AZACITIDINE 25 mg /Ml Powder

Contents of the leaflet

1. Package Leaflet: Information for the User
2. Azacitidine EVER Pharma, 25 mg/mL, Powder for Suspension for Injection
   1. Read All of This Leaflet Carefully Before You Start Using This Medicine Because It Contains Important Information for You.
   2. Contents of the Pack
3. What Azacitidine EVER Pharma Is and What It Is Used For
   1. What Azacitidine EVER Pharma Is
   2. What Azacitidine EVER Pharma Is Used For
   3. How Azacitidine EVER Pharma Works
4. Before You Use Azacitidine EVER Pharma
   1. When Not to Use Azacitidine EVER Pharma
   2. Warnings and Precautions
   3. Children and Adolescents
   4. Azacitidine EVER Pharma and Other Medicines
   5. Pregnancy, Breastfeeding, and Fertility
   6. Driving and Using Machines
5. How to Use Azacitidine EVER Pharma
6. Possible Side Effects
   1. Reporting of Side Effects
7. How to Store Azacitidine EVER Pharma
8. Contents of the Pack and Other Information
   1. What Azacitidine EVER Pharma Contains
   2. What Azacitidine EVER Pharma Looks Like and Contents of the Pack
   3. Marketing Authorization Holder
   4. Manufacturer
   5. This Medicinal Product Is Authorized in the Member States of the European Economic Area Under the Following Names:
   6. Information Intended for Healthcare Professionals Only:

Package Leaflet: Information for the User

Azacitidine EVER Pharma, 25 mg/mL, Powder for Suspension for Injection

Azacitidinum

Read All of This Leaflet Carefully Before You Start Using This Medicine Because It Contains Important Information for You.

• You should keep this leaflet. You may need to read it again.
• If you have any further 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 Pack

• 1. What Azacitidine EVER Pharma is and What It Is Used For
• 2. Before You Use Azacitidine EVER Pharma
• 3. How to Use Azacitidine EVER Pharma
• 4. Possible Side Effects
• 5. How to Store Azacitidine EVER Pharma
• 6. Contents of the Pack and Other Information

1. What Azacitidine EVER Pharma Is and What It Is Used For

What Azacitidine EVER Pharma Is

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

What Azacitidine EVER Pharma Is Used For

Azacitidine EVER Pharma is used in adults who cannot receive a bone marrow transplant to treat:

• 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 EVER Pharma Works

Azacitidine EVER Pharma 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 abnormalities in the maturation and growth of young blood cells in the bone marrow that cause myelodysplastic syndromes, and that they kill cancer cells in leukemia. If you have any questions about how Azacitidine EVER Pharma works or why it has been prescribed for you, ask your doctor or nurse.

2. Before You Use Azacitidine EVER Pharma

When Not to Use Azacitidine EVER Pharma

Warnings and Precautions

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

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

Azacitidine EVER Pharma may cause a severe immune reaction called "differentiation syndrome" (see section 4). Blood Tests Before starting treatment with Azacitidine EVER Pharma and at the beginning of each treatment cycle, blood tests will be performed to check if you have enough blood cells and if your liver and kidneys are working properly.

Children and Adolescents

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

Azacitidine EVER Pharma and Other Medicines

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

Pregnancy, Breastfeeding, and Fertility

Pregnancy You should not use Azacitidine EVER Pharma if you are pregnant, as it may harm your baby. You should use effective contraception during treatment and for 3 months after treatment. If you become pregnant during treatment, you should tell your doctor immediately. 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 You should not breastfeed while using Azacitidine EVER Pharma, as it is not known whether this medicine passes into breast milk. Fertility Men should not father a child during treatment with Azacitidine EVER Pharma. You should use effective contraception during treatment and for 3 months after treatment. You should consult your doctor before starting treatment if you wish to conserve sperm.

Driving and Using Machines

If you experience side effects such as tiredness, do not drive or operate machinery.

