Azacitidine Sandoz

Package leaflet: Information for the user

Azacitidine Sandoz 25 mg/ml powder for injectable suspension

Equivalent medicine
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 questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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 Azacitidina Sandoz is and what it is used for

What Azacitidina Sandoz is
Azacitidina Sandoz is an anticancer agent belonging to a group of medicines called
"antimetabolites". Azacitidina Sandoz contains the active substance "azacitidine".
What Azacitidina Sandoz is used for
Azacitidina Sandoz is used in adults who are not eligible for stem cell transplantation to treat:

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

These diseases affect the bone marrow and can cause problems with the normal production of
blood cells.
How Azacitidina Sandoz works
Azacitidina Sandoz works by preventing cancer cells from growing. 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 cells switch genes on and off, and also by interfering
with the production of new RNA and DNA. These actions are thought to correct the abnormalities
related to 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 Azacitidina Sandoz works or why it has been prescribed for you,
please consult your doctor or nurse.

2. What you should know before using Azacitidine Sandoz

Do not use Azacitidine Sandoz

• if you are allergic to azacitidine or to any of the other ingredients of this medicine (listed in section 6).
• if you have advanced liver cancer.
• if you are breastfeeding.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Azacitidine Sandoz:

• if you have a reduced platelet count, red blood cells, or white blood cells
• if you have kidney disease
• if you have liver disease, or if you have previously had heart disease, a heart attack, or a history of lung disease.

Blood tests
Before starting treatment with Azacitidine Sandoz and at the beginning of each treatment cycle, blood tests will be performed to check whether you have an adequate number of blood cells and to ensure that your liver and kidneys are functioning normally.

Children and adolescents
The use of Azacitidine Sandoz is not recommended in children and adolescents under 18 years of age.

Other medicines and Azacitidine Sandoz
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Azacitidine Sandoz may affect how other medicines work. Conversely, other medicines may affect how Azacitidine Sandoz works.

Pregnancy, breastfeeding, and fertility

Pregnancy
You must not use Azacitidine Sandoz during pregnancy, as it may harm the unborn child. Use an effective method of contraception during treatment and for at least 3 months after treatment ends. Inform your doctor immediately if you become pregnant during treatment.
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Breastfeeding
You must not breastfeed while using Azacitidine Sandoz. It is not known whether this medicine passes into breast milk.

Fertility
Male patients must not father a child during treatment with Azacitidine Sandoz. Use an effective method of contraception during treatment and for at least 3 months after treatment ends.
Consult your doctor if you wish to preserve sperm before starting this treatment.

Driving and using machines
Do not drive or operate tools or machinery if you experience side effects such as fatigue.

3. How to use Azacitidina Sandoz

Before administering Azacitidina Sandoz, your doctor will give you 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. Your doctor will determine the dose of this medicine according to your general condition, height, and body weight. Your doctor will monitor your progress and, if necessary, adjust the dose.
• Azacitidina Sandoz is administered daily for one week, followed by a 3-week break. This "treatment cycle" will be repeated every 4 weeks. Generally, at least 6 treatment cycles are administered.

This medicine will be administered by a doctor or nurse via subcutaneous injection (under the skin). The injection may be given in the skin of the thigh, abdomen, or upper arm.
If you have any doubts about how to use 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.
Contact your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremor, jaundice, abdominal swelling and easy bruising. These may be symptoms of liver failure and could be life-threatening.
• Swelling of the legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness and nausea, vomiting or reduced appetite, confusion, restlessness or fatigue. These may be symptoms of kidney failure and could be life-threatening.
• Fever. This may be due to an infection caused by a low number of white blood cells, which could be life-threatening.
• Chest pain or shortness of breath, possibly accompanied by fever. This may be due to a lung infection called "pneumonia" and could be life-threatening.
• Bleeding. For example, blood in the stools due to bleeding in the stomach or intestine, or bleeding inside the head. These may be symptoms of low platelet levels in the blood.
• Difficulty breathing, swollen 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). You may feel tired and weak.
• Low white blood cell count. This may be accompanied by fever. You may also be more prone to infections.
• Low platelet count in the blood (thrombocytopenia). You may be more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue.
• Reaction at the injection site, with redness, pain or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Red or purple spots under the skin.
• Stomach pain (abdominal pain).
• Itching.
• Fever.
• Irritation of the nose and throat.
• Dizziness.
• Headache.
• Difficulty sleeping (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding inside the head.
• Blood infection due to bacteria (sepsis), which may be caused by a low number of white blood cells in the blood.
• Bone marrow failure, which may lead to a reduction in red blood cells, white blood cells and platelets.
• A type of anaemia with reduced red blood cells, white blood cells and platelets.
• Urinary tract infection.
• Viral infection causing sores (herpes).
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anus due to haemorrhoids (haemorrhagic haemorrhage), bleeding in the eye, bleeding under or into the skin (haematoma).
• Blood in the urine.
• Ulceration in the mouth or on the tongue.
• Skin changes at the injection site, including swelling, hard nodule, bruising, bleeding into the skin (haematoma), rash, itching and skin colour changes.
• Skin redness.
• Skin infection (cellulitis).
• Infection of the nose and throat, or sore throat.
• Irritated or runny nose or sinuses (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Sore throat and larynx pain.
• Indigestion.
• Lethargy.
• General feeling of being unwell.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating covering the tongue, inside of the cheeks, and sometimes the palate, gums and tonsils (fungal infection of the mouth).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension), causing dizziness upon standing or sitting up.
• Drowsiness, numbness.
• Bleeding due to catheter.
• Illness affecting the intestine that may cause fever, vomiting and stomach pain (diverticulitis).
• Fluid accumulation around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• Raised, itchy skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

