Azacitidine stada

Package leaflet: Information for the user

Azacitidine STADA, 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.

Contents of the leaflet:

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

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

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

What Azacitidine STADA is used for
Azacitidine STADA is used in adult patients who are not eligible for haematopoietic 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 the normal production of blood cells.

How Azacitidine STADA works
Azacitidine STADA 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 altering the way genes are activated and deactivated, as well as interfering with the production of RNA and DNA. These actions are thought to correct the impaired 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 STADA works or why this medicine has been prescribed for you, please ask your doctor or nurse.

2. Important information before using Azacitidine STADA

When not to use Azacitidine STADA

• 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 STADA, 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 STADA may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Before starting treatment with Azacitidine STADA 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 STADA is not recommended for use in children and adolescents under 18 years of age.
Azacitidine STADA and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take. Azacitidine STADA may affect the way some other medicines work. Likewise, some other medicines may affect the way Azacitidine STADA works.
Pregnancy, breastfeeding, and fertility
Pregnancy
Do not use Azacitidine STADA 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 STADA and for 6 months after stopping treatment with this medicine.
Inform your doctor immediately if pregnancy occurs during treatment with Azacitidine STADA.
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.
Breastfeeding
Do not breastfeed while taking Azacitidine STADA. It is not known whether this medicine passes into human milk.
Effect on fertility
Men should not father a child during treatment with Azacitidine STADA.
Men should use an effective method of contraception during treatment with Azacitidine STADA and for 3 months after stopping treatment with Azacitidine STADA.
The patient should consult with their doctor if they wish to store sperm before starting this treatment.
Driving and operating machinery
If adverse effects such as fatigue occur, do not drive, use tools, or operate machinery.

3. How to use Azacitidine STADA

Before administering Azacitidine STADA to the patient, the doctor will give an additional 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 STADA 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 STADA 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 STADA is given as a subcutaneous injection by a doctor or nurse.
It may be administered subcutaneously in the thigh, abdomen, or arm.
If you have any further questions regarding the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

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

• Drowsiness, tremors, jaundice, abdominal bloating and easy bruising. These may be symptoms of liver failure, which can 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, which can be life-threatening.
• Fever. This may be due to infection caused by a low white blood cell count, which can be life-threatening.
• Chest pain or shortness of breath, possibly accompanied by fever. This may be due to a lung infection called "pneumonia", which can 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. These 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 (anaemia). The patient may feel tired and look pale.
• Low white blood cell count. 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.
• 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.
• Pain in nose and throat.
• Dizziness.
• Headache.
• Sleep problems (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low blood potassium levels.

Common side effects (may affect up to 1 in 10 people)

• Bleeding inside the skull.
• Blood infection caused by bacteria (sepsis). This may be due to low levels of white blood cells in the blood.
• Bone marrow failure. This may lead to low numbers of red and white blood cells and platelets.
• A type of anaemia in which the numbers of red blood cells, white blood cells and platelets are reduced.
• Urinary tract infection.
• Viral infection causing cold sores.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anal area due to haemorrhoids (haemorrhoidal bleeding), bleeding in the eye, bleeding under or into the skin (haematomas).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site. These include swelling, hard lumps, bruising, bleeding into the skin (haematomas), rash, itching and skin colour changes.
• Redness of the skin.
• Skin infection (cellulitis).
• Infection of nose and throat or sore throat.
• Nasal pain or runny nose, or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Pain in throat and larynx.
• Indigestion.
• Drowsiness.
• General malaise.
• Anxiety.
• Disorientation.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside of 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 rash on the skin (urticaria).
• 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-coloured, raised, painful skin patches, with fever.
• Painful skin ulceration (pyoderma gangrenosum).
• 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 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 calcium levels, 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, spreading rapidly and causing damage to skin and tissue, which may be life-threatening (necrotizing 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 side effects
If any side effects occur, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. Side effects 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
Side effects can also be reported to the marketing authorisation holder.
Reporting side effects helps to provide more information on the safety of this medicine.

