Azacitidine Mylan

Package leaflet: Information for the user

Azacitidine Mylan 25 mg/mL powder for injectable suspension

azacitidine
Please read all of this leaflet carefully before you start 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, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

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

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

What Azacitidina Mylan is
Azacitidina Mylan is an anticancer agent belonging to a group of medicines called "antimetabolites". Azacitidina Mylan contains the active substance "azacitidine".
What Azacitidina Mylan is used for
Azacitidina Mylan 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 Mylan works
Azacitidina Mylan 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 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 Mylan works or why it has been prescribed for you, please consult your doctor or nurse.

2. What you need to know before using Azacitidine Mylan

Do not use Azacitidine Mylan

• 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 Mylan:

• 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, a heart attack, or a history of lung disease.

Azacitidine Mylan may cause a serious immune reaction called “differentiation syndrome” (see section 4).
Blood tests
Before starting treatment with Azacitidine Mylan and at the beginning of each treatment period (called a “cycle”), blood tests will be performed to check whether you have sufficient blood cells and whether your liver and kidneys are functioning normally.
Children and adolescents
The use of Azacitidine Mylan is not recommended in children and adolescents under 18 years of age.
Other medicines and Azacitidine Mylan
Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.
This is because Azacitidine Mylan may affect how other medicines work. Conversely, other medicines may affect how Azacitidine Mylan works.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
You must not use Azacitidine Mylan during pregnancy, as it may harm the unborn baby.
If you are a woman of childbearing potential, you must use an effective method of contraception during treatment with Azacitidine Mylan and for 6 months after stopping treatment with Azacitidine Mylan.
Inform your doctor immediately if you become pregnant during treatment with azacitidine.
Breastfeeding
You must not breastfeed while using Azacitidine Mylan. It is not known whether this medicine passes into breast milk.
Fertility
Men must not father a child during treatment with Azacitidine Mylan. Men should use an effective method of contraception while taking Azacitidine Mylan and for 3 months after stopping treatment with Azacitidine Mylan.
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 Mylan

Before administering Azacitidina Mylan, 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 Mylan 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 can be given under the skin of the thigh, abdomen, or upper arm.
If you have any doubts about 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 everyone will experience 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 can be life-threatening.
• Swelling of legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness, nausea, 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 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" and can be life-threatening.
• Bleeding. For example, blood in the stool due to bleeding in the stomach or intestines, or bleeding inside the head. These may be symptoms of low platelet levels in the blood.
• Difficulty breathing, swollen lips, itching or skin 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. Also, you may 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.
• 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.
• Stomach pain (abdominal pain).
• Itching.
• Fever.
• Irritation of 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 white blood cell count.
• Bone marrow failure, which may cause 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 irritation (herpes).
• Bleeding gums, bleeding in the stomach or intestines, bleeding from the anus due to haemorrhoids (haemorrhagic haemorrhage), bleeding in the eye, bleeding under or into the skin (haematoma).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site, including swelling, hard lump, 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 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.
• Indigestion.
• Lethargy.
• General feeling of being unwell.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating covering the tongue, inside of 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 when moving to a standing or sitting position.
• Drowsiness, lethargy (drowsiness).
• 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 (shivering).
• 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 (drumstick fingers).
• Tumour lysis syndrome: metabolic complications that may occur during cancer treatment and sometimes even without treatment. These complications are caused by the products released from 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 layers of the skin, spreading rapidly and damaging skin and tissues, which may be fatal (necrotising fasciitis).
• Severe immune reaction (differentiation syndrome) that 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 skin rash (cutaneous vasculitis).
  Reporting of side effects If you experience any side effect, including those 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 Mylan

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

For immediate use
Once prepared, the suspension must be administered within 1 hour.

For later use
If the Azacitidine Mylan 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 refrigerated for a maximum of 8 hours.
If the Azacitidine Mylan 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 refrigerated for a maximum of 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.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Azacitidina Mylan contains

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

Description of the appearance of Azacitidina Mylan and contents of the pack
Azacitidina Mylan is a white powder for injectable suspension, supplied in a glass vial containing 100 mg of azacitidine. Each pack contains 1 or 7 vials.
Marketing Authorisation Holder
Mylan Pharmaceuticals Limited
Damastown Industrial Park,
Mulhuddart, Dublin 15,
DUBLIN,
Ireland
Manufacturer
APIS Labor GmbH
Resslstraße 9
Ebenthal 9065
Austria
Or
Fundació Privada Dau
Carrer Lletra C De La Zona Franca. 12-14
08040 Barcelona
Spain
Or
Drehm Pharma GmbH
Hietzinger Hauptstraße 37
Wien, 1130, Austria
Or
Mylan Germany GmbH
Benzstrasse 1, Bad Homburg
61352, Germany

