Azacitidine onko

Package leaflet: Information for the user

Azacitidine Onko, 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. 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.

Leaflet contents:
What Azacitidine Onko is and what it is used for

Important information before using Azacitidine Onko
How to use Azacitidine Onko
Possible side effects
How to store Azacitidine Onko
Contents of the pack and other information

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

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

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

These diseases affect the bone marrow and may cause difficulties in producing blood cells properly.
How Azacitidine Onko works
Azacitidine Onko 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 changing the way genes are activated and deactivated, as well as by interfering with the production of RNA and DNA. These actions are thought to correct the abnormalities in the 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 Azacitidine Onko works or why this medicine has been prescribed for you, please ask your doctor or nurse.

2. Important information before using Azacitidine Onko

When not to use Azacitidine Onko

• if the patient is allergic (hypersensitive) to azacitidine or to 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 Onko, 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 Onko may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Before starting treatment with Azacitidine Onko and at the beginning of each treatment period (so-called "cycle"), blood tests will be performed. 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 Onko is not recommended for use in children and adolescents under 18 years of age.
Azacitidine Onko with other medicines
Tell your doctor, pharmacist, or nurse about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take. Azacitidine Onko may affect the way some other medicines work. Likewise, some other medicines may affect the way Azacitidine Onko works.
Pregnancy, breastfeeding, and effects on fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.
Pregnancy
Azacitidine Onko must not be used during pregnancy, as it may be harmful to the unborn child. Women of childbearing potential should use an effective method of contraception during treatment with Azacitidine Onko and for at least 6 months after completion of treatment with Azacitidine Onko. Inform your doctor immediately if pregnancy occurs during treatment with Azacitidine Onko.
Breastfeeding
Breastfeeding must not be performed during treatment with Azacitidine Onko. It is unknown whether this medicine passes into human milk.
Effects on fertility
Men should not father a child while receiving treatment with Azacitidine Onko. Men should use an effective method of contraception during treatment with this medicine and for 3 months after completion of treatment with this medicine.
The patient should consult with their doctor if they wish to store semen before starting this treatment.
Driving and operating machinery
If adverse effects such as fatigue occur, the patient should not drive, use tools, or operate machinery.

3. How to use Azacitidine Onko

Before administering Azacitidine Onko to the patient, the doctor will give 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. The doctor selects the appropriate dose of Azacitidine Onko for the patient depending on the patient's general condition, height, and weight. The doctor monitors treatment progress and may adjust the dose if necessary.
• Azacitidine Onko is administered daily for one week, followed by a rest period lasting 3 weeks. This "treatment cycle" is repeated every 4 weeks. Patients usually receive at least 6 treatment cycles.

Azacitidine Onko is given as a subcutaneous injection by a doctor or nurse.
It may be administered subcutaneously in the thigh, abdomen, or arm.
If there are any further doubts regarding the use of this medicine, consult the doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody gets them.
You should tell your doctor immediately if you notice any of the following adverse reactions:

• Drowsiness, tremors, jaundice, abdominal swelling and easy bruising. These may be symptoms of liver failure, which may be life-threatening.
• Swelling of the legs and feet, back pain, reduced urine output, increased thirst, rapid heartbeat, dizziness and nausea, vomiting or loss of appetite, and feeling confused, anxious or tired. These may be symptoms of kidney failure, which may be life-threatening.
• Fever. This may be due to infection caused by a low white blood cell count, 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" which may be life-threatening.
• Bleeding. For example, blood in the stool due to bleeding in the stomach or intestine, or bleeding inside the head. These may be symptoms of a low platelet count.
• Difficulty breathing, swelling of the lips, itching or rash. This may be due to an allergic (hypersensitivity) reaction.

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

• Low number of red blood cells (anaemia). The patient may feel tired and look pale.
• Low number of white blood cells. This may be accompanied by fever. The patient is also more prone to infections.
• Low number of platelets (thrombocytopenia). The patient is more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue.
• 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.
• Pain in nose and throat.
• Dizziness, headache.
• Trouble sleeping (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness.
• Weight loss.
• Low blood potassium levels.

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

• Bleeding inside the skull.
• Blood infection caused by bacteria (sepsis). This may be due to a low white blood cell count.
• Bone marrow failure. This may lead to low numbers of red blood cells, 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 on the lips.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anal area due to haemorrhoids (haemorrhoidal haemorrhage), bleeding in the eye, bleeding under or into the skin (haematomas).
• Blood in the urine.
• Mouth or tongue ulceration.
• Skin changes at the injection site. These include swelling, hard lumps, bruising, bleeding into the skin (haematomas), rash, itching and skin colour changes.
• Skin redness.
• Skin infection (cellulitis).
• Nose or 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.
• Sore throat and larynx.
• Indigestion.
• Lethargy.
• General malaise.
• Anxiety.
• Disorientation.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside of the cheeks, and sometimes on the palate, gums 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.
• Bleeding at the catheter insertion site.
• Disease affecting the intestine, which may present with 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 occur in up to 1 in 100 people)

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, plum-coloured, raised, painful skin patches, with fever.
• Painful skin ulceration (necrotising fasciitis).
• Inflammation of the membrane surrounding the heart (pericarditis).

Rare adverse reactions (may occur in 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 levels of calcium, leading to kidney dysfunction, heart rhythm disturbances, seizures, and sometimes death.

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

• Infection of deep skin layers that spreads rapidly, causing damage to skin and tissue, 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, tell your doctor, pharmacist or nurse. Adverse reactions can also 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, PL-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 this medicine.

