Azacitidine Accord 25 mg/ml powder for injectable suspension EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Azacitidine Accord 25mg/ml powder for injectable suspension EFG

azacitidine

Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you experience any adverse reactions, consult your doctor, pharmacist or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

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

1. What Azacitidine Accord is and what it is used for

What Azacitidine Accord is

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

What Azacitidine Accord is used for

Azacitidine Accord is used in adults who cannot receive a stem cell transplant to treat:

• High-risk myelodysplastic syndromes (MDS).
• Chronic myelomonocytic leukemia (CMML).
• Acute myeloid leukemia (AML).

These diseases affect the bone marrow and can cause problems in the normal production of blood cells.

How Azacitidine Accord works

Azacitidine Accord works by inhibiting the growth of cancer cells. 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 or off, by interfering with the production of new RNA and DNA. These actions are thought to correct the problems in maturation and growth of healthy blood cells in the bone marrow caused by myelodysplastic disorders, and to kill cancer cells in leukemia.

Consult your doctor or nurse if you have any questions about how Azacitidine Accord works or why this medicine has been prescribed for you.

2. What you need to know before using Azacitidine Accord

Do not use Azacitidine Accord

• 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.
• During breastfeeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting treatment with Azacitidine Accord:

• 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 ever had heart disease, myocardial infarction, or have a history of lung disease.

Azacitidine may cause a serious immune reaction called “differentiation syndrome” (see section 4).

Blood tests

Before starting treatment with Azacitidine Accord and at the beginning of each treatment period (called a “cycle”), you will have blood tests. These are performed to ensure that you have an adequate number of blood cells and that your liver and kidneys are functioning properly.

Children and adolescents

The use of Azacitidine Accord is not recommended in children and adolescents under 18 years of age.

Other medicines and Azacitidine Accord

Tell your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines. This is because Azacitidine Accord may affect how other medicines work. Likewise, other medicines may affect how Azacitidine Accord works.

Pregnancy, breastfeeding, and fertility

Pregnancy

You must not use Azacitidine Accord during pregnancy because it may harm the unborn baby.

If you are a woman of childbearing potential, you must use an effective method of contraception while taking Azacitidine Accord and for 6 months after stopping treatment with Azacitidine Accord.

Inform your doctor immediately if you become pregnant during treatment.

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before using this medicine.

Breastfeeding

Azacitidine Accord must not be used during breastfeeding. It is unknown whether this medicine is excreted in human breast milk.

Fertility

Men must not father a child while receiving treatment with Azacitidine Accord.

Men should use an effective method of contraception while taking Azacitidine Accord and for 3 months after completion of treatment with Azacitidine Accord.

Consult your doctor if you wish to preserve your sperm before starting this treatment.

Driving and use of machines

Do not drive or operate tools or machinery if you experience adverse effects such as fatigue.

3. How to use Azacitidina Accord

Before administering Azacitidina Accord, your doctor will give you another medication to prevent nausea and vomiting at the beginning of each treatment cycle.

• The recommended dose is 75 mg/m2 of body surface area. Your doctor will determine your dose of this medicine based on your general condition, height, and weight. Your doctor will monitor your progress and, if necessary, may adjust your dose.
• Azacitidina Accord is administered daily for one week, followed by a rest period of three weeks. This "treatment cycle" will be repeated every four weeks. You will usually receive at least six treatment cycles.

A doctor or nurse will administer this medicine as an injection under the skin (subcutaneous route). It may be given under the skin of the thigh, abdomen, or arm (above the elbow).

If you have any further questions about the use of this medicine, ask your doctor, pharmacist, or nurse.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Immediately inform your doctor if you notice any of the following adverse effects:

• Drowsiness, tremors, jaundice, abdominal swelling, and easy bruising. These may be symptoms of liver failure, which can be potentially fatal.
• Swelling of legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness and nausea, vomiting or loss of appetite, and confusion, restlessness, or fatigue. These may be symptoms of kidney failure, which can be potentially fatal.
• Fever. This could be due to an infection resulting from low white blood cell counts, which can be potentially fatal.
• Chest pain or difficulty breathing, possibly accompanied by fever. This may be due to a lung infection known as "pneumonia" and can be potentially fatal.
• 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, swelling of the lips, itching, or skin rash. These may be due to an allergic reaction (hypersensitivity).

