Azacitidine Eugia

Package Leaflet: Information for the User

Azacitidine Eugia, 25 mg/mL, Powder for Suspension for Injection

Azacitidinum

Read the package leaflet carefully before using the medicine, as it contains important information for the patient.

Keep this package leaflet, you may need to read it again.
In case of any doubts, consult a doctor, pharmacist, or nurse.
This medicine has been prescribed to a specific person. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same.
If the patient experiences any side effects, including any not listed in this leaflet, they should inform their doctor, pharmacist, or nurse.
See section 4.

Package Leaflet Contents:

• 1. What is Azacitidine Eugia and what is it used for
• 2. Important information before using Azacitidine Eugia
• 3. How to use Azacitidine Eugia
• 4. Possible side effects
• 5. How to store Azacitidine Eugia
• 6. Package contents and other information

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

What is Azacitidine Eugia

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

What is Azacitidine Eugia used for

Azacitidine Eugia is used in adults who are not eligible for stem cell transplantation, 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 normal blood cell production.

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 thought that its action involves changing the way genes are activated and deactivated, as well as disrupting the production of new RNA and DNA. It is believed that these actions repair the disturbances in the maturation and growth of young blood cells in the bone marrow, which cause myelodysplastic disorders, and that they kill cancer cells in leukemia.
If you have any questions about how Azacitidine Eugia works or why it has been prescribed, ask your doctor or nurse.

2. Important information before using Azacitidine Eugia

When not to use Azacitidine Eugia

• if you are allergic to azacitidine or 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

Before starting treatment with Azacitidine Eugia, discuss with your doctor, pharmacist, or nurse if you:

• have a low platelet count, red blood cells, or white blood cells.
• have kidney disease.
• have liver disease.
• have a history of 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 period (so-called "cycle"), you will have blood tests. The purpose of these tests is to check if you have a sufficient number of blood cells and if your liver and kidneys are working 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 you are taking or have recently taken, as well as any medicines you plan to take. Azacitidine Eugia may affect the action of some other medicines. Also, some other medicines may affect the action of Azacitidine Eugia.

Pregnancy, breastfeeding, and fertility

Pregnancy
Do not use Azacitidine Eugia during pregnancy, as it may harm the baby.
If you can become pregnant, you should use effective contraception during treatment with Azacitidine Eugia and for 6 months after the end of treatment with Azacitidine Eugia. Tell your doctor immediately if you become pregnant during treatment.
If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Breastfeeding
Do not breastfeed while using Azacitidine Eugia. It is not known if this medicine passes into human milk.
Fertility
Men should not father a child during treatment with Azacitidine Eugia. Men should use effective contraception during and for 3 months after the end of treatment with Azacitidine Eugia.
You should consult your doctor if you wish to preserve sperm before starting this treatment.

Driving and using machines

If you experience side effects such as fatigue, do not drive, use tools, or operate machinery.

3. How to use Azacitidine Eugia

This medicine should always be used as directed by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist.
Before administering Azacitidine Eugia, 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 square meter of body surface area. Your doctor will decide on the dose based on your overall condition, height, and weight. Your doctor will monitor your progress and may change the dose if necessary.
• Azacitidine Eugia is given daily for one week, followed by a 3-week break. This "treatment cycle" is repeated every 4 weeks. You will usually receive at least 6 cycles of treatment.

This medicine will be given as a subcutaneous injection by your doctor or nurse. The medicine can be injected under the skin in the thigh, abdomen, or arm.
If you have any further doubts about using this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

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

Tell your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremors, 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 decreased appetite, as well as feelings of disorientation, anxiety, or fatigue.These may be symptoms of kidney failure and can be life-threatening.
• Fever. The cause may be an infection due to a low white blood cell count, which can be life-threatening.
• Chest pain or shortness of breath, which may be accompanied by fever.The cause may be a lung infection called "pneumonia" and can be life-threatening.
• Bleeding. Such as blood in the stool due to bleeding in the stomach or intestines, 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 caused by 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 prone to infections.
• Low platelet count (thrombocytopenia). You have a greater tendency to bleed and bruise.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue (tiredness).
• Reaction at the injection site, including redness, pain, or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Sleep disturbances (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 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 (herpes).
• Bleeding gums, bleeding in the stomach or intestines, bleeding from the anus due to hemorrhoids (hemorrhoidal bleeding), eye bleeding, bleeding under the skin or in the skin (hematomas).
• Blood in the urine.
• Mouth or tongue ulcers.
• 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 (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath on exertion.
• Throat and larynx pain.
• Nausea.
• Apathy.
• General malaise.
• Anxiety.
• Disorientation.
• Hair loss.
• Kidney failure.
• Dehydration.
• White patches on the tongue, inside the cheeks, and sometimes on the gums, palate, 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 catheter site.
• Bowel disease that can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• Raised, itchy rash on the skin (hives).
• Fluid accumulation around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, plum-colored, raised, painful spots on the skin, with accompanying fever.
• Painful skin ulcers (necrotizing fasciitis).
• Inflammation of the heart sac (pericarditis).

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

• Dry cough.
• Painless swelling of the fingertips (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 products 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(frequency cannot be estimated from the available data)

• Infection of the deep skin layers, which can spread quickly, causing skin and tissue damage, and can be life-threatening (necrotizing fasciitis).
• 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 lead to a rash (cutaneous vasculitis).

