Azacitidine zentiva

Package leaflet: Information for the user

Azacitidine Zentiva, 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, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents

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

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

What Azacitidine Zentiva is
Azacitidine Zentiva is an anticancer medicine belonging to a group of medicines called
"antimetabolites". Azacitidine Zentiva contains the active substance azacitidine.

What Azacitidine Zentiva is used for
Azacitidine Zentiva is used in adult patients who cannot receive a stem cell transplant, for the treatment of:

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

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

How Azacitidine Zentiva works
Azacitidine Zentiva 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 altering the way genes are switched on and off, as well as interfering with the production of RNA and DNA. These actions are thought to correct the abnormal maturation and growth of young blood cells in the bone marrow that lead to myelodysplastic disorders, and to kill cancer cells in leukaemia.

If you have any questions about how Azacitidine Zentiva works or why this medicine has been prescribed for you, please consult your doctor or nurse.

2. Important information before using Azacitidine Zentiva

When not to give Azacitidine Zentiva

• 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 Zentiva, discuss with your doctor, pharmacist,
or nurse if the patient:

• has low platelet counts, red blood cells, or white blood cells;
• has kidney disease;
• has liver disease;
• has previously had heart disease, myocardial infarction, or any lung disease.

Azacitidine Zentiva may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Blood tests will be performed before starting treatment with Azacitidine Zentiva and at the beginning of each treatment period (called a cycle). These tests are intended to check whether the patient has an adequate number of blood cells and whether the liver and kidneys are functioning properly.
Children and adolescents
Use of Azacitidine Zentiva is not recommended in children and adolescents under 18 years of age.
Azacitidine Zentiva and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking or has recently taken, and any medicines the patient plans to take. Azacitidine may affect the way some other medicines work. Likewise, some other medicines may affect how azacitidine works.
Pregnancy, breastfeeding, and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a baby, she should consult her doctor or pharmacist before using this medicine.
Pregnancy
Do not use Azacitidine Zentiva during pregnancy, as it may be harmful to the unborn child.
Women of childbearing potential must use an effective method of contraception during treatment with Azacitidine Zentiva and for 6 months after stopping treatment with this medicine. If the patient becomes pregnant during treatment, she should consult her doctor immediately.
Breastfeeding
Do not breastfeed while taking Azacitidine Zentiva. It is unknown whether this medicine passes into human milk.
Fertility
Men should not father a child while receiving treatment with Azacitidine Zentiva.
Men should use an effective method of contraception during treatment with Azacitidine Zentiva and for 3 months after stopping treatment with this medicine. Patients should consult their doctor before starting treatment if they wish to preserve sperm.
Driving and operating machinery
If undesirable effects such as fatigue occur, the patient should not drive, use tools, or operate machinery.

3. How to use Azacitidine Zentiva

Before administering Azacitidine Zentiva to the patient, the doctor will give another medicine to help prevent nausea and vomiting at the beginning of each treatment cycle.

• The recommended dose is 75 mg per m² of body surface area. Your doctor will determine the appropriate dose based on your overall condition, height, and body weight. Your doctor will monitor your progress and may adjust the dose if necessary.
• Azacitidine Zentiva is administered daily for one week, followed by a 3-week break. This treatment cycle is repeated every 4 weeks. Patients usually receive at least 6 treatment cycles.

This medicine is given by a doctor or nurse as a subcutaneous injection. It may be injected under the skin of the thigh, abdomen, or upper arm.
If you have any further questions about the use of this medicine, please consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
You must inform the doctor immediately if the patient experiences any of the following adverse reactions:

• Drowsiness, tremor, jaundice, abdominal bloating and easy bruising. These may be symptoms of liver failure and 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 feelings of disorientation, anxiety or fatigue. These may be symptoms of kidney failure and may be life-threatening.
• Fever. This may be due to infection resulting from 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" 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 due to 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 appear 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.
• Lung inflammation (pneumonitis).
• 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.
• Pain in nose and throat.
• Dizziness.
• Headache.
• Sleep problems (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness.
• Weight loss.
• Low blood potassium levels.

Common adverse reactions (may affect less than 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 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.
• Bleeding gums, stomach or intestinal bleeding, bleeding from the anal area due to haemorrhoids (haemorrhoidal haemorrhage), eye bleeding, bleeding under or into the skin (haematomas).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site, including swelling, hard lumps, bruising, bleeding into the skin (haematomas), rash, itching and skin discoloration.
• 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.
• Pain in the throat and larynx.
• Indigestion.
• Apathy.
• General malaise.
• Anxiety.
• Disorientation.
• Excessive 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, somnolence.
• Bleeding at the catheter insertion site.
• A bowel condition that 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 affect less than 1 in 100 people):

• Allergic reaction (hypersensitivity).
• Tremor.
• Liver failure.
• Large, raised, painful plum-coloured skin lesions with fever.
• Inflammation of the membrane surrounding the heart (pericarditis).

Rare adverse reactions (may affect less than 1 in 1000 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 breakdown 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, heart rhythm disturbances, seizures, and sometimes death.

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

• Infection of the deep layers of the skin that spreads rapidly, causing damage to the 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 the 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 be reported directly to the Department of Monitoring Adverse Drug Reactions of the 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
Adverse reactions can also be reported to the marketing authorisation holder or its representative.
Reporting adverse reactions helps provide more information on the safety of the medicine.