Uncommon side effects (may affect up to 1 in 100 people)

• Allergic reaction (hypersensitivity).
• Tremor.
• Liver failure.
• Appearance of large, painful, raised plum-coloured skin patches with fever.
• Painful skin ulceration (pyoderma gangrenosum).
• Inflammation of the lining around the heart (pericarditis).

Rare side effects (may affect 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 breakdown products of dying tumour cells and may include the following: changes in blood parameters; high levels of potassium, phosphate and uric acid; and low calcium levels, leading consequently to changes in kidney function, heart rhythm, seizures and sometimes death.

Not known (frequency cannot be estimated from the available data)

• Infection of the deeper skin layers that spreads rapidly, damaging the skin and tissues, which may be fatal (necrotising fasciitis).

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this 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 carton and on the label of the vial after Exp.
The expiry date refers to the last day of that month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Sandoz. They are also responsible for the correct preparation and disposal of any unused Azacitidine Sandoz.

For unopened vials of this medicine:
This medicine requires no special storage conditions.

For immediate use
Once reconstituted, the suspension must be administered within 60 minutes.

For subsequent use
If Azacitidine Sandoz suspension is reconstituted with unrefrigerated water for injections, the suspension must be immediately refrigerated (2 °C – 8 °C) after preparation and stored in the refrigerator for a maximum of 24 hours.
If Azacitidine Sandoz suspension is reconstituted with refrigerated water for injections (2 °C – 8 °C), the reconstituted suspension must be immediately refrigerated (2 °C – 8 °C) after preparation and stored in the refrigerator for a maximum of 36 hours when kept in the vial, or for 30 hours at 2 °C – 8 °C when stored in a syringe.

Before administration, allow up to 30 minutes for the suspension to reach room temperature (20 °C – 25 °C).
Do not use this medicine if large particles are present.

6. Package contents and other information

What Azacitidine Sandoz contains

• The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution with 4 mL of water for injectable preparations, the reconstituted suspension contains 25 mg/mL of azacitidine.
• The other component is mannitol (E421).

Description of the appearance of Azacitidine Sandoz and contents of the pack
Azacitidine Sandoz is a white powder for injectable suspension, supplied in a glass vial with a rubber stopper and an aluminium seal with a plastic flip-off cap, containing 100 mg of azacitidine. The vial is packed in a box.
Pack size: 1 vial.
Marketing Authorization Holder
Sandoz S.p.A.,
L.go U. Boccioni 1,
21040 Origgio (VA),
Italy
Manufacturer
Pharmadox Healthcare Ltd
KW20A Kordin Industrial Park
PLA 3000 Paola
Malta
LEK Pharmaceuticals d.d.
Verovskova ulica 57
1526 Ljubljana
Slovenia
Salutas Pharma GmbH
Otto-von-Guericke-Allee 1
39179 Barleben
Germany
This medicinal product is authorized in the European Economic Area countries under the
following names:
Austria Azacitidin Sandoz 25 mg/mL – Powder for the preparation of an
injectable suspension
Belgium Azacitidin Sandoz 25 mg/mL powder for injection suspension
Bulgaria Азацитидин Сандоз 25 mg/mL powder for injection suspension
Croatia Azacitidin Sandoz 25 mg/mL powder for injection suspension
Denmark Azacitidine Sandoz
Finland Azacitidine Sandoz
France AZACITIDINE SANDOZ 25 mg/mL powder for injectable suspension
Germany Azacitidin HEXAL 25 mg/mL powder for the preparation of an
injectable suspension
Greece Azacitidine/Sandoz 25 mg/mL powder for injectable suspension
Ireland Azacitidine Rowex 25 mg/mL Powder for suspension for injection
Iceland Azacitidine Sandoz
Italy Azacitidina Sandoz
Norway Azacitidine Sandoz
Netherlands Azacitidine Sandoz 25 mg/mL, powder for injection suspension
Poland Azacitidine Sandoz
Portugal Azacitidina Sandoz
United Kingdom Azacitidine Sandoz 25 mg/mL powder for suspension for injection
Czech Republic Azacitidin Sandoz
Slovakia Azacitidine Sandoz 25 mg/mL powder for injection suspension
Romania Azacitidină Sandoz 25 mg/mL powder for injectable suspension
Slovenia Azacitidin Sandoz 25 mg/mL powder for injection suspension
Spain Azacitidina Sandoz 25 mg/mL powder for injectable suspension EFG
Sweden Azacitidine Sandoz
Hungary Azacitidin Sandoz 25 mg/mL powder for suspension for injection

