Azacitidine Betapharm

Package leaflet: Information for the user

Azacitidina betapharm 25 mg/mL powder for injectable suspension

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

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

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

2. What you need to know before using Azacitidine betapharm

Do not use Azacitidine betapharm

• 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 betapharm:

• 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 betapharm may cause a serious immune reaction called 'differentiation syndrome' (see section 4).
Blood tests
Before starting treatment with Azacitidine betapharm 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 to assess whether your liver and kidneys are functioning normally.
Children and adolescents
The use of Azacitidine betapharm is not recommended in children and adolescents under 18 years of age.
Other medicines and Azacitidine betapharm
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Azacitidine betapharm may affect how other medicines work. Likewise, other medicines may affect how Azacitidine betapharm works.
Pregnancy, breastfeeding, and fertility
If you are pregnant, think you might be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
You must not use Azacitidine betapharm 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 Azacitidine betapharm and for 6 months after stopping treatment with Azacitidine betapharm. Inform your doctor immediately if you become pregnant during treatment with Azacitidine betapharm.
Breastfeeding
You must not breastfeed while using Azacitidine betapharm. It is not known whether this medicine passes into breast milk.
Fertility
Male patients must not father a child during treatment with Azacitidine betapharm. Men should use an effective method of contraception while taking Azacitidine betapharm and for 3 months after stopping treatment with Azacitidine betapharm. 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 betapharm

Before administering Azacitidina betapharm, 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 betapharm 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 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.
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, 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 could 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 intestines, 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.
• 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 intestines, bleeding from the anus due to haemorrhoids (haemorrhoidal bleeding), bleeding in the eye, bleeding under or into the skin (bruising).
• Blood in the urine.
• Ulcers in the mouth or on the tongue.
• Skin changes at the injection site, including swelling, hard lump, bruising, bleeding into the skin (bruising), 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.
• Pain in the 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 a standing or sitting position.
• Drowsiness, numbness.
• Bleeding due to the catheter.
• Disease affecting the intestine that may cause fever, vomiting and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• 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, 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 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, spreading rapidly and damaging the skin and tissues, which may be fatal (necrotizing 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 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 betapharm

The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine betapharm,
as well as for the preparation and proper disposal of unused medicine.
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.
For unopened vials of this medicine – no special storage conditions are required.

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

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

6. Package contents and other information

What Azacitidina betapharm contains

• The active substance is azacitidine. One vial 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 component is mannitol (E 421).

Description of the appearance of Azacitidina betapharm and contents of the pack
Azacitidina betapharm is a white to off-white powder for injectable suspension, supplied in a
glass vial containing 100 mg of azacitidine. Each pack contains one vial.

Marketing Authorisation Holder and Manufacturer
betapharm Arzneimittel GmbH
Kobelweg 95
86156 Augsburg
Germany

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

België/Belgique/Belgien Lietuva
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Tél/Tel: + 49 821 74881 0 Tel: + 49 821 74881 0
[email protected] [email protected]

България Luxembourg/Luxemburg
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Teл.: +49 821 74881 0 Tél/Tel: + 49 821 74881 0
[email protected] [email protected]

Česká republika Magyarország
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Tel: +49 821 74881 0 Tel.: + 49 821 74881 0
[email protected] [email protected]

Danmark Malta
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Tlf: + 49 821 74881 0 Tel: + 49 821 74881 0
[email protected] [email protected]

Deutschland Nederland
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Kobelweg 95 Tel: + 49 821 74881 0
86156 Augsburg [email protected]
Tel: + 49 821 74881 0
[email protected]

Eesti Norge
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Tel: + 49 821 74881 0 Tlf: + 49 821 74881 0
[email protected] [email protected]

Ελλάδα Österreich
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Τηλ: + 49 821 74881 0 Tel: + 49 821 74881 0
[email protected] [email protected]

España Polska
Reddy Pharma Iberia S.A.U. betapharm Arzneimittel GmbH
Avenida Josep Tarradellas nº 38 Tel.: + 49 821 74881 0
E-08029 Barcelona [email protected]
Tel: + 34 93 355 49 16
[email protected]

France Portugal
Reddy Pharma SAS betapharm Arzneimittel GmbH
9 avenue Edouard Belin Tel: + 49 821 74881 0
F-92500 Rueil-Malmaison [email protected]
Tél: + 33 1 85 78 17 34
[email protected]

Hrvatska România
betapharm Arzneimittel GmbH Dr. Reddy´s Laboratories Romania SRL
Tel: + 49 821 74881 0 Tel: + 4021 224 0032
[email protected] [email protected]

Ireland Slovenija
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Tel: + 49 821 74881 0 Tel: + 49 821 74881 0
[email protected] [email protected]

Ísland Slovenská republika
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Sími: + 49 821 74881 0 Tel: + 49 821 74881 0
[email protected] [email protected]

Italia Suomi/Finland
Dr. Reddy’s S.r.l. betapharm Arzneimittel GmbH
Piazza Santa Maria Beltrade, 1 Puh/Tel: + 49 821 74881 0
I-20123 Milano [email protected]
Tel: + 39(0)2 70106808
[email protected]

Κύπρος Sverige
betapharm Arzneimittel GmbH betapharm Arzneimittel GmbH
Τηλ: + 49 821 74881 0 Tel: + 49 821 74881 0
[email protected] [email protected]

Latvija United Kingdom (Northern Ireland)
betapharm Arzneimittel GmbH Dr. Reddy's Laboratories (UK) Limited
Tel: + 49 821 74881 0 6 Riverview Road, East Riding Of Yorkshire
[email protected] HU17 0LD Beverley
Tel: + 44(0)1482 389858
[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.
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The following information is intended exclusively for healthcare professionals:

Recommendations for safe handling
Azacitidina betapharm 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 should be used. In case of contact with reconstituted azacitidine on the skin, immediately and thoroughly wash with water and soap. 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
Azacitidina betapharm 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: 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 remaining 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 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 it contains large particles or aggregates. Do not filter the suspension after reconstitution, as this may remove the active substance. Note that filters may be present in certain adapters, needles, or closed systems; therefore, such systems must not be used for administration after reconstitution.
5. Clean the rubber stopper and insert a new syringe with 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 needle from the vial and dispose of the needle.
6. Firmly 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 preparation of 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 aspirate all of 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 it contains large particles or aggregates.

Storage of the reconstituted medicinal product
For immediate use
The azacitidine betapharm suspension may be prepared immediately before use, and the reconstituted suspension must be administered within 45 minutes. If more than 45 minutes elapse, the reconstituted suspension must be properly 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 in a refrigerator (2 °C–8 °C) after reconstitution and kept refrigerated for up to 8 hours. If the storage time in the refrigerator exceeds 8 hours, the suspension must be properly 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 in a refrigerator (2 °C–8 °C) after reconstitution and kept refrigerated for up to 22 hours. If the storage time in the refrigerator exceeds 22 hours, the suspension must be properly 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 elapse, 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 solution of Azacitidina betapharm 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 injection sites.
Rotate injection sites alternately. Subsequent injections must be administered at least 2.5 cm away from the previous site and never into sensitive, bruised, red, or hardened areas.
Disposal
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.