Reporting side effects

If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety, Ministry of Health, via the online reporting system at [insert website].
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidine Eugia

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after: EXP. The expiry date refers to the last day of the month.
Your doctor, pharmacist, or nurse is responsible for storing Azacitidine Eugia and for the proper disposal of any unused medicine.
Unopened vials - no special storage instructions.
For immediate use
The reconstituted suspension should be administered within 45 minutes. If more than 45 minutes have passed, the reconstituted suspension should be discarded and a new dose prepared.
For later use
If the suspension was prepared with unrefrigerated water for injections, the reconstituted suspension should be stored in the refrigerator (2°C - 8°C) immediately after reconstitution and for no more than 8 hours. If the storage time in the refrigerator was longer than 8 hours, the suspension should be discarded and a new dose prepared.
If the suspension was prepared with refrigerated (2°C - 8°C) water for injections, the reconstituted suspension should be stored in the refrigerator (2°C - 8°C) immediately after reconstitution and for no more than 22 hours. If the storage time in the refrigerator was longer than 22 hours, the suspension should be discarded and a new dose prepared.
Before administration, the suspension should be left at room temperature (20°C - 25°C) for 30 minutes to allow it to reach room temperature. If more than 30 minutes have passed, the suspension should be discarded and a new dose prepared.
From a microbiological point of view, the reconstituted medicine should be used immediately. If not used immediately, the storage conditions and expiry date before use are the responsibility of the user.
If the suspension contains large particles, it should be discarded.

6. Package contents and other information

What Azacitidine Eugia 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.

What Azacitidine Eugia looks like and contents of the pack

White or off-white lyophilized cake or powder for suspension for injection.
Azacitidine Eugia is supplied in a glass vial containing 100 mg of azacitidine.
Each pack contains one vial of azacitidine.
The vials may be packaged in plastic protective covers.
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 authorization holder and manufacturer

Marketing authorization 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 medicine is authorized in the Member States of the European Economic Area 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

Date of last revision of the package leaflet: 12/2023

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Information intended for healthcare professionals only:

Recommendations for safe handling
Azacitidine Eugia is a cytotoxic medicine, and as with other potentially toxic compounds, caution should be exercised when handling and preparing the azacitidine suspension. Proper handling and disposal procedures for anti-cancer medicines should be followed.
In case of contact with the prepared azacitidine, wash the skin immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.
Incompatibilities
The medicine should not be mixed with other medicines, except for those listed 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 reconstituting it with refrigerated (2°C - 8°C) water for injections. Detailed information on the storage of the medicine after reconstitution is given 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) for injection with needle(s).
• 2. Draw up 4 mL of water for injections into the syringe and ensure that the air has been removed 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 then inject the water for injections 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 the suspension will contain 25 mg of azacitidine (100 mg/4 mL). The reconstituted medicine is a uniform, cloudy suspension without agglomerates. The medicine should be discarded if it contains large particles or agglomerates. Do not filter the suspension after reconstitution, as this may remove the active substance. Note that some adapters, needles, and closed systems contain filters, so these systems should not be used to administer the reconstituted medicine.
• 5. Clean the rubber stopper and insert a new syringe with a needle into the vial. Then, turn the vial upside down, ensuring that the needle tip is below the level of the liquid. Then, pull back the plunger to draw up the required amount of medicine to administer the correct dose. Ensure that the air has been removed from the syringe. Then, withdraw the needle from the vial with the syringe.
• 6. Attach a new subcutaneous injection needle (25 G recommended) firmly to the syringe. Do not flush the needle before injection to reduce the frequency of local reactions at the injection site.
• 7. If more than one vial is needed, repeat all the above steps to prepare the suspension. For doses requiring more than one vial, divide the dose evenly, e.g., 150 mg dose = 6 mL, 2 syringes with 3 mL each. Due to settling on the vial walls and in the 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, leave the syringe filled with the reconstituted suspension to reach a temperature of approximately 20°C - 25°C. If more than 30 minutes have passed, discard the suspension and prepare a new dose. To resuspend, vigorously rotate the syringe between your hands until a uniform, cloudy suspension is obtained. Discard the medicine if it contains large particles or agglomerates.

Storage of the reconstituted medicine
For immediate use
The reconstituted suspension of Azacitidine Eugia can be prepared immediately before use, and the reconstituted suspension should be administered within 45 minutes. If more than 45 minutes have passed, the reconstituted suspension should be discarded and a new dose prepared.
For later use
If the suspension was prepared with unrefrigerated water for injections, the reconstituted suspension should be stored in the refrigerator (2°C - 8°C) immediately after reconstitution and for no more than 8 hours. If the storage time in the refrigerator was longer than 8 hours, the suspension should be discarded and a new dose prepared.
If the suspension was prepared with refrigerated (2°C - 8°C) water for injections, the reconstituted suspension should be stored in the refrigerator (2°C - 8°C) immediately after reconstitution and for no more than 22 hours. If the storage time in the refrigerator was longer than 22 hours, the suspension should be discarded and a new dose prepared.
Before administration, leave the syringe at room temperature (20°C - 25°C) for 30 minutes to allow it to reach room temperature. If more than 30 minutes have passed, discard the suspension and prepare a new dose.
From a microbiological point of view, the reconstituted medicine should be used immediately. If not used immediately, the storage conditions and expiry date before use are the responsibility of the user.
If the suspension contains large particles, it should be discarded.

Calculation of individual dose
The total dose can be calculated based on 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 individual doses of azacitidine based on an average BSA of 1.8 m2.

Administration method
Do not filter the reconstituted suspension.
Azacitidine Eugia should be administered subcutaneously (insert the needle at an angle of 45-90°) using a 25 G needle.
Doses greater than 4 mL should be injected into two different sites.
Rotate the injection sites. New injections should be given at least 2.5 cm away from the previous site and never in sensitive, bruised, red, or hardened areas.
Disposal of the medicine and all materials used for reconstitution, dilution, and administration should be disposed of in accordance with standard hospital procedures for cytotoxic medicines, taking into account applicable regulations for the disposal of hazardous waste.