The following information is intended exclusively for healthcare professionals:

Recommendations for safe handling
Azacitidine Sandoz is a cytotoxic medicinal product; therefore, as with other potentially toxic compounds, caution must be exercised during handling and preparation of azacitidine suspensions. Appropriate procedures for handling and disposal of antineoplastic medicinal products must be followed.
In case of contact with reconstituted azacitidine on 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 section “Reconstitution procedure”).

Reconstitution procedure
Azacitidine Sandoz must be reconstituted with Water for Injections. The shelf life of the reconstituted medicinal product can be extended if reconstitution is performed using refrigerated (2°C–8°C) Water for Injections. Details on the storage of the reconstituted medicinal product are provided below.

1. Prepare 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 the syringe, ensuring that any air bubbles in the syringe are expelled.
3. Insert the needle of the syringe containing 4 ml of Water for Injections into the rubber stopper of the azacitidine vial, and then inject the Water for Injections into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a uniform, opaque suspension is formed. After reconstitution, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a homogeneous, opaque suspension, free from aggregates. The suspension must be discarded if large particles or aggregates are present. Do not filter the suspension after reconstitution, as this may remove the active substance. Note that some adapters, needles, and closed systems contain filters; therefore, such systems must not be used for administration of the medicinal product after reconstitution.
5. Clean the rubber stopper and insert a new syringe with an attached needle into the vial. Invert the vial, ensuring that the tip of the needle is below the liquid level. Pull back the plunger to withdraw the required amount of medicinal product for the correct dose, ensuring that any air bubbles remaining in the syringe are expelled. Then remove the syringe with the needle from the vial and dispose of the needle.
6. At this point, securely attach a new subcutaneous injection needle (25 gauge needles are recommended) to the syringe. The suspension should not be pushed into the needle prior to injection in order to reduce the incidence of local reactions at the injection site.
7. When more than one vial is required, repeat the steps described for suspension preparation. For doses requiring more than one vial, divide the dose equally (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 all the suspension from the vial.
8. The contents of the dosing syringe must be resuspended immediately before administration. Prior to administration, allow up to 30 minutes for the filled syringe containing the reconstituted suspension to reach approximately 20°C–25°C. If more than 30 minutes have elapsed, the suspension must be discarded and properly disposed of, and a new dose must be prepared. To resuspend, roll the syringe vigorously between the palms of the hands until a uniform, opaque suspension is obtained. The suspension must be discarded if large particles or aggregates are present.

Storage of the reconstituted medicinal product
When Azacitidine Sandoz is reconstituted with non-refrigerated Water for Injections, the chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated to be 60 minutes at 25°C and 24 hours at 2°C–8°C when stored in the vial and in the syringe.
The shelf life of the reconstituted medicinal product can be extended if reconstitution is performed using refrigerated Water for Injections (2°C–8°C). When Azacitidine Sandoz is reconstituted with refrigerated Water for Injections (2°C–8°C), the chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated to be 36 hours at 2°C–8°C when stored in the vial and 30 hours at 2°C–8°C when stored in the syringe.
From a microbiological standpoint, the reconstituted product should be used immediately. If not used immediately, the conditions and duration of storage prior to use are the responsibility of the user and must not exceed 24 hours at 2°C–8°C.

Individual dose calculation
The total dose based on body surface area (BSA) can be calculated as follows:
Total dose (mg) = Dose (mg/m²) × BSA (m²)
The table below is only 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 reconstitution.
The reconstituted solution of Azacitidina Sandoz must be injected subcutaneously (insert the needle at an angle of 45–90°) into the upper arm, thigh, or abdomen, using a 25 gauge needle.
Doses exceeding 4 ml must be administered at two different sites. Rotate injection sites regularly.
Subsequent injections should be administered at least 2.5 cm away from the previous injection site and never into areas that are tender, bruised, red, or hardened.
Any unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.