effects such as fatigue occur, the patient should not drive, use tools, or operate machinery.

3. How to use Azacitidine Eugia

This medicine should always be used exactly as directed by the doctor or pharmacist. If in doubt,
consult the doctor or pharmacist.
Before administering Azacitidine Eugia, the doctor will give another medicine to prevent nausea and vomiting
at the beginning of each treatment cycle.

• The recommended dose of this medicine is 75 mg per m^2 of body surface area. The doctor will determine the dose of this medicine based on the patient's general condition, height and body weight. The doctor will monitor treatment progress and may adjust the dose if necessary.
• Azacitidine Eugia is administered daily for one week, followed by a three-week break. This "treatment cycle" is repeated every four weeks. Patients usually receive at least six treatment cycles.

This medicine will be administered as a subcutaneous injection by a doctor or nurse. The medicine can
be given subcutaneously in the thigh, abdomen, or upper arm.
If there are any further doubts regarding the use of this medicine, consult the doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will get them.
You must immediately tell your doctor if you notice any of the following adverse reactions:

• Drowsiness, tremors, jaundice, abdominal distension and easy bruising. These may be symptoms of liver failure and may be life-threatening.
• Swelling of the feet and legs, back pain, reduced urine output, increased thirst, rapid heartbeat, dizziness and nausea, vomiting or loss of appetite, and feelings of disorientation, restlessness or fatigue. These may be symptoms of kidney failure and may be life-threatening.
• Fever. This may be due to infection caused by a low number of white blood cells, which may be life-threatening.
• Chest pain or shortness of breath, possibly accompanied by fever. This may be due to a lung infection called "pneumonia" and may be life-threatening.
• Bleeding. Such as blood in the stool due to gastrointestinal bleeding, or bleeding inside the head. These may be symptoms of a low platelet count.
• Difficulty breathing, swelling of the lips, itching or rash. These may be caused by an allergic reaction (hypersensitivity).

Other adverse reactions include:
Very common adverse reactions (may affect more than 1 in 10 people)

• Decreased number of red blood cells (anaemia). The patient may feel tired and look pale.
• Decreased number of white blood cells. This may be accompanied by fever. The patient is also more susceptible to infections.
• Low platelet count (thrombocytopenia). The patient is more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue (tiredness).
• Injection site reaction, including redness, pain or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nasal and throat pain.
• Dizziness.
• Headache.
• Sleep disturbances (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low blood potassium levels.

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

• Bleeding inside the skull.
• Blood infection caused by bacteria (sepsis). This may be due to a low number of white blood cells.
• Bone marrow failure. This may lead to low numbers of red and white blood cells and platelets.
• A type of anaemia in which the number of red blood cells, white blood cells and platelets is reduced.
• Urinary tract infection.
• Viral infection causing cold sores (herpes).
• Bleeding gums, gastrointestinal bleeding, bleeding from the anal area due to haemorrhoids (haemorrhoidal bleeding), eye bleeding, skin or subcutaneous bleeding (haematomas).
• Blood in the urine.
• Mouth or tongue ulceration.
• Skin changes at the injection site. These include swelling, hard lumps, bruising, skin bleeding (haematomas), rash, itching and skin discoloration.
• Skin redness.
• Skin infection (cellulitis).
• Nose and throat infection or sore throat.
• Nasal pain or congestion, or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Throat and larynx pain.
• Indigestion.
• Apathy.
• General malaise.
• Anxiety.
• Disorientation.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside of the cheeks, and sometimes on the gums, palate and tonsils (oral candidiasis).
• Fainting.
• Drop in blood pressure upon standing (orthostatic hypotension), leading to dizziness when changing to a standing or sitting position.
• Drowsiness, somnolence.
• Bleeding at the catheter insertion site.
• Bowel disease which may cause fever, vomiting and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle cramps.
• Raised, itchy skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremor.
• Liver failure.
• Large, plum-coloured, raised, painful skin lesions accompanied by fever.
• Painful skin ulceration (pyoderma gangrenosum).
• Inflammation of the membrane surrounding the heart (pericarditis).

