azacitidine: package leaflet

What Onureg is
Onureg is an anti-cancer medicine that belongs to a group of medicines called anti-metabolites.
Onureg contains the active substance azacitidine.

What Onureg is used for
Onureg is used to treat adults with acute myeloid leukaemia (AML). This is a form of cancer which affects your bone marrow and can cause problems with producing normal blood cells.

Onureg is used to keep the disease in control (remission, when the disease is less severe or not active).

How Onureg works
Onureg works by preventing cancer cells from growing. Azacitidine, the active substance in Onureg, works by altering the way the cell turns genes on and off. It also reduces the production of new genetic material (RNA and DNA). These effects are thought to block growth of cancer cells in leukaemia.

Talk to your doctor or nurse if you have any questions about how Onureg works or why this medicine has been prescribed for you.

Do not take Onureg
- if you are allergic to azacitidine or any of the other ingredients of this medicine (listed in section 6).
- if you are breast-feeding.

Warnings and precautions

Blood tests
You will have blood tests before you begin treatment with Onureg and during treatment with Onureg to check that you have enough blood cells and that your liver and kidneys are working properly. Your doctor will decide how often you have blood tests.

Tell your doctor, pharmacist or nurse straight away if you get any of these symptoms during treatment with Onureg:
- bruising or bleeding - this could be due to a low count of blood cells called platelets;
- fever - this could be due to an infection as a result of having low levels of white blood cells, which can be life-threatening;
- diarrhoea, vomiting or nausea (feeling sick).

Azacitidine can cause a serious immune reaction called ‘differentiation syndrome’(see section 4 ‘Possible side effects’).

Your doctor may need to change the dose, interrupt treatment or stop treatment with Onureg completely. The doctor may prescribe other medicines to help manage these symptoms (see section 3 ‘How to take Onureg’).

Children and adolescents
Onureg is not recommended for use in children and adolescents below the age of 18.

Other medicines and Onureg
Tell your doctor if you are taking, have recently taken or might take any other medicines. This is because Onureg may affect the way some other medicines work. Also, some other medicines may affect the way Onureg works.

Pregnancy, contraception and breast-feeding
If you are pregnant or breast-feeding, you think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Men should not father a child while receiving treatment with Onureg.

Pregnancy
Do not take Onureg during pregnancy as it may be harmful to your baby. Tell your doctor straight away if you become pregnant during treatment.

Contraception
If you are a woman who can become pregnant you should use an effective method of contraception while taking Onureg and for 6 months after stopping treatment with Onureg. Men should use an effective method of contraception while taking Onureg and for 3 months after stopping treatment with Onureg.

Your doctor will discuss with you the most suitable method of contraception for you to use.

Breast-feeding
Do not breast-feed while taking Onureg as it may be harmful to your child (see section 2 ‘Do not take Onureg’).

Fertility
Onureg may affect your ability to have a baby. Talk to your doctor for advice before using it.

Driving and using machines or tools
You may feel tired, weak or have trouble concentrating. If this happens to you or if you have other side effects, do not drive or use any machines or tools.

Onureg contains lactose
Onureg contains lactose monohydrate. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicine.

Onureg contains sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

How much to take
- The recommended dose is 300 mg taken by mouth once daily.
- Your doctor may reduce your dose to 200 mg once daily in the events of adverse reactions.

Onureg is given in treatment cycles of 28 days.
- You take Onureg every day for the first 14 days of each 28-day cycle.
- This is followed by a treatment-free period of 14 days for the rest of the cycle.

Your doctor will tell you what dose of Onureg to take. The doctor may decide to:
- extend your treatment beyond 14 days in each treatment cycle
- lower your dose or temporarily stop treatment
- reduce your treatment to 7 days.

Always take Onureg as prescribed by your doctor.

Your doctor will give you a medicine that helps to reduce nausea (feeling sick) and vomiting. You take it 30 minutes before each Onureg tablet, during your first and second treatment cycles. Your doctor will tell you to take it for a longer period, if you need it.

Taking this medicine
- Take Onureg once a day - at the same time each day.
- Swallow the tablets whole with a full glass of water.
- To make sure you get the right dose, do not break, crush, dissolve or chew the tablets.
- You can take the medicine with food or between meals.

If you vomit after taking a tablet, do not take another dose on the same day. Instead, wait till the next day and take your next scheduled dose then. Do not take two doses on the same day.

If powder from a broken tablet touches your skin, wash the skin straight away and thoroughly with soap and water. If the powder gets into your eyes, nose or mouth, flush the area thoroughly with water.

If you take more Onureg than you should
If you take more tablets than you should, contact your doctor or go to a hospital straightaway. If possible, take the medicine pack and this leaflet with you.

If you forget to take Onureg
If you forget to take Onureg at the usual time, take your usual dose as soon as you remember on the same day and take your next dose at the usual time the next day. Do not take a double dose to make up for a forgotten or vomited tablet.

