Vidaza

Package leaflet: Information for the user

Vidaza 25 mg/mL powder for injectable suspension

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

1. What Vidaza is and what it is used for

What Vidaza is
Vidaza is an anticancer agent belonging to a group of medicines called "antimetabolites".
Vidaza contains the active substance "azacitidine".

What Vidaza is used for
Vidaza 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 Vidaza works
Vidaza 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 the maturation and growth of young blood cells in the bone marrow that cause myelodysplastic disorders, and to kill cancer cells in leukaemia.

Speak to your doctor or nurse if you have any questions about how Vidaza works or why it has been prescribed for you.

2. What you need to know before using Vidaza

Do not use Vidaza

• 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 Vidaza:

• 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.

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

Before administering Vidaza, 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.
• Vidaza 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 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.
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.
• Swollen legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness and nausea, vomiting or reduced appetite and feeling confused, restless or tired. 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 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. Also, you may be more likely to get 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 the 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 low white blood cell count in the blood.
• 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 sores (herpes).
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anus due to haemorrhoids (haemorrhoidal bleeding), bleeding in the eye, bleeding under the skin 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 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.
• 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 when moving to an upright or sitting position.
• Drowsiness, stupor (drowsiness).
• Bleeding due to the 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 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).
• Tremor.
• Liver failure.
• Appearance on the skin of large, painful, raised purple-coloured 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 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 layers of the skin, which spreads rapidly and damages the skin and tissues and 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 the 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 Vidaza

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

For immediate use
Once prepared, the suspension must be administered within 45 minutes.

For later use
If the Vidaza 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 a maximum of 8 hours.
If the Vidaza 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 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.

6. Package contents and other information

What Vidaza contains

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

Description of the appearance of Vidaza and contents of the pack
Vidaza is a white powder for injectable suspension, supplied in a glass vial containing 100 mg of azacitidine. Each pack contains one vial of Vidaza.
Marketing Authorisation Holder
Bristol-Myers Squibb Pharma EEIG
Plaza 254
Blanchardstown Corporate Park 2
Dublin 15, D15 T867
Ireland
Manufacturer
Celgene Distribution B.V.
Orteliuslaan 1000
3528 BD Utrecht
The Netherlands

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

Belgique/België/Belgien Lietuva
N.V. Bristol-Myers Squibb Belgium S.A. Swixx Biopharma UAB
Tél/Tel: + 32 2 352 76 11 Tel: + 370 52 369140
[email protected] [email protected]

България Luxembourg/Luxemburg
Swixx Biopharma EOOD N.V. Bristol-Myers Squibb Belgium S.A.
Teл.: + 359 2 4942 480 Tél/Tel: + 32 2 352 76 11
[email protected] [email protected]

Česká republika Magyarország
Bristol-Myers Squibb spol. s r.o. Bristol-Myers Squibb Kft.
Tel: + 420 221 016 111 Tel.: + 36 1 301 9797
[email protected] [email protected]

Danmark Malta
Bristol-Myers Squibb Denmark A.M. Mangion Ltd
Tlf: + 45 45 93 05 06 Tel: + 356 23976333
[email protected] [email protected]

Deutschland Nederland
Bristol-Myers Squibb GmbH & Co. KGaA Bristol-Myers Squibb B.V.
Tel: 0800 0752002 (+ 49 89 121 42 350) Tel: + 31 (0)30 300 2222
[email protected] [email protected]

Eesti Norge
Swixx Biopharma OÜ Bristol-Myers Squibb Norway AS
Tel: + 372 640 1030 Tlf: + 47 67 55 53 50
[email protected] [email protected]

Ελλάδα Österreich
Bristol-Myers Squibb A.E. Bristol-Myers Squibb GesmbH
Τηλ: + 30 210 6074300 Tel: + 43 1 60 14 30
[email protected] [email protected]

España Polska
Bristol-Myers Squibb, S.A. Bristol-Myers Squibb Polska Sp. z o.o.
Tel: + 34 91 456 53 00 Tel.: + 48 22 2606400
[email protected] [email protected]

France Portugal
Bristol-Myers Squibb SAS Bristol-Myers Squibb Farmacêutica Portuguesa, S.A.
Tél: + 33 (0)1 58 83 84 96 Tel: + 351 21 440 70 00
[email protected] [email protected]

Hrvatska România
Swixx Biopharma d.o.o. Bristol-Myers Squibb Marketing Services S.R.L.
Tel: + 385 1 2078 500 Tel: + 40 (0)21 272 16 19
[email protected] [email protected]

Ireland Slovenija
Bristol-Myers Squibb Pharmaceuticals uc Swixx Biopharma d.o.o.
Tel: 1 800 749 749 (+ 353 (0)1 483 3625) Tel: + 386 1 2355 100
[email protected] [email protected]

Ísland Slovenská republika
Vistor hf. Swixx Biopharma s.r.o.
Sími: + 354 535 7000 Tel: + 421 2 20833 600
[email protected] [email protected]
[email protected]

Italia Suomi/Finland
Bristol-Myers Squibb S.r.l. Oy Bristol-Myers Squibb (Finland) Ab
Tel: + 39 06 50 39 61 Puh/Tel: + 358 9 251 21 230
[email protected] [email protected]

Κύπρος Sverige
Bristol-Myers Squibb A.E. Bristol-Myers Squibb Aktiebolag
Τηλ: 800 92666 (+ 30 210 6074300) Tel: + 46 8 704 71 00
[email protected] [email protected]

Latvija
Swixx Biopharma SIA
Tel: + 371 66164750
[email protected]

More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu. In addition, links to other websites on rare diseases and their therapeutic treatments are provided.

The following information is intended exclusively for healthcare professionals:

Safe Handling Recommendations
Vidaza is a cytotoxic medicinal product and, 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 the event of contact with reconstituted azacitidine on the skin, wash immediately and thoroughly with soap and water. In case of mucous membrane contact, 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
Vidaza 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 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 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 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 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 remaining air bubbles in the syringe are expelled. Then remove the syringe with needle from the vial and dispose of the needle.

6. At this point, securely attach a new subcutaneous-use needle to the syringe (use of 25-gauge needles is recommended). 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. The suspension temperature 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 Medicinal Product
For immediate use
The Vidaza suspension may be prepared immediately before use, and the reconstituted suspension must be administered within 45 minutes. If more than 45 minutes have 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 refrigeration period 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 refrigeration period 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 appropriately 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 doses of azacitidine based on an average BSA of 1.8 m².

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