Azacitidine sandoz

Package leaflet: Information for the patient

Azacitidine Sandoz, 100 mg, powder for solution for injection
Azacitidinum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents:

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

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

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

What Azacitidine Sandoz is used for
Azacitidine Sandoz is used in adults 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 are diseases that affect the bone marrow and may cause difficulties in the normal production of blood cells.

How Azacitidine Sandoz works
Azacitidine Sandoz works by preventing the growth of cancer cells. Azacitidine is incorporated into the genetic material of cells (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]). Its mechanism of action is believed to involve altering the way genes are activated and deactivated within the cell, as well as interfering with the synthesis of RNA and DNA. These actions are thought to correct the impaired maturation and growth of blood cells in the bone marrow seen in myelodysplastic disorders, and to kill cancer cells in leukaemia.

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

2. Important information before using Azacitidine Sandoz

When not to use Azacitidine Sandoz

• 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 Sandoz, 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 Sandoz may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Blood tests will be performed before starting treatment with Azacitidine Sandoz and at the beginning of each treatment period (called a cycle). These tests are to check whether the patient has sufficient blood cells and whether the liver and kidneys are functioning properly.
Children and adolescents
Use of Azacitidine Sandoz is not recommended in children and adolescents under 18 years of age.
Azacitidine Sandoz and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take. Azacitidine Sandoz may affect the way some other medicines work. Likewise, some other medicines may affect the way Azacitidine Sandoz works.
Pregnancy, breastfeeding, and fertility
Pregnancy
Do not use Azacitidine Sandoz 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 Sandoz and for 6 months after stopping treatment with Azacitidine Sandoz. If the patient becomes pregnant during treatment, she must consult her doctor immediately.
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.
Breastfeeding
Do not breastfeed during treatment with Azacitidine Sandoz. It is unknown whether this medicine passes into breast milk.
Fertility
Men should not father a child while receiving treatment with Azacitidine Sandoz. Men must use an effective method of contraception during treatment with Azacitidine Sandoz 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 using machines
If adverse effects such as fatigue occur, the patient should not drive, operate tools, or use machinery.

3. How to use Azacitidine Sandoz

Before administering Azacitidine Sandoz 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 treating doctor will determine the dose based on the patient's general condition, height, and body weight. The doctor will monitor progress and may adjust the dose if necessary.
• Azacitidine Sandoz is administered daily for one week, followed by a 3-week break. This treatment cycle is repeated every 4 weeks. Typically, a patient receives at least 6 treatment cycles.

This medicine is given as a subcutaneous injection by a doctor or nurse. 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 should immediately inform the doctor if the patient experiences any of the
following adverse reactions:

• Drowsiness, tremor, jaundice, abdominal distension 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 caused by a low number of white blood cells, which may 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 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. This may be due to an allergic reaction (hypersensitivity).

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

• Decreased number of red blood cells (anaemia). The patient may feel tired and look 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.
• 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.
• Weight loss.
• Low blood potassium levels.

Common adverse reactions (may occur in less than 1 in 10 people):

• Bleeding inside the skull.
• Blood infection caused by bacteria (sepsis). This may be due to a low number of white blood cells.
• 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, gastrointestinal bleeding, bleeding from the anal area due to haemorrhoids (haemorrhoidal bleeding), eye bleeding, bleeding under or into the skin (haematomas).
• Blood in the urine.
• Ulceration of the mouth or tongue.
• 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).
• Infection of the nose and throat 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, lethargy.
• Bleeding at the catheter insertion site.
• Intestinal disease 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 occur in less than 1 in 100 people):

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

Rare adverse reactions (may occur in less than 1 in 1000 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 breakdown products of dying tumour cells and may include: changes in blood chemistry; high levels of potassium, phosphate, uric acid, and low calcium levels, leading consequently to kidney dysfunction, irregular heart rhythm, seizures, and sometimes death.

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

• Infection of deep skin layers that spreads rapidly, causing skin and tissue damage 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 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.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Azacitidine Sandoz

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 on the carton after EXP. The expiry date refers to the last day of the stated month.
Your doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Sandoz.
They are also responsible for the preparation of Azacitidine Sandoz and the proper disposal of any unused remnants.
Unopened vials:
No special storage instructions are required for this medicine.
For immediate use
After reconstitution, the suspension should be administered within 60 minutes.
For later use
If the Azacitidine Sandoz suspension was prepared using unrefrigerated water for injections, the prepared suspension must be immediately placed in a refrigerator (2°C − 8°C) after preparation and stored in the refrigerator for no longer than 24 hours.
If the Azacitidine Sandoz suspension was prepared using refrigerated (2°C − 8°C) water for injections, the prepared suspension must be immediately placed in a refrigerator (2°C − 8°C) after preparation and stored in the refrigerator for no longer than 36 hours in the vial and 30 hours in a syringe at 2°C − 8°C.
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.

6. Contents of the pack and other information

What Azacitidine Sandoz contains
The active substance is azacitidine.

• 1 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.

