Azacitidine Kabi

Package leaflet: Information for the user

Azacitidina Kabi 25 mg/mL powder for injectable suspension

azacitidine
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, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

1. What Azacitidina Kabi is and what it is used for

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

• 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 Kabi works
Azacitidina Kabi works by preventing cancer cells from growing. Azacitidine becomes 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 in 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 Kabi works or why it has been prescribed for you, please speak to your doctor or nurse.

2. What you need to know before using Azacitidine Kabi

Do not use Azacitidine Kabi

• 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 Kabi:

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

Azacitidine Kabi can cause a serious immune reaction called 'differentiation syndrome'
(see section 4).
Blood tests
Before starting treatment with Azacitidine Kabi and at the beginning of each treatment period
(called a "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 this medicine is not recommended in children and adolescents under 18 years of age.
Other medicines and Azacitidine Kabi
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Azacitidine Kabi may affect how other medicines work.
Other medicines may also affect how Azacitidine Kabi works.
Pregnancy, breastfeeding and fertility
Pregnancy
You must not use Azacitidine Kabi during pregnancy, as it may harm the unborn child.
If you are a woman of childbearing age, you must use an effective method of contraception during treatment with Azacitidine Kabi and for 6 months after stopping treatment with Azacitidine Kabi.
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 Kabi. It is not known whether this medicine passes into breast milk.
Fertility
Male patients must not father a child during treatment with Azacitidine Kabi.
Men must use an effective method of contraception while taking Azacitidine Kabi and for 3 months after stopping treatment with Azacitidine Kabi.
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 Kabi

Before administering Azacitidina Kabi, 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 based on your general condition, height, and body weight. Your doctor will monitor your progress and, if necessary, adjust the dose.
• Azacitidina Kabi 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 injection under the
skin (subcutaneous). The injection can be given under 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.
Tell 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 can be life-threatening.
• Swollen legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness, nausea, vomiting or reduced appetite, confusion, restlessness or fatigue. These may be symptoms of kidney failure and can be life-threatening.
• Fever. This may be due to an infection caused by a low number of white blood cells, 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" and can 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. In addition, you are more likely to get infections.
• Low platelet count in the blood (thrombocytopenia). You are more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Tiredness (fatigue).
• Reaction at the injection site, with redness, pain or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Small red or purple spots under the skin.
• Abdominal pain (stomach pain).
• Itching.
• Fever.
• Irritation of nose and throat.
• Dizziness.
• Headache.
• Difficulty sleeping (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low levels of potassium 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 reduced number of white blood cells in the blood.
• Bone marrow failure, which may cause a reduction in the number of 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 irritation (herpes).
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anus due to haemorrhoids (haemorrhagic haemorrhage), bleeding in the eye, bleeding under the skin 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 changes in skin colour.
• Skin redness.
• Skin infection (cellulitis).
• Infection of the nose and throat, or irritated 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.
• 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 (orthostatic hypotension), causing dizziness when moving to a standing or sitting position.
• Drowsiness, drowsiness (somnolence).
• Bleeding due to catheter.
• Illness affecting the intestine that may cause fever, vomiting and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (shivering).
• Muscle spasms.
• Raised, itchy 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, purple-coloured raised patches on the skin, accompanied by 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 haematological 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 layers of the skin, which spreads rapidly and damages the skin and tissues, which may be fatal (necrotising fasciitis).
• Severe immune reaction (differentiation syndrome) which may cause fever, cough, difficulty breathing, rash, reduced urine output, low blood pressure (hypotension), swelling of arms or legs and rapid weight gain.
• Inflammation of blood vessels in the skin which may cause a rash (cutaneous vasculitis).

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor, pharmacist or nurse.
You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidine Kabi

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 packaging.
The expiry date refers to the last day of that month.
The doctor, pharmacist, or nurse are responsible for the storage of Azacitidine Kabi.
They are also responsible for the preparation and proper disposal of any unused medicine.
For unopened vials of this medicine – no special storage conditions are required.

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

For subsequent use
If the Azacitidine Kabi suspension is reconstituted with non-refrigerated water for injections, the suspension must be placed in a refrigerator (2 °C − 8 °C) immediately after preparation and stored in the refrigerator for up to 8 hours.
If the Azacitidine Kabi suspension is reconstituted with refrigerated (2 °C − 8 °C) water for injections, the reconstituted suspension must be placed in a refrigerator (2 °C − 8 °C) immediately after preparation and stored in the refrigerator for up to 22 hours.
Before administration, allow up to 30 minutes for the suspension to reach room temperature (20 °C – 25 °C).
The suspension must be discarded if large particles are present.

6. Package contents and other information

What Azacitidina Kabi 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 Azacitidina Kabi and contents of the pack
Azacitidina Kabi 25 mg/mL powder for injectable suspension is a powder or mass ranging in colour from white to almost white, supplied in a glass vial.
Each pack contains one vial in a cardboard box.

Marketing Authorization Holder
Fresenius Kabi Deutschland GmbH
Else-Kröner-Straße 1,
61352 Bad Homburg v.d.Höhe
Germany

Manufacturer
Fresenius Kabi Deutschland GmbH
Pfingstweide 53, 61169 Friedberg,
Germany

More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Safe Handling Recommendations
Azacitidina Kabi 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 of reconstituted azacitidine with the skin, immediately and thoroughly wash with soap and water. In case of mucous membrane contact, thoroughly rinse with water.

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

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

1. Prepare the following: 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 into the syringe 4 mL of Water for Injections, ensuring that any air bubbles in the syringe are expelled.

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 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 attached needle into the vial. Invert the vial, ensuring the needle tip 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 needle from the vial and dispose of the needle.

6. Attach firmly to the syringe a new subcutaneous injection needle (use of 25-gauge needles is recommended). Do not push the suspension into the needle before 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 above for preparing the suspension. For doses requiring more than one vial, divide the dose equally (e.g., 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. The temperature of the suspension at the time of injection should be between approximately 20 ºC – 25 ºC. 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 Product
For immediate use
The suspension of Azacitidina Kabi may be prepared immediately before use, and the reconstituted suspension must be administered within 60 minutes. If more than 60 minutes have elapsed, the reconstituted suspension must be properly discarded and a new dose prepared.
For subsequent use
If Azacitidina Kabi suspension is reconstituted with non-refrigerated Water for Injections, the suspension must be placed in a refrigerator (2 °C − 8 °C) immediately after reconstitution and stored in the refrigerator for up to 8 hours. If more than 8 hours have elapsed, the reconstituted suspension must be properly discarded and a new dose prepared.
If Azacitidina Kabi suspension is reconstituted with refrigerated Water for Injections (2 °C − 8 °C), the reconstituted suspension must be placed in a refrigerator (2 °C − 8 °C) immediately after preparation and stored in the refrigerator for up to 22 hours. If more than 22 hours have elapsed, the suspension must be properly discarded and a new dose prepared.
Prior to administration, allow up to 30 minutes for the filled syringe containing the reconstituted suspension to reach a temperature of approximately 20 ºC – 25 ºC. If more than 30 minutes have elapsed, the suspension must be discarded and properly disposed of, and a new dose must be prepared.

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 azacitidine doses based on an average BSA of 1.8 m².

Method of administration
Do not filter the suspension after reconstitution.
The reconstituted azacitidine solution 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 systematically. Subsequent injections should be administered at least 2.5 cm away from the previous site and never into sensitive, bruised, red, or hardened areas.
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.