If you stop taking Onureg
Do not stop taking Onureg unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects
Tell your doctor, pharmacist or nurse straight away if you get any of these symptoms during treatment with Onureg:

Very common: may affect more than 1 in 10 people
- bruising or bleeding - this could be due to a low count of blood cells called platelets;
- fever - this could be due to an infection as a result of having low levels of white blood cells, which can be life-threatening;
- diarrhoea, vomiting or nausea (feeling sick).

Other side effects include:

Very common: may affect more than 1 in 10 people
- constipation
- pain in your belly
- infections of the nose, sinuses and throat
- infection of the lungs
- feeling tired or weak
- loss of appetite
- pain that affect different parts of the body - this can range from a sharp pain to a dull ache
- stiff joints
- back pain.

Common: may affect up to 1 in 10 people
- an infection of the blood caused by bacteria (sepsis) - this may be due to low levels of white cells in your blood
- flu
- infection of the urinary tract
- hay fever
- anxiety
- loss of weight.

Not known (frequency cannot be estimated from the available data)
- Serious immune reaction (differentiation syndrome) that may cause fever, cough, difficulty breathing, rash, decreased urine, low blood pressure (hypotension), swelling of the arms or legs and rapid weight gain.

Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V.
By reporting side affects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP.
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Onureg contains
- The active substance is azacitidine. Each film-coated tablet contains either 200 mg or 300 mg azacitidine.
- The other ingredients are croscarmellose sodium (E468), magnesium stearate (E572), mannitol (E421), and silicified microcrystalline cellulose (E460, E551).
- The 200 mg tablet coating – Opadry II pink contains: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, polyethylene glycol/macrogols (E1521), triacetin (E1518), and iron oxide red (E172). See section 2 “Onureg contains lactose and sodium”.
- The 300 mg tablet coating – Opadry II brown contains: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, polyethylene glycol/macrogols (E1521), triacetin (E1518), iron oxide red (E172), iron oxide yellow (E172), and iron oxide black (E172). See section 2 “Onureg contains lactose and sodium”.

What Onureg looks like and contents of the pack

Onureg 200 mg film-coated tablets (tablets) are pink and oval shaped with “200” imprinted on one side and “ONU” on the other side.

Onureg 300 mg film-coated tablets (tablets) are brown and oval shaped with “300” imprinted on one side and “ONU” on the other side.

The tablets are packaged in aluminium foil blisters.

Each pack contains either 7 or 14 film-coated tablets. Not all pack sizes may be marketed.

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
Netherlands

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgique/België/Belgien
N.V. Bristol-Myers Squibb Belgium S.A.
Tél/Tel: + 32 2 352 76 11 medicalinfo.belgium@bms.com
Lietuva
Swixx Biopharma UAB
Tel: + 370 52 369140 medinfo.lithuania@swixxbiopharma.com

България
Swixx Biopharma EOOD
Teл.: + 359 2 4942 480 medinfo.bulgaria@swixxbiopharma.com
Luxembourg/Luxemburg
N.V. Bristol-Myers Squibb Belgium S.A.
Tél/Tel: + 32 2 352 76 11 medicalinfo.belgium@bms.com
Česká republika
Bristol-Myers Squibb spol. s r.o.
Tel: + 420 221 016 111 medinfo.czech@bms.com
Magyarország
Bristol-Myers Squibb Kft.
Tel.: + 36 1 301 9797
Medinfo.hungary@bms.com
Danmark
Bristol-Myers Squibb Denmark
Tlf: + 45 45 93 05 06 medinfo.denmark@bms.com
Malta
A.M. Mangion Ltd
Tel: + 356 23976333 pv@ammangion.com
Deutschland
Bristol-Myers Squibb GmbH & Co. KGaA
Tel: 0800 0752002 (+ 49 89 121 42 350) medwiss.info@bms.com
Nederland
Bristol-Myers Squibb B.V.
Tel: + 31 (0)30 300 2222 medischeafdeling@bms.com
Eesti
Swixx Biopharma OÜ
Tel: + 372 640 1030 medinfo.estonia@swixxbiopharma.com
Norge
Bristol-Myers Squibb Norway AS
Tlf: + 47 67 55 53 50 medinfo.norway@bms.com
Ελλάδα
Bristol-Myers Squibb A.E.
Τηλ: + 30 210 6074300 medinfo.greece@bms.com
Österreich
Bristol-Myers Squibb GesmbH
Tel: + 43 1 60 14 30 medinfo.austria@bms.com
España
Bristol-Myers Squibb, S.A.
Tel: + 34 91 456 53 00 informacion.medica@bms.com
Polska
Bristol-Myers Squibb Polska Sp. z o.o.
Tel.: + 48 22 2606400 informacja.medyczna@bms.com
France
Bristol-Myers Squibb SAS
Tél: + 33 (0)1 58 83 84 96 infomed@bms.com
Portugal
Bristol-Myers Squibb Farmacêutica Portuguesa,
S.A.
Tel: + 351 21 440 70 00 portugal.medinfo@bms.com
Hrvatska
Swixx Biopharma d.o.o.
Tel: + 385 1 2078 500 medinfo.croatia@swixxbiopharma.com
România
Bristol-Myers Squibb Marketing Services S.R.L.
Tel: + 40 (0)21 272 16 19 medinfo.romania@bms.com
Ireland
Bristol-Myers Squibb Pharmaceuticals uc
Tel: 1 800 749 749 (+ 353 (0)1 483 3625) medical.information@bms.com
Slovenija
Swixx Biopharma d.o.o.
Tel: + 386 1 2355 100 medinfo.slovenia@swixxbiopharma.com
Ísland
Vistor ehf.
Sími: + 354 535 7000 medical.information@bms.com
Slovenská republika
Swixx Biopharma s.r.o.
Tel: + 421 2 20833 600 medinfo.slovakia@swixxbiopharma.com