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

• Dry cough.
• Painless swelling of the fingertips (clubbing).
• Tumour lysis syndrome – metabolic complications that may occur during cancer treatment, and sometimes even without treatment. These complications are caused by the products of dying tumour cells and may include: changes in blood chemistry; high levels of potassium, phosphate and uric acid, and low calcium levels, leading to kidney dysfunction, cardiac arrhythmias, seizures, and sometimes death.

Frequency not known (frequency cannot be estimated from available data)

• Infection of deep skin layers that spreads rapidly, causing skin and tissue damage, which may be life-threatening (necrotising fasciitis).
• Severe immune reaction (differentiation syndrome), which may cause fever, cough, difficulty breathing, rash, reduced urine output, low blood pressure (hypotension), swelling of hands or feet, and sudden weight gain.
• Inflammation of blood vessels in the skin, which may lead to a rash (cutaneous vasculitis).

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, 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
Reporting adverse reactions helps provide more information on the safety of the medicine.
Adverse reactions can also be reported to the marketing authorisation holder.

5. How to store Azacitidine Eugia

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton following:
EXP. The expiry date refers to the last day of the stated month.
Storage of Azacitidine Eugia is the responsibility of the doctor, pharmacist, or nurse. They are also responsible for the proper preparation and disposal of any unused Azacitidine Eugia.
Unopened vials – no special storage requirements.

For immediate use
After reconstitution, the suspension should be administered within 45 minutes.

For later use
If the Azacitidine Eugia suspension was prepared using unrefrigerated Water for Injections, the prepared suspension must be immediately stored in a refrigerator (2°C - 8°C) and kept for no longer than 8 hours.
If the Azacitidine Eugia suspension was prepared using refrigerated Water for Injections (2°C - 8°C), the prepared suspension must be immediately stored in a refrigerator (2°C - 8°C) and kept for no longer than 22 hours.
Prior to administration, allow the suspension to stand for up to 30 minutes to reach room temperature (20°C - 25°C).

From a microbiological point of view, the medicine should be used immediately after reconstitution. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user.
If large particles are present in the suspension, it should be discarded.

6. Contents of the pack and other information

What Azacitidine Eugia contains
The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution
by adding 4 mL of water for injections, the prepared suspension contains 25 mg/mL of azacitidine.
Other ingredient: mannitol.
What Azacitidine Eugia looks like and contents of the pack
A white or almost white lyophilized powder or cake for reconstitution into an injectable suspension.
Azacitidine Eugia is supplied in a glass vial containing 100 mg of azacitidine.
Each pack contains one vial of azacitidine.
Vials may be packed in plastic protective sleeves if necessary.
100 mg of azacitidine is available in packs containing 1, 5, 7 and 10 vials, in a cardboard box.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Eugia Pharma (Malta) Ltd.
Vault 14, level 2
Valletta Waterfront
Floriana, FRN 1914
Malta
e-mail: [email protected]
Manufacturer/Importer:
APL Swift Services (Malta) Ltd.
HF26, Hal Far Industrial Estate, Hal Far
Birzebbugia, BBG 3000
Malta
Generis Farmacêutica, S.A.
Rua João de Deus 19, Venda Nova
2700-487 Amadora
Portugal
Arrow Génériques
26 Avenue Tony Garnier
69007 Lyon
France
This medicinal product is authorised in the European Economic Area member states under the following names:
Belgium: Azacitidine Eugia 25mg/ml poeder voor suspensie voor injectie/poudre pour suspension injectable/Pulver zur Herstellung einer Injektionssuspension
Germany: Azacitidin PUREN 25 mg/ml Pulver zur Herstellung einer Injektionssuspension
France: AZACITIDINE ARROW 25 mg/ml, poudre pour suspension injectable
Italy: Azacitidina Aurobindo
Netherlands: Azacitidine Eugia 25 mg/ml poeder voor suspensie voor injectie
Poland: Azacitidine Eugia
Portugal: Azacitidina Eugia
Spain: Azacitidina Eugia 25 mg/ml polvo para suspensión inyectable EFG

Information intended exclusively for medical professionals:

Safe handling recommendations
Azacitidine Eugia is a cytotoxic medicine, and as with other potentially toxic compounds, caution must be exercised when handling and preparing azacitidine suspension. Appropriate procedures for handling and disposal of cytotoxic anticancer drugs should be followed.
In case of contact of the prepared azacitidine with the skin, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.