5. How to store Azacitidine STADA

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial and carton.
The expiry date refers to the last day of the stated month.
The doctor, pharmacist, or nurse is responsible for storing Azacitidine STADA,
as well as for the preparation of the medicine and the proper disposal of any unused portions.
Unopened vials – no special storage instructions required.
For immediate use
After reconstitution, the suspension should be administered within 60 minutes.
For later use
If the Azacitidine STADA suspension was prepared using unrefrigerated water for injections,
the prepared suspension must be placed immediately in a refrigerator (2°C–8°C) after preparation
and stored refrigerated for no more than 24 hours.
If the Azacitidine STADA suspension was 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 refrigerated for no more than 36 hours if stored in the vial, or 30 hours if stored in a syringe.
Allow the suspension to reach room temperature (20°C–25°C) for a maximum of 30 minutes before administration.
If large particles are present in the suspension, it should be discarded.

6. Contents of the pack and other information

What Azacitidine STADA contains
The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution by adding 4 mL of water for injections, the resulting suspension contains 25 mg/mL of azacitidine.
Excipient: mannitol.

What Azacitidine STADA looks like and contents of the pack
Azacitidine STADA is a white powder for suspension for injection, supplied in a colourless, transparent Type I glass vial with a capacity of 30 mL, containing 100 mg of azacitidine. Vials may be placed, if necessary, into protective polypropylene vials or directly packed into clean cardboard boxes.
Each pack contains one vial of Azacitidine STADA.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
STADA Arzneimittel AG
Stadatrasse 2-18
61118 Bad Vilbel
Germany

Manufacturer/Importer:
Pharmadox Healthcare Ltd
KW20A Kordin Industrial Park
Paola, PLA3000
Malta
STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

This medicinal product is authorised in the European Economic Area countries under the following names:
Czech Republic: AZACITIDIN STADA Arzneimittel AG
Hungary: Azacitidine Stada Arzeimittel 25 mg/mL por szuszpenziós injekcióhoz
Netherlands: Azacitidine STADA Arzneimittel 25 mg/mL, poeder voor suspensie voor injectie
Poland: Azacitidine STADA
Romania: AZACITIDINA STADA 25mg/mL pulbere pentru suspensie injectabilă
Slovakia: Azacitidine STADA Arzneimittel
Bulgaria: Azacitidine STADA Arzneimittel 25 mg/mL powder for suspension for injection
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Information intended exclusively for medical professionals:

Safe handling recommendations
Azacitidine STADA is a cytotoxic medicinal product, and as with other potentially toxic compounds, caution should be exercised when preparing and handling azacitidine suspension. Appropriate procedures for handling and disposal of antineoplastic medicinal products should be followed.
In case of contact of prepared azacitidine with skin, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.

Pharmaceutical incompatibilities
The medicinal product must not be mixed with other medicinal products except as specified below (see "Preparation procedure").

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

1. Gather the following items: vial(s) of azacitidine, vial(s) of water for injections, non-sterile surgical gloves, alcohol swabs, 5 mL syringe(s) with needle(s).
2. Draw up 4 mL of water for injections into a syringe. Ensure that all air has been expelled 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 slowly inject the water into the vial.
4. After removing the syringe and needle, shake the vial vigorously 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 free from agglomerates. Discard the suspension if it contains large particles or agglomerates. Do not filter the suspension after preparation, as this may lead to removal of the active substance. Note that some adapters, spikes, and closed systems contain filters. Therefore, such components should not be used for administration of the medicinal product after preparation.
5. Clean the rubber stopper and insert a new needle with syringe into the vial. 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.
6. Firmly attach a fresh subcutaneous injection needle (25 G recommended) to the syringe. Do not flush the needle prior to 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 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, it may not be possible to withdraw the entire suspension from the vial.
8. The suspension in the syringe must be resuspended immediately before administration. The injection temperature should be approximately 20°C–25°C. To resuspend, vigorously roll the syringe between the palms 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 STADA suspension may be prepared immediately before use, and the prepared suspension should be administered within 60 minutes. If more than 60 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 longer than 24 hours. If more than 24 hours have elapsed, 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 longer than 36 hours (in vial) or 30 hours (in syringe).
If storage time in the refrigerator exceeds 36 hours (when stored in vial) or 30 hours (when stored in syringe), the suspension should be properly discarded and a new dose prepared.
Allow the syringe filled with the prepared suspension to reach a temperature of approximately 20°C–25°C for up to 30 minutes before administration. 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 merely an example of how individual azacitidine doses are calculated based on an average BSA of 1.8 m².

Method of administration
The suspension should not be filtered after preparation.
The prepared Azacitidine STADA 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 injection 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 product or waste material should be disposed of in accordance with local regulations.