Italia
Bristol-Myers Squibb S.r.l.
Tel: + 39 06 50 39 61 medicalinformation.italia@bms.com
Suomi/Finland
Oy Bristol-Myers Squibb (Finland) Ab
Puh/Tel: + 358 9 251 21 230 medinfo.finland@bms.com
Κύπρος
Bristol-Myers Squibb A.E.
Τηλ: 800 92666 (+ 30 210 6074300) medinfo.greece@bms.com
Sverige
Bristol-Myers Squibb Aktiebolag
Tel: + 46 8 704 71 00 medinfo.sweden@bms.com
Latvija
Swixx Biopharma SIA
Tel: + 371 66164750 medinfo.latvia@swixxbiopharma.com

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

Vial(s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol wipes;
5 mL injection syringe(s) with needle(s).

trapped within the syringe.

the rubber top of the azacitidine vial followed by injection of the water for injections into the vial.

uniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain 25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudy suspension, free of agglomerates. The product should be discarded if it contains large particles or agglomerates. Do not filter the suspension after reconstitution since this could remove the active substance. It must be taken into account that filters are present in some adaptors, spikes and closed systems; therefore such systems should not be used for administration of the medicinal product after reconstitution.

should then be turned upside down, making sure the needle tip is below the level of the liquid.
The plunger should then be pulled back to withdraw the amount of medicinal product required for the proper dose, making sure to purge any air trapped within the syringe. The syringe with needle should then be removed from the vial and the needle disposed of.

syringe. The needle should not be purged prior to injection, in order to reduce the incidence of local injection site reactions.
7.
When more than 1 vial is needed all the above steps for preparation of the suspension should be repeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial.
8.
The contents of the dosing syringe must be re-suspended immediately prior to administration.
The temperature of the suspension at the time of injection should be approximately 20 ºC-25 ºC.
To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved. The product should be discarded if it contains large particles or agglomerates.

Storage of the reconstituted product

For immediate use
The Vidaza suspension may be prepared immediately before use and the reconstituted suspension should be administered within 45 minutes. If elapsed time is greater than 45 minutes, the reconstituted suspension should be discarded appropriately and a new dose prepared.

For later use
When reconstituting using water for injections that has not been refrigerated, the reconstituted suspension must be placed in a refrigerator (2 °C to 8 °C) immediately after reconstitution, and kept in the refrigerator for a maximum of 8 hours. If the elapsed time in the refrigerator is greater than 8 hours, the suspension should be discarded appropriately and a new dose prepared.

When reconstituting using refrigerated (2 °C to 8 °C) water for injections, the reconstituted suspension must be placed in a refrigerator (2 °C to 8 °C) immediately after reconstitution, and kept in a refrigerator for a maximum of 22 hours. If the elapsed time in the refrigerator is greater than 22 hours, the suspension should be discarded appropriately and a new dose prepared.

The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior to administration to reach a temperature of approximately 20 ºC-25 ºC. If the elapsed time is longer than 30 minutes, the suspension should be discarded appropriately and a new dose prepared.

Calculation of an individual dose
The total dose, according to the body surface area (BSA) can be calculated as follows:

Total dose (mg) = Dose (mg/m2) x BSA (m2)

The following table is provided only as an example of how to calculate individual azacitidine doses based on an average BSA value of 1.8 m2.

Dose mg/m2
(% of recommended starting dose)
Total dose based on BSA value of 1.8 m2
Number of vials required
Total volume of reconstituted suspension required
75 mg/m2 (100%)
135 mg
2 vials
5.4 mL
37.5 mg/m2 (50%)
67.5 mg
1 vial
2.7 mL
25 mg/m2 (33%)
45 mg
1 vial
1.8 mL

Method of administration
Do not filter the suspension after reconstitution.

Reconstituted Vidaza should be injected subcutaneously (insert the needle at a 45-90° angle) using a 25-gauge needle into the upper arm, thigh or abdomen.

Doses greater than 4 mL should be injected into two separate sites.

Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.