Pharmaceutical incompatibilities
This medicine must not be mixed with other medicinal products, except as specified below (see "Reconstitution procedure").

Reconstitution procedure
Azacitidine Eugia should be reconstituted with water for injections. The shelf life of the reconstituted medicine can be extended by using cooled (2°C to 8°C) water for injections. Detailed information on storage after reconstitution is provided below.

1. Prepare the following materials: 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 4 mL of water for injections into the syringe and ensure that all air has been expelled 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 and inject the water into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a uniform, cloudy suspension is obtained. After reconstitution, each mL of suspension will contain 25 mg of azacitidine (100 mg/4 mL). The prepared medicine is a uniform, cloudy suspension without agglomerates. Discard the medicine if it contains large particles or agglomerates. Do not filter the suspension after reconstitution, as this may result in removal of the active substance. Note that some adapters, spikes, and closed system transfer devices contain filters; therefore, such systems should not be used for administration of the reconstituted medicine.
5. Clean the rubber stopper and insert a new syringe with needle into the vial. Invert the vial, ensuring that the tip of the needle is below the fluid level. Pull back the plunger to withdraw the required volume of medicine to deliver the correct dose. Ensure that all air has been expelled from the syringe. Then withdraw the needle and syringe from the vial and discard the needle.
6. Firmly attach a new subcutaneous injection needle (25 G recommended) to the syringe. Do not flush the needle prior to injection to reduce the frequency of local reactions at the injection site.
7. If more than one vial is required, repeat all the above steps to prepare the suspension. For doses requiring more than one vial, the dose should be evenly divided, e.g., a 150 mg dose = 6 mL, two syringes with 3 mL each. Due to adherence to vial walls and needle, complete recovery of the suspension from the vial may not be possible.
8. The suspension in the syringe must be resuspended immediately before administration. Up to 30 minutes before administration, allow the syringe filled with the prepared suspension to stand to reach a temperature of approximately 20°C – 25°C. If more than 30 minutes has elapsed, the suspension should be properly discarded and a new dose prepared. To resuspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is obtained. Discard the medicine if it contains large particles or agglomerates.

Storage after reconstitution
For immediate use
The azacitidine Eugia suspension may be prepared immediately before use, and the reconstituted suspension should be administered within 45 minutes. If more than 45 minutes has elapsed, the prepared suspension should be properly discarded and a new dose prepared.
For later use
If the medicine was prepared using uncooled water for injections, the reconstituted suspension should be placed immediately in a refrigerator (2°C – 8°C) after reconstitution and stored for a maximum of 8 hours. If the storage time in the refrigerator exceeds 8 hours, the suspension should be properly discarded and a new dose prepared.
If the medicine was prepared using cooled (2°C – 8°C) water for injections, the reconstituted suspension should be placed immediately in a refrigerator (2°C – 8°C) after preparation and stored for a maximum of 22 hours. If the storage time in the refrigerator exceeds 22 hours, the suspension should be properly discarded and a new dose prepared.
The syringe filled with the prepared suspension should be allowed to stand for up to 30 minutes before administration to reach a temperature of approximately 20°C – 25°C. If more than 30 minutes has elapsed, the suspension should be properly discarded and a new dose prepared.

Individual dose calculation
The total dose can be calculated based on body surface area (BSA) as follows:
Total dose (mg) = dose (mg/m²) × BSA (m²)
The table below is merely 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.
After reconstitution, Azacitidine Eugia should be administered subcutaneously (insert the needle at an angle of 45–90°) using a 25 G needle into the upper arm, thigh, or abdomen.
Doses exceeding 4 mL should 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 areas that are tender, bruised, erythematous, or hardened.
Any residual medicinal product and all materials used for reconstitution, dilution, and administration must be destroyed in accordance with standard hospital procedures for cytotoxic anticancer drugs, taking into account applicable regulations for the disposal of hazardous waste.