Other adverse effects include:

Very common adverse effects (may affect more than 1 in 10 people)

• Decreased red blood cell count (anemia). You may feel tired and look pale.
• Decreased white blood cell count. This may be accompanied by fever. You are also more likely to get infections.
• Low platelet count in the blood (thrombocytopenia). You are more prone to bleeding and bruising.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, difficulty breathing.
• Tiredness (fatigue).
• Reaction at the injection site, including redness, pain, or a skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Pain in nose and throat.
• Dizziness.
• Headache.
• Trouble falling asleep (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low blood potassium levels.

Common adverse effects (may affect up to 1 in 10 people)

• Bleeding inside the head.
• Blood infection caused by bacteria (sepsis). This may be due to low white blood cell counts.
• Bone marrow failure. This may cause low levels of red and white blood cells and platelets.
• A type of anemia characterized by reduced red and white blood cells and platelets.
• Urinary tract infection.
• A viral infection causing herpes-like lesions.
• Bleeding from gums, bleeding from stomach or intestine, bleeding from lower back due to hemorrhoidal bleeding, bleeding in the eyes, bleeding under or into the skin (hematoma).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site. These may include swelling, a hard lump, bruising, bleeding into the skin (hematoma), skin rash, itching, and changes in skin color.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection, or sore throat.
• Pain or excessive discharge from nose or sinuses (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Pain in the throat and larynx.
• Indigestion.
• Drowsiness (lethargy).
• Feeling 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 in the mouth).
• Fainting.
• Drop in blood pressure upon standing (orthostatic hypotension), causing dizziness when standing up or sitting.
• Sleepiness, drowsiness (somnolence).
• Bleeding from a catheter site.
• A condition affecting the intestine that may cause fever, vomiting, and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Shivering (chills).
• Muscle spasms.
• Itchy skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

Uncommon adverse effects (may affect up to 1 in 100 people)

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Painful, large, raised plum-colored spots on the skin and fever.
• Painful skin ulcers (pyoderma gangrenosum).
• Inflammation of the lining around the heart (pericarditis).

Rare adverse effects (may affect up to 1 in 1,000 people)

• Dry cough.
• Painless swelling of the fingertips (drumstick fingers).
• Tumor lysis syndrome – metabolic complications may occur during cancer treatment and sometimes even without treatment. These complications arise from the breakdown products of dying tumor cells and may include: changes in blood chemistry, high levels of potassium, phosphate, and uric acid, and low calcium levels, leading to changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known (cannot be estimated from available data)

• Deep skin layer infection that spreads rapidly, damaging skin and tissue, which can be potentially fatal (necrotizing fasciitis).
• Severe immune reaction (differentiation syndrome) that may cause fever, cough, difficulty breathing, skin rash, reduced urine output, low blood pressure (hypotension), swelling of arms or legs, and rapid weight gain.
• Inflammation of blood vessels in the skin that may cause skin rash (cutaneous vasculitis).

Reporting of adverse effects

If you experience any adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidina Accord

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 the month indicated.

Your doctor, pharmacist, or nurse is responsible for the storage of Azacitidina Accord. They are also responsible for the correct preparation and disposal of any unused Azacitidina Accord.

Unopened vials of this medicine do not require special storage conditions.

If used subsequently

If the Azacitidina Accord suspension is prepared using non-refrigerated water for injections, the suspension must be placed in a refrigerator (between 2 °C and 8 °C) immediately after preparation and may be stored in the refrigerator for up to 8 hours.

If the Azacitidina Accord suspension is prepared using refrigerated water for injections (between 2 °C and 8 °C), the suspension must be placed in a refrigerator (between 2 °C and 8 °C) immediately after preparation and may be stored in the refrigerator for up to 22 hours.

The suspension should be allowed to reach room temperature (20 °C to 25 °C) for a maximum of 30 minutes prior to administration.

The suspension must be discarded if it contains large particles.

6. Pack contents and additional information

Composition of Azacitidina Accord

• 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 ingredient is mannitol (E421).

Appearance of the product and contents of the pack

Azacitidina Accord is a white powder for injectable suspension supplied in a glass vial containing 100 mg of azacitidine. Each pack contains one vial of Azacitidina Accord.

Marketing Authorization Holder

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n,

Edifici Est 6th floor,

08039 Barcelona, Spain

Manufacturer

Or

Accord Healthcare Polska Sp.z o.o.

ul. Lutomierska 50,

95-200 Pabianice

Poland

Or

Laboratori Fundació Dau

C/ C, 12-14 Pol. Ind.

Zona Franca, Barcelona, 08040,

Spain

Or

Accord Healthcare B.V.