For further information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Lietuva
Viatris Viatris Healthcare UAB
Tél/Tel: + 32 (0)2 658 61 00 Tel: +370 5 205 1288
България Luxembourg/Luxemburg
Майлан ЕООД Viatris
Тел.: +359 2 44 55 400 Tél/Tel: + 32 (0)2 658 61 00
(Belgique/Belgien)
Česká republika Magyarország
Viatris CZ s.r.o. Viatris Healthcare EPD Kft.
Tel: + 420 222 004 400 Tel.: + 36 1 465 2100
Danmark Malta
Viatris ApS V.J. Salomone Pharma Ltd
Tlf: +45 28 11 69 32 Tel: + 356 21 22 01 74
Deutschland Nederland
Viatris Healthcare GmbH Mylan BV
Tel: +49 800 0700 800 Tel: +31 (0)20 426 3300
Eesti Norge
Viatris OÜ Tel: + 372 6363 052 Viatris AS
Tlf: + 47 66 75 33 00
Ελλάδα Österreich
Viatris Hellas Ltd Viatris Austria GmbH
Τηλ: +30 210 0 100 002 Tel: +43 1 86390
España Polska
Viatris Pharmaceuticals, S.L. Viatris Healthcare Sp. z o.o.
Tel: + 34 900 102 712 Tel.: + 48 22 546 64 00
France Portugal
Viatris Santé Mylan, Lda.
Tél: +33 4 37 25 75 00 Tel: + 351 214 127 200
Hrvatska România
Viatris Hrvatska d.o.o. BGP Products SRL
Tel: +385 1 23 50 599 Tel: +40 372 579 000
Ireland Slovenija
Viatris Limited Tel: +353 Viatris d.o.o.
1 8711600 Tel: + 386 1 23 63 180
Ísland Slovenská republika
Icepharma hf. Viatris Slovakia s.r.o.
Sími: +354 540 8000 Tel: +421 2 32 199 100
Italia Suomi/Finland
Viatris Italia S.r.l. Viatris Oy
Tel: + 39 02 612 46921 Puh/Tel: +358 20 720 9555
Κύπρος Sverige
GPA Pharmaceuticals Ltd Viatris AB
Τηλ: +357 22863100 Tel: +46 (0)8 630 19 00
Latvija
Viatris SIA
Tel: +371 676 055 80

Other sources of information
More detailed information on this medicine is available on the website of the European Medicines Agency, http://www.ema.europa.eu.
This leaflet is available in all languages of the European Union/European Economic Area on the website of the European Medicines Agency.

The following information is intended for healthcare professionals only:

Safe handling recommendations
Azacitidina Mylan is a cytotoxic medicine and, therefore, as with other potentially toxic compounds, caution should be exercised during handling and preparation of azacitidine suspensions. Appropriate procedures for handling and disposal of antineoplastic drugs must be used.
In case of skin contact with reconstituted azacitidine, wash immediately and thoroughly with soap and water. In case of mucous membrane contact, rinse thoroughly with water.

Incompatibilities
This medicine must not be mixed with other medicinal products except those mentioned below (see section “Reconstitution procedure”).

Reconstitution procedure
Azacitidina Mylan must be reconstituted with water for injections. The shelf life of the reconstituted medicine may be extended if reconstitution is performed using refrigerated water for injections (2 °C – 8 °C). Details on storage of the reconstituted medicine 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 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 through 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 will contain 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 medicine 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 medicine 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. At this point, firmly attach a new subcutaneous needle to the syringe (use of 25 gauge needles is recommended). The suspension should not be pushed into the needle before injection to reduce the incidence of local reactions at the injection site.

7. When more than 1 vial is required, repeat the steps described for suspension preparation. For doses requiring more than 1 vial, divide the dose equally (e.g., 150 mg dose = 6 mL, 2 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 approximately 20 °C – 25 °C. 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 medicine
For immediate use
The suspension of Azacitidina Mylan may be prepared immediately before use, and the reconstituted suspension must be administered within 1 hour. If more than 1 hour has elapsed, the reconstituted suspension must be appropriately discarded and a new dose prepared.
For subsequent use
When reconstitution is performed using non-refrigerated water for injections, the reconstituted suspension must be stored immediately after reconstitution in a refrigerator (2 °C – 8 °C) and kept refrigerated for a maximum of 8 hours. If the storage time exceeds 8 hours, the suspension must be appropriately discarded and a new dose prepared.
When reconstitution is performed using refrigerated water for injections (2 °C – 8 °C), the reconstituted suspension must be stored immediately after reconstitution in a refrigerator (2 °C – 8 °C) and kept refrigerated for a maximum of 22 hours. If the storage time exceeds 22 hours, the suspension must be appropriately discarded and a new dose prepared.
Before administration, allow up to 30 minutes for the filled syringe containing the reconstituted suspension to reach a temperature of approximately 20 °C – 25 °C. If more than 30 minutes have elapsed, the suspension must be discarded and a new dose 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
Reconstituted Azacitidine Mylan solution must be administered by subcutaneous injection (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 injection sites.
Injection sites should be rotated regularly. Subsequent injections should be administered at least 2.5 cm away from the previous site and never into areas that are tender, bruised, red, or hardened.
Disposal
Any unused medicine and waste material arising from this medicine must be disposed of in accordance with local regulations.