Azacitidine Hikma 25 mg/ml powder for injectable suspension EFG

Patient Information Leaflet

Introduction

Patient Information Leaflet

Azacitidine Hikma 25 mg/ml powder for injectable suspension EFG

Read all of this leaflet carefully before you start using this medicine, as 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 side effects, talk to your doctor, pharmacist, or nurse, even if they are side effects not listed in this leaflet. See section 4.

Leaflet Contents

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

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

What Azacitidine Hikma is

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

What Azacitidine Hikma is used for

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

• Higher-risk myelodysplastic syndromes (MDS).
• Chronic myelomonocytic leukaemia (CMML).
• Acute myeloid leukaemia (AML).

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

How Azacitidine Hikma works

Azacitidine works by preventing the growth of cancer cells. 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 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 leukaemia.

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

2. What you need to know before using Azacitidine Hikma

Do not use Azacitidine Hikma

• 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:

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

Blood tests

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

Children and adolescents

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

Other medicines and Azacitidine Hikma

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

Pregnancy, breastfeeding, and fertility

Pregnancy

You must not use azacitidine during pregnancy as it may harm the unborn baby.

If you are a woman who can become pregnant, you must use an effective method of contraception while taking azacitidine and for 6 months after stopping treatment. Inform your doctor immediately if you become pregnant during treatment.

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

Breastfeeding

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

Fertility

Men must not father a child while receiving treatment with Azacitidine. Men should use an effective method of contraception while taking azacitidine and for up to 3 months after completing treatment with this medicine.

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

Driving and using machines

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

3. How to use Azacitidina Hikma

Before administering Azacitidina, 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/m2 of body surface area. Your doctor will determine your dose of this medicine depending on your general condition, height, and weight. Your doctor will monitor your progress and, if necessary, may adjust your dose.

• Azacitidina is administered daily for one week, followed by a three-week rest period. 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 can 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.

Tell your doctor immediately 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 caused by low levels of white blood cells, which can be potentially fatal.
• Chest pain or difficulty breathing, which may be 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 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, 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 (anaemia). 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, diarrhoea, 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 sleeping (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 levels of white blood cells in the blood.
• Bone marrow failure. This may cause low levels of red and white blood cells and platelets.
• A type of anaemia in which there is a reduction in red blood cells, white blood cells, and platelets.
• Urinary tract infection.
• A viral infection causing herpes-like lesions.
• Bleeding from gums, bleeding from stomach or intestine, bleeding around the rectum due to haemorrhoids (haemorrhoidal bleeding), bleeding in the eyes, bleeding under or into the skin (haematoma).
• Blood in the urine.
• Ulcers in the mouth or tongue.
• Skin changes at the injection site. These may include swelling, a hard lump, bruising, bleeding into the skin (haematoma), skin rash, itching, and changes in skin colour.
• Redness of the skin.
• Skin infection (cellulitis).
• Infection of nose and throat, 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.
• Feeling confused.
• 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.
• Decrease in blood pressure upon standing (orthostatic hypotension), causing dizziness when standing up or sitting.
• Sleepiness, drowsiness (somnolence).
• Bleeding due to a catheter site.
• A disease 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-coloured spots on the skin and fever.
• Painful skin ulcers (pyoderma gangrenosum).
• Inflammation of the lining surrounding the heart (pericarditis).

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

• Dry cough.
• Painless swelling of fingertips (drumstick fingers).
• Tumour lysis syndrome – metabolic complications may occur during cancer treatment and sometimes even without treatment. These complications arise from the breakdown products of dying tumour cells and may include: changes in blood biochemistry, 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 the skin and tissue, which can be potentially fatal (necrotising 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, which may cause a skin rash (cutaneous vasculitis).

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidine Hikma

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, after EXP. The expiry date refers to the last day of the month indicated.

Your doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Hikma, as well as for the correct preparation and disposal of any unused medicine.

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

When Azacitidine Hikma is reconstituted using non-refrigerated water for injections, chemical and physical in-use stability of the reconstituted medicine has been demonstrated for 45 minutes at 25 °C and for 8 hours at 2 °C to 8 °C.

The in-use shelf life of the reconstituted medