Azacitidine Onko

Leaflet accompanying the packaging: information for the user

Azacitidine Onko, 25 mg/mL, powder for suspension for injection

Azacitidine

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

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor, pharmacist, or nurse.
• 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.

Table of contents of the leaflet:

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

What is Azacitidine Onko

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

What is Azacitidine Onko used for

Azacitidine Onko is used in adults who are not eligible for stem cell transplantation to treat:

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

These diseases affect the bone marrow and can cause problems with the production of blood cells.

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 that its action involves changing the way genes are activated and deactivated, as well as disrupting the production of RNA and DNA. It is believed that these actions repair disorders related to the maturation and growth of young blood cells in the bone marrow that cause myelodysplastic disorders, and that they kill cancer cells in leukemia. If you have any questions about how Azacitidine Onko works or why it has been prescribed, 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 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 it 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 had heart disease, heart attack, or any lung disease in the past.

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 if you have a sufficient number of blood cells and if your liver and kidneys are working properly.

Children and adolescents

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

Azacitidine Onko and other medicines

Tell your doctor, pharmacist, or nurse about all medicines you are taking or have recently taken, as well as any medicines you plan to take. Azacitidine Onko may affect the way some other medicines work. Also, some other medicines may affect the way Azacitidine Onko works.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child, consult your doctor or pharmacist before using this medicine.
Pregnancy
Azacitidine Onko should not be used during pregnancy, as it may harm the baby. Women who can become pregnant should use effective contraception during treatment with Azacitidine Onko and for at least 6 months after the end of treatment with Azacitidine Onko. If you become pregnant during treatment with Azacitidine Onko, tell your doctor immediately.
Breastfeeding
Azacitidine Onko should not be used during breastfeeding. It is not known whether this medicine passes into human milk.
Fertility
Men should not father a child during treatment with Azacitidine Onko. Men should use effective contraception during treatment with this medicine and for 3 months after the end of treatment with this medicine.
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 Onko

Before administering Azacitidine Onko to the patient, the doctor will give 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. The doctor will choose the correct dose of Azacitidine Onko for the patient, depending on the patient's overall condition, height, and weight. The doctor will check the progress of the treatment and, if necessary, may change the dose.
• Azacitidine Onko is given daily for one week, followed by a rest period of 3 weeks. This "treatment cycle" is repeated every 4 weeks. The patient usually receives at least 6 cycles of treatment.

Azacitidine Onko is given as a subcutaneous injection by a doctor or nurse. It can be injected under the skin of the thigh, abdomen, or arm. If you have any further doubts about using this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Azacitidine Onko 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, which can be life-threatening.
• Swelling of the legs and feet, back pain, decreased urine output, increased thirst, rapid heartbeat, dizziness, and nausea, vomiting, or loss of appetite, as well as a feeling of disorientation, anxiety, or fatigue. These may be symptoms of kidney failure, which 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 it 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 symptoms of a low platelet count.
• Difficulty breathing, swelling of the lips, itching, or rash. The cause may be 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 susceptible to infections.
• Low platelet count (thrombocytopenia). You are more susceptible 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.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• 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). The cause may be a low white blood cell count in the blood.
• Bone marrow failure. This can 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 low.
• 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, or bleeding under the skin or in the skin (hematomas).
• Blood in the urine.
• Ulcers in the mouth or tongue.
• Skin changes at the injection site. These include swelling, hard lumps, bruising, bleeding in the skin (hematomas), rash, itching, and skin discoloration.
• 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.
• Indifference.
• Disorientation.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating 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 injection 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, plum-colored, raised, painful spots on the skin, with fever.
• Painful ulcers on the skin (necrotizing fasciitis).
• Inflammation of the membrane 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 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 dysfunction, heart rhythm disturbances, seizures, and sometimes death.

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

• Infection of the deep layers of the skin, which can spread quickly, causing skin and tissue damage, which 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, 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. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidine Onko

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.
The expiry date refers to the last day of the month.
The doctor, pharmacist, or nurse is responsible for storing Azacitidine Onko. They are also responsible for preparing Azacitidine Onko and properly disposing of any unused remains.
Unopened vials of the medicine - no special storage precautions.
For immediate use
After preparation, the suspension should be administered within 45 minutes.
For later use
If the Azacitidine Onko suspension was prepared using uncooled water for injection, the prepared suspension should be placed in the refrigerator (2 °C – 8 °C) immediately after preparation and stored in the refrigerator for no more than 8 hours.
If the Azacitidine Onko suspension was prepared using cooled (2 °C – 8 °C) water for injection, the prepared suspension should be placed in the refrigerator (2 °C – 8 °C) immediately after preparation and stored in the refrigerator for no more than 22 hours.
Within 30 minutes before administration, allow the syringe with the prepared suspension to reach room temperature (20 ºC – 25 ºC). If more than 30 minutes have passed, the suspension should be discarded and a new dose prepared.
If the suspension contains large particles, it should be discarded.