3. How to Use Azacitidine EVER Pharma

Before administering Azacitidine EVER Pharma to you, your doctor will give you 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. Your doctor will decide on the dose based on your overall health, height, and weight. Your doctor will monitor your progress and may adjust the dose if necessary.
• Azacitidine EVER Pharma is given daily for one week, followed by a rest period of three weeks. This treatment cycle is repeated every four weeks. You will usually receive at least six treatment cycles.

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

4. Possible Side Effects

Like all medicines, Azacitidine EVER Pharma can cause side effects, although not everybody gets them. You should tell your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal distension, and easy bruising.These may be signs 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, and feeling disoriented, anxious, or tired.These may be signs 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 signs 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)

• Low red blood cell count (anemia). You may feel tired and pale.
• Low white blood cell count. This may be accompanied by fever. You are also more prone to infections.
• Low platelet count (thrombocytopenia). You are more prone 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 spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat congestion.
• 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.
• Bone marrow failure. This can lead to a low red and white blood cell and platelet count.
• A type of anemia where the red, white, and platelet count 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 (hematoma).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site, including swelling, hard lumps, bruising, bleeding in the skin (hematoma), rash, itching, and skin discoloration.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection or sore throat.
• Nose or sinus congestion (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath on exertion.
• Throat and larynx pain.
• Nausea.
• Numness.
• General feeling of being unwell.
• Anxiety.
• Disorientation.
• 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.
• Bleeding at the catheter site.
• A disease affecting the intestines, which 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 patches on the skin, with fever.
• Painful skin ulcers (necrotizing fasciitis).
• Inflammation of the sac surrounding the heart (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 cancer treatment, which can also occur 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, irregular heartbeat, seizures, and sometimes death. Frequency Not Known(frequency 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 of Side Effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in the "Further information" section. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to Store Azacitidine EVER Pharma

Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and label after "EXP". The expiry date refers to the last day of that month. Your doctor, pharmacist, or nurse is responsible for storing Azacitidine EVER Pharma. They are also responsible for preparing Azacitidine EVER Pharma and disposing of any unused medicine. Unopened vials - no special storage instructions. After reconstitution:

The chemical and physical stability of the reconstituted azacitidine solution has been demonstrated for 45 minutes at 25°C and for 8 hours at 2°C to 8°C. The shelf-life of the reconstituted product can be extended by reconstituting the product with cold (2°C to 8°C) water for injection. For the azacitidine solution reconstituted with cold (2°C to 8°C) water for injection, the chemical and physical stability of the reconstituted product has been demonstrated for 32 hours at 2°C to 8°C. For microbiological reasons, the reconstituted product should be used immediately. If not used immediately, the user is responsible for the storage conditions and expiration date prior to use, which should not exceed 8 hours at 2°C to 8°C for the product reconstituted with unchilled water for injection or 32 hours for the product reconstituted with chilled (2°C to 8°C) water for injection. Before administration, allow the suspension to reach room temperature (20°C - 25°C) for a maximum of 30 minutes. Discard the suspension if it contains large particles.

6. Contents of the Pack and Other Information

What Azacitidine EVER Pharma Contains

• The active substance is azacitidine. One mL of the reconstituted suspension contains 25 mg of azacitidine. One vial contains 100 mg or 150 mg of azacitidine.
• The other ingredient is mannitol.

What Azacitidine EVER Pharma Looks Like and Contents of the Pack

Azacitidine EVER Pharma is a white powder for suspension for injection and is provided in a glass vial with a stopper made of bromobutyl rubber coated with ETFE (the top of the stopper is also coated with silicone RB2-40) and an aluminum seal (white for 100 mg and orange for 150 mg). Pack sizes: 1 vial containing 100 mg of azacitidine. 1 vial containing 150 mg of azacitidine.