What Azacitidine Sandoz looks like and contents of the pack
Azacitidine Sandoz is a white powder for suspension for injection. The powder is contained in a glass vial with a rubber stopper and an aluminium seal with a plastic cap, containing 100 mg of azacitidine. The vial is packed in a cardboard box.
Pack size: 1 vial.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Sandoz GmbH
Biochemiestrasse 10
6250 Kundl
Austria

Manufacturers/Importers
Pharmadox Healthcare Ltd
KW20A Kordin Industrial Park
Paola, PLA 3000
Malta
Lek Pharmaceuticals d.d.
Verovskova ulica 57
1526 Ljubljana
Slovenia
Salutas Pharma GmbH
Otto-von-Guericke-Allee 1
39179 Barleben
Germany

For further information about this medicinal product, please contact:
Sandoz Polska Sp. z o.o.
ul. Domaniewska 50 C
02-672 Warszawa
tel. 22 209 70 00

This medicinal product is authorised for marketing in the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:
Netherlands Azacitidine Sandoz 25 mg/ml, poeder voor suspensie voor injectie
Austria Azacitidin Sandoz 25 mg/ml – Pulver zur Herstellung einer Injektionssuspension
Belgium Azacitidin Sandoz 25 mg/ml poeder voor suspensie voor injectie
Bulgaria Азацитидин Сандоз 25 mg/ml прах за инжекционна суспензия
Czech Republic Azacitidin Sandoz
Germany Azacitidin HEXAL 25 mg/ml Pulver zur Herstellung einer Injektionssuspension
Denmark Azacitidine Sandoz
Greece Azacitidine/Sandoz 25 mg/ml κόνις για ενέσιμο εναιώρημα
Spain Azacitidina Sandoz 25mg/ml polvo para solucion inyectable EFG
Finland Azacitidine Sandoz
France AZACITIDINE SANDOZ 25 mg/ml poudre pour suspension injectable
Croatia Azacitidin Sandoz 25 mg/ml prašak za suspenziju za injekciju
Hungary Azacitidin Sandoz 25 mg/ml por szuszpenziós injekcióhoz
Ireland Azacitidine Rowex 25 mg/ml Powder for suspension for injection
Iceland Azacitidine Sandoz
Italy Azacitidina Sandoz
Norway Azacitidine Sandoz
Poland Azacitidine Sandoz
Portugal Azacitidina Sandoz
Romania Azacitidină Sandoz 25 mg/ml pulbere pentru suspensie injectabilă
Sweden Azacitidine Sandoz
Slovenia Azacitidin Sandoz 25 mg/ml prašek za suspenzijo za injiciranje
Slovakia Azacitidine Sandoz 25 mg/ml prášok na injekčnú suspenziu
Northern Ireland Azacitidine Sandoz 25 mg/ml powder for suspension for injection

Information intended exclusively for medical professionals:

Safe handling recommendations
Azacitidine Sandoz 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 cytotoxic anticancer medicinal products should be followed.

In case of contact of prepared azacitidine with the skin, wash immediately and thoroughly 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 Sandoz 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 on storage of the prepared product are provided below.

1. Gather the following supplies: vial(s) of azacitidine, vial(s) of water for injections, non-sterile surgical gloves, alcohol-impregnated swabs, 5 ml syringe(s) with needle(s).
2. Draw up 4 ml of water for injections into a syringe and 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 inject the water into the vial.
4. 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 large particles or agglomerates are present. Do not filter the suspension after preparation, as this may result in loss of active substance. Note that some adapters, spikes, and closed system devices contain filters. Therefore, such components should not be used when administering the medicinal product after reconstitution.
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 for the prescribed 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. Attach a fresh subcutaneous injection needle (25 G recommended) firmly 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 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 filled syringe containing the prepared suspension may be left at room temperature (approximately 20°C–25°C) for up to 30 minutes before administration. If more than 30 minutes elapses, the suspension should be properly discarded and a new dose prepared. To resuspend, roll the syringe vigorously between the palms until a homogeneous, cloudy suspension is obtained. Discard the suspension if large particles or agglomerates are present.

Storage after preparation
For Azacitidine Sandoz prepared with unrefrigerated water for injections, the chemical and physical in-use stability of the prepared medicinal product has been demonstrated for 60 minutes at 25°C and for 24 hours at 2°C–8°C, when stored in the vial or in the syringe.
The shelf life of the prepared medicinal product can be extended by using cooled (2°C–8°C) water for injections. For Azacitidine Sandoz prepared with cooled (2°C–8°C) water for injections, the chemical and physical in-use stability of the prepared medicinal product has been demonstrated for 36 hours when stored in the vial and for 30 hours when stored in the syringe, both at 2°C–8°C.
From a microbiological standpoint, the reconstituted product should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user. The solution should not be stored for longer than 24 hours at 2°C–8°C.

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 to calculate individual azacitidine doses based on an average BSA of 1.8 m².

Method of administration
Do not filter the suspension after preparation.
The prepared Azacitidine Sandoz product should be administered subcutaneously (insert 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 injected 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, erythematous, or hardened areas.
Any unused product or waste material should be disposed of in accordance with local regulations.