5. How to store Azacitidine Zentiva

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton or vial label following EXP. The expiry date refers to the last day of the stated month.
Your doctor, pharmacist, or nurse is responsible for storing Azacitidine Zentiva.
They are also responsible for preparing Azacitidine Zentiva and properly disposing of any unused portions.
Unopened vials of this medicine – no special storage instructions are required.
For immediate use
After reconstitution, the suspension should be administered within 60 minutes.
For later use
If the Azacitidine Zentiva suspension has been prepared using unrefrigerated water for injections, the prepared suspension must be placed immediately in a refrigerator (2°C - 8°C) after preparation and stored in the refrigerator for no longer than 8 hours.
If the Azacitidine Zentiva suspension has been prepared using refrigerated (2°C - 8°C) water for injections, the prepared suspension must be placed immediately in a refrigerator (2°C - 8°C) after preparation and stored in the refrigerator for no longer than 22 hours.
Before administration, allow the suspension to reach room temperature (20°C - 25°C) for up to a maximum of 30 minutes.
Do not use the medicine if large particles are visible in the suspension.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

What Azacitidine Zentiva contains
The active substance is azacitidine.
One vial contains 100 mg of azacitidine. After reconstitution with 4 ml of water for injections,
the suspension contains 25 mg/ml of azacitidine.
The other ingredient is: mannitol (E 421).

What Azacitidine Zentiva looks like and contents of the pack
Azacitidine Zentiva is a white powder for suspension for injection, supplied in a vial made of colourless type I glass, closed with a dark grey chlorobutyl rubber stopper with a single slit or a dark grey bromobutyl rubber stopper for lyophilisation with a single slit, and an aluminium seal with a flip-off cap, containing 100 mg of azacitidine.
Each pack of Azacitidine Zentiva contains 1 vial.

Marketing Authorisation Holder
Zentiva k.s.
U kabelovny 130
Dolni Měcholupy
102 37 Prague 10
Czech Republic

Importer
APIS Labor GmbH
Resslstraße 9
9065 Ebenthal
Austria
LABORATORI FUNDACIÓ DAU
C/ De la letra C
12-14, Polígono Industrial de la Zona Franca
08040 Barcelona
Spain

This medicinal product is authorised in the European Economic Area countries under the following names:
Netherlands, Poland, Czech Republic, Slovakia: Azacitidine Zentiva
Portugal: Azacitidina Zentiva

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder in Poland:
Zentiva Polska Sp. z o.o.
ul. Bonifraterska 17
00-203 Warsaw
tel: +48 22 375 92 00

Information intended exclusively for healthcare professionals:

Safe handling recommendations
Azacitidine 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.
If the prepared Azacitidine Zentiva medicinal product comes into contact with the skin, wash thoroughly immediately with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned below (see "Preparation procedure").

Preparation procedure
The medicinal product Azacitidine Zentiva 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 above.

1. Gather the following equipment: Vial(s) of Azacitidine Zentiva medicinal product; vial(s) of water for injections; sterile surgical gloves; alcohol-impregnated swabs; 5 ml syringe(s) with needle(s).

2. Draw 4 ml of water for injections into the syringe, ensuring that no air bubbles are present in the syringe.

3. Insert the needle of the syringe containing 4 ml of water for injections through the rubber stopper of the Azacitidine Zentiva vial and inject the water into the vial.

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

5. Clean the rubber stopper and insert a new syringe with a needle into the vial. Invert the vial, ensuring that the needle tip remains 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.

6. 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.

7. If more than one vial is required, repeat all the above steps for suspension preparation. For doses requiring more than one vial, the dose should be evenly divided.
   e.g., a dose of 150 mg = 6 ml, two syringes with 3 ml each. Due to retention in the vial and needle, complete withdrawal of the suspension from the vial may not be achievable.

8. The suspension in the syringe must be resuspended immediately before administration. The filled syringe should be allowed to reach approximately 20°C–25°C for up to 30 minutes before administration. If more than 30 minutes elapses, the suspension must 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 suspension if large particles or agglomerates are present.

Storage of the prepared product
For immediate use
The medicinal product Azacitidine Zentiva may be prepared immediately before administration and administered within 60 minutes. If more than 60 minutes elapses, the prepared suspension must be properly discarded and a new dose prepared.

For later use
If the product was prepared using uncooled water for injections, the prepared suspension must be placed in a refrigerator (2°C–8°C) immediately after preparation and stored in the refrigerator for no longer than 8 hours. If more than 8 hours have elapsed, the suspension must 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 must be placed in a refrigerator (2°C–8°C) immediately after preparation and stored for no longer than 22 hours. If more than 22 hours have elapsed, the suspension must be properly discarded and a new dose prepared.
Allow the syringe filled with the prepared suspension to reach approximately 20°C–25°C for up to 30 minutes before administration. If more than 30 minutes elapses, the suspension must 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 an example of how to calculate an individual azacitidine dose based on a body surface area of 1.8 m².

| Dose mg/m² BSA | Total dose based on BSA 1.8 m² (mg) | Number of vials required | Total volume of prepared suspension required (ml) |
|----------------|--------------------------------------|--------------------------|---------------------------------------------------|
| 75 mg/m² BSA (100%) | 135 mg | 2 vials | 5.4 ml |
| 37.5 mg/m² BSA (50%) | 67.5 mg | 1 vial | 2.7 ml |
| 25 mg/m² BSA (33%) | 45 mg | 1 vial | 1.8 ml |

Method of administration
Do not filter the suspension after reconstitution.
The prepared Azacitidine Zentiva product should be administered subcutaneously (insert the needle at a 45–90º angle) using a 25G 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 previous injection sites and never into irritated, bruised, red, or hardened areas.

Any unused medicinal product and waste material must be disposed of in accordance with local regulations.