Winthontlaan, 200

3526 KV Utrecht

The Netherlands

Date of the most recent review of this leaflet: {MM/YYYY}.

Detailed information on this medicine is available on the website of the European Medicines Agency:

http://www.ema.europa.eu/. Links to other websites on rare diseases and orphan medicinal products are also available.

This information is intended for healthcare professionals only:

Recommendations for safe handling

Azacitidina Accord is a cytotoxic medicine and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Procedures for the proper handling and disposal of anticancer medicines should be followed.

If reconstituted azacitidine comes into contact with the skin, the affected area should be washed immediately and thoroughly with water and soap. If contact occurs with mucous membranes, they should be thoroughly rinsed with water.

Incompatibilities

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

Reconstitution procedure

Azacitidina Accord must be reconstituted with water for injections. The shelf life of the reconstituted medicine can be extended by reconstituting it with refrigerated water for injections (between 2 °C and 8 °C). Information on storage of the reconstituted medicine is provided below.

1. The following items should be assembled:

Vial(s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol-impregnated wipes; 5 ml syringes with needles.

2. Withdraw 4 ml of water for injections into the syringe, ensuring that air trapped in the syringe is purged.
3. Insert the needle of the syringe containing 4 ml of water for injections through the rubber stopper of the azacitidine vial; then inject the water for injections into the vial.
4. After removing the syringe and needle, the vial should be shaken vigorously until a uniform cloudy suspension is obtained. After reconstitution, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a cloudy, homogeneous suspension without clumps. The suspension should be discarded if large particles or clumps are present. Do not filter the suspension after reconstitution, as this may remove the active substance. Note that some adapters, infusion needles, and closed systems contain filters; therefore, such systems should not be used for administration of the medicine after reconstitution.
5. Clean the rubber stopper and insert a new syringe with a needle into the vial. Invert the vial, ensuring that the tip of the needle is below the liquid level. Then pull back the plunger to withdraw the required amount of medicine for the correct dose, ensuring that any trapped air in the syringe is purged. Remove the syringe with needle from the vial and discard the needle.
6. Firmly attach a new subcutaneous needle (25 gauge is recommended) to the syringe for injection. The needle should not be purged before injection to reduce the incidence of local reactions at the injection site.
7. When more than one vial is required, repeat all the above steps for preparation of the suspension. For doses requiring more than one vial, the dose should be divided equally, e.g., 150 mg dose = 6 ml; two syringes with 3 ml in each syringe. 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 should be resuspended immediately before administration. The temperature of the suspension at the time of injection should be approximately 20 °C to 25 °C. To resuspend, roll the syringe vigorously between the palms of the hands until a uniform cloudy suspension is obtained. The suspension should be discarded if large particles or clumps are present.

Storage of the reconstituted medicine

For immediate use

. If more than 60 minutes have elapsed, the reconstituted suspension should be properly discarded and a new dose prepared.

For later use

When reconstituted with non-refrigerated water for injections, the reconstituted suspension should be placed in a refrigerator (temperature between 2 °C and 8 °C) immediately after reconstitution and stored in the refrigerator for up to 8 hours. If more than 8 hours have elapsed in the refrigerator, the suspension should be properly discarded and a new dose prepared.

When reconstituted with refrigerated water for injections (between 2 °C and 8 °C), the reconstituted suspension should be placed in a refrigerator (between 2 °C and 8 °C) immediately after reconstitution and stored in the refrigerator for up to 22 hours. If more than 22 hours have elapsed in the refrigerator, the suspension should be properly discarded and a new dose prepared.

The syringe filled with the reconstituted suspension should be allowed to reach a temperature of approximately 20 °C to 25 °C for a maximum of 30 minutes before administration. If more than 30 minutes have elapsed, the suspension should be properly discarded and a new dose prepared.

Calculation of an individual dose

The total dose, based on body surface area (BSA), can be calculated as follows:

Total dose (mg) = dose (mg/m²) × BSA (m²)

The following table is provided only as an example for calculating individual doses of azacitidine, based on an average BSA of 1.8 m².

Administration method

Do not filter the suspension after reconstitution.

Reconstituted Azacitidina Accord must be administered by subcutaneous injection (insert the needle at an angle of 45 to 90°), using a 25-gauge needle, into the arm, thigh, or abdomen.

Doses exceeding 4 ml must be administered at two separate injection sites.

Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous injection site and never into areas that are tender, bruised, red, or hardened.

Disposal

The disposal of unused medicine and of all materials that have come into contact with it must be carried out in accordance with local regulations.