5. How to store Azacitidine Onko

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.
The expiry date refers to the last day of the stated month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Onko. They are also
responsible for the preparation of Azacitidine Onko and the proper disposal of any unused
remnants.
Unopened vials – no special storage instructions required.
For immediate use
After reconstitution, the suspension should be administered within 45 minutes.
For later use
If the Azacitidine Onko suspension was prepared using unrefrigerated water for injections, the
reconstituted suspension must be placed immediately in a refrigerator (2 °C – 8 °C) after
preparation and stored in the refrigerator for no more than 8 hours.
If the Azacitidine Onko suspension was prepared using refrigerated (2 °C – 8 °C) water for
injections, the reconstituted suspension must be placed immediately in a refrigerator (2 °C – 8 °C)
after preparation and stored in the refrigerator for no more than 22 hours.
Allow the suspension to reach room temperature (20 ºC – 25 ºC) for up to 30 minutes before
administration.
If large particles are present in the suspension, discard it.

6. Contents of the pack and other information

What Azacitidine Onko contains

• The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution with 4 mL of water for injections, the resulting suspension contains 25 mg/mL of azacitidine.
• The other ingredient is mannitol.

What Azacitidine Onko looks like and contents of the pack
Azacitidine Onko is a white powder for the preparation of a suspension for injection and is supplied in a glass vial containing 100 mg of azacitidine. Each pack contains one vial of Azacitidine Onko.

Marketing Authorisation Holder
Onko Pharmaceuticals Bulgaria Ltd EOOD
Gramada 18 Str.
1680 Sofia
Bulgaria

Manufacturer
Wessling GmbH
Johann-Krane-Weg 42
48149 Muenster
Germany

This medicinal product is authorised in the following European Economic Area countries under the following names:
Germany Azacitidin Onko 25 mg/ml Powder for the preparation of a suspension for injection
Poland Azacitidine Onko, 25 mg/mL, powder for the preparation of a suspension for injection
Romania Azacitidină Onko 25 mg/ml powder for injectable suspension

Information intended exclusively for healthcare professionals:

Safe handling recommendations
Azacitidine Onko is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution must be exercised when preparing and handling azacitidine suspension. Appropriate procedures for handling and disposal of antineoplastic medicinal products should be followed.

In case of skin contact with prepared azacitidine, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.

Pharmaceutical incompatibilities
Do not mix the medicinal product with other medicinal products except those mentioned below (see "Preparation procedure").

Preparation procedure
Azacitidine Onko should be prepared using water for injections. The shelf life of the prepared medicinal product can be extended by using cooled (2°C – 8°C) water for injections. Details regarding storage of the prepared product are provided below.

The following items should be prepared:
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).

Draw 4 mL of water for injections into a syringe. Ensure that all air has been expelled from the syringe.

Insert the needle of the syringe containing 4 mL of water for injections through the rubber stopper of the azacitidine vial and slowly inject the water into the vial.

After removing the syringe and needle, shake the vial vigorously until a homogeneous, cloudy suspension is obtained. After preparation, each mL of suspension contains 25 mg of azacitidine (100 mg/4 mL). The prepared product is a homogeneous, cloudy suspension without agglomerates. Discard the suspension if it contains large particles or agglomerates. Do not filter the suspension after preparation, as this may result in removal of the active substance. Note that some adapters, spikes, and closed-system devices contain filters. Therefore, such components should not be used for administration of the medicinal product after preparation.

Clean the rubber stopper and insert a new needle attached to a syringe into the vial. Then 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 medicinal product for the appropriate dose. Ensure that all air has been expelled from the syringe. Then remove the needle and syringe from the vial and discard the needle.

Firmly attach a fresh subcutaneous injection needle (recommended 25 G) to the syringe. Do not flush the needle before injection to reduce the frequency of local reactions at the injection site.

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 retention in the vial and needle, complete recovery of the suspension from the vial may not be possible.

The contents of the syringe containing the dose must be resuspended immediately before administration. The temperature of the suspension at the time of injection should be approximately 20°C – 25°C. To resuspend, vigorously roll the syringe between the palms until a homogeneous, cloudy suspension is obtained. Discard the suspension if it contains large particles or agglomerates.

Storage after preparation
For immediate use
The Azacitidine Onko suspension may be prepared immediately before use, and the prepared suspension should be administered within 45 minutes. If more than 45 minutes have elapsed, the prepared suspension should be properly discarded and a new dose prepared.

For later use
If the product was prepared using uncooled water for injections, the prepared suspension should be placed immediately in a refrigerator (2°C – 8°C) after preparation and stored in the refrigerator for no more than 8 hours. If more than 8 hours have elapsed during refrigerated storage, the suspension should be properly discarded and a new dose prepared.

If the product was prepared using cooled (2°C – 8°C) water for injections, the prepared suspension should be placed immediately in a refrigerator (2°C – 8°C) after preparation and stored in the refrigerator for no more than 22 hours. If more than 22 hours have elapsed during refrigerated storage, the suspension should be properly discarded and a new dose prepared.

For up to 30 minutes prior to administration, allow the syringe filled with the prepared suspension to reach a temperature of approximately 20°C – 25°C. If more than 30 minutes have 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 = dose (mg/m²) × BSA (m²)
The table below is only an example of how individual azacitidine doses are calculated based on an average BSA of 1.8 m².

Method of administration
Do not filter the suspension after preparation.
The prepared Azacitidine Onko product should be administered subcutaneously (inserting the needle at an angle of 45–90°) using a 25 G needle into the arm, thigh, or abdomen.
Doses exceeding 4 mL should be administered at two different sites.
Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous injection site, and injections should never be given into irritated, bruised, red, or hardened areas.
Any unused portions of the medicinal product or waste materials should be disposed of in accordance with local regulations.