Marketing Authorization Holder

EVER Valinject GmbH Oberburgau 3 4866 Unterach am Attersee Austria

Manufacturer

AqVida GmbH Kaiser-Wilhelm-Str. 89 20355 Hamburg Germany EVER Pharma Jena GmbH Otto-Schott-Str. 15 07745 Jena Germany

This Medicinal Product Is Authorized in the Member States of the European Economic Area Under the Following Names:

Austria Azacitidin EVER Pharma 25 mg/mL Pulver zur Herstellung einer Injektionssuspension Denmark Azacitidine EVER Pharma 25 mg/mL pulver til injektionsvæske, suspension Finland Azacitidine EVER Pharma 25 mg/mL injektiokuiva-aine, suspensiota varten France Azacitidine EVER Pharma 25 mg/mL, poudre pour suspension injectable Spain Azacitidina Ever Pharma 25 mg/mL polvo para suspensión inyectable EFG Ireland Azacitidine EVER Pharma 25 mg/mL powder for suspension for injection Netherlands Azacitidine EVER Pharma 25 mg/mL poeder voor suspensie voor injectie Germany Azacitidin EVER Pharma 25 mg/mL Pulver zur Herstellung einer Injektionssuspension Norway Azacitidine EVER Pharma Poland Azacitidine EVER Pharma Czech Republic Azacitidine EVER Pharma Slovakia Azacitidín EVER Pharma 25 mg/mL prášok na injekcnú suspenziu Sweden Azacitidine EVER Pharma 25 mg/mL pulver till injektionsvätska, suspension Italy Azacitidina EVER Pharma Date of Last Revision of the Leaflet:12.2023

Information Intended for Healthcare Professionals Only:

Recommendations for Safe Handling Azacitidine EVER Pharma 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 and disposal of anti-cancer medicinal products. If you come into contact with the reconstituted azacitidine, wash the affected area thoroughly with soap and water. If you come into contact with the mucous membranes, rinse them thoroughly with water. Pregnant women in the healthcare staff should not handle the product. Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned below (see "Reconstitution Procedure"). Reconstitution Procedure Azacitidine EVER Pharma should be reconstituted with water for injection. The shelf-life of the reconstituted product can be extended by reconstituting the product with cold (2°C to 8°C) water for injection. Details of storage of the reconstituted product are given below.

• 1. You will need the following: vial(s) of azacitidine, vial(s) of water for injection, non-sterile surgical gloves, alcohol swabs, injection syringe(s) with needle(s).
• 2. Draw up the appropriate volume of water for injection into the syringe (see table below). Ensure that the air has been removed from the syringe.

• 3. Insert the needle of the syringe containing water for injection through the rubber stopper of the vial of azacitidine and then slowly inject the water for injection into the vial.
• 4. After removing the syringe and needle, vigorously shake the vial until a uniform, cloudy suspension is obtained. After reconstitution, each mL of suspension contains 25 mg of azacitidine. The reconstituted product is a uniform, cloudy suspension without agglomerates. Discard the suspension 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. Such devices should not be used to administer the product after reconstitution.

The shelf-life of the reconstituted product can be extended by reconstituting the product with cold (2°C to 8°C) water for injection. For the azacitidine solution reconstituted with cold (2°C to 8°C) water for injection, the chemical and physical stability of the reconstituted product has been demonstrated for 32 hours at 2°C to 8°C. For microbiological reasons, the reconstituted product should be used immediately. If not used immediately, the user is responsible for the storage conditions and expiration date prior to use, which should not exceed 8 hours at 2°C to 8°C for the product reconstituted with unchilled water for injection or 32 hours for the product reconstituted with chilled (2°C to 8°C) water for injection. Allow the syringe filled with the reconstituted suspension to reach room temperature (20°C - 25°C) for up to 30 minutes before administration. If more than 30 minutes have passed, discard the suspension and prepare a new dose. Individual Dose Calculation The total dose can be calculated based on body surface area (BSA) as follows: Total dose = 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 The reconstituted Azacitidine EVER Pharma should not be filtered after reconstitution. The reconstituted product should be administered subcutaneously (at an angle of 45 - 90°) using a 25 G needle in the arm, thigh, or abdomen.

• Doses greater than 4 mL should be administered at two different injection sites.

Rotate the injection sites. New injections should be given at least 2.5 cm from the previous injection site and never in sensitive, bruised, red, or hardened areas. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.