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 preparation by adding 4 mL of water for injection, the prepared 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 suspension for injection and is supplied in a glass vial containing 100 mg of azacitidine. Each pack contains one vial of Azacitidine Onko.

Marketing authorization holder

Onko Pharmaceuticals Bulgaria Ltd EOOD
Ul. Gramada 18
1680 Sofia
Bulgaria

Manufacturer

Wessling GmbH
Johann-Krane-Weg 42
48149 Muenster
Germany

This medicine is authorized in the Member States of the European Economic Area under the following names:

Germany
Azacitidin Onko 25 mg/ml Pulver zur Herstellung einer Injektionssuspension
Poland
Azacitidine Onko, 25 mg/mL, powder for suspension for injection
Romania
Azacitidină Onko 25 mg/ml pulbere pentru suspensie injectabilă

Date of last revision of the leaflet: 15.02.2024

Information intended for healthcare professionals only:

Recommendations for safe handling
Azacitidine Onko is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling the azacitidine suspension. The procedures for the safe handling and disposal of anti-cancer medicinal products should be followed.
In the event of skin contact with the prepared azacitidine, it should be washed immediately with soap and water. In the event of contact with mucous membranes, they should be rinsed with water.
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 in water for injection. The shelf-life of the prepared medicinal product can be extended by dissolving the product with cooled (2 °C – 8 °C) water for injection. Details on the storage of the prepared product are given below.
Obtain the following products:
vial(s) of azacitidine, vial(s) of water for injection, non-sterile surgical gloves, alcohol swabs, 5 mL syringe(s) for injection with needle(s).
Draw 4 mL of water for injection into the syringe. Ensure that the air has been removed from the syringe.
Insert the needle of the syringe containing 4 mL of water for injection through the rubber stopper of the vial of azacitidine and then slowly inject the water for injection into the vial.
After removing the syringe and needle, vigorously shake the vial until a uniform, cloudy suspension is obtained. After preparation, each mL of suspension contains 25 mg of azacitidine (100 mg/4 mL).
The prepared product is a uniform, cloudy suspension without agglomerates. Discard the suspension if it contains large particles or agglomerates. Do not filter the suspension after preparation, as this may remove the active substance. Note that some adapters, needles, and closed systems contain filters. Therefore, such components should not be used to administer the medicinal product after preparation.
Clean the rubber stopper and insert a new needle with a syringe into the vial. Then, turn the vial upside down, ensuring that the needle tip is below the level of the liquid. Then, draw back the plunger to draw up the required amount of medicinal product for the correct dose. Ensure that the air has been removed from the syringe. Then, withdraw the needle with the syringe from the vial and discard the needle.
A new needle for subcutaneous injection (25 G recommended) should be firmly attached 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 needed, repeat all the above steps to prepare the suspension. For doses where more than one vial is required, divide the dose evenly, e.g., 150 mg dose = 6 mL, 2 syringes with 3 mL in each syringe.
Due to retention in the vial and needle, it may not be possible to withdraw the entire suspension from the vial.
The contents of the syringe with the dose must be resuspended immediately before administration.
The temperature of the suspension at the time of injection should be around 20 ºC – 25 ºC. To resuspend, vigorously rotate the syringe between the hands until a uniform, cloudy suspension is obtained. Discard the suspension if it contains large particles or agglomerates.
Storage of the product after preparation
For immediate use
The Azacitidine Onko suspension can be prepared immediately before use, and the prepared suspension should be administered within 45 minutes. If more than 45 minutes have passed, the prepared suspension should be discarded and a new dose prepared.
For later use
If the product was prepared using uncooled water for injection, the prepared suspension should be placed in the refrigerator (2 °C – 8 °C) immediately after preparation and stored in the refrigerator for no more than 8 hours. If more than 8 hours of refrigerated storage have passed, the suspension should be discarded and a new dose prepared.
If the product was prepared using cooled (2 °C – 8 °C) water for injection, the prepared suspension should be placed in the refrigerator (2 °C – 8 °C) immediately after preparation and stored in the refrigerator for no more than 22 hours. If more than 22 hours of refrigerated storage have passed, the suspension should be discarded and a new dose prepared.
Within 30 minutes before administration, allow the syringe with the prepared suspension to reach room temperature (20 ºC – 25 ºC). If more than 30 minutes have passed, the suspension should be discarded and a new dose prepared.
Calculating the individual dose
The total dose can be calculated based on the 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.

Method of administration
Do not filter the suspension after preparation.
The prepared Azacitidine Onko should be injected subcutaneously (insert the needle at an angle of 45 - 90°) using a 25 G needle in the arm, thigh, or abdomen.

• Doses above 4 mL should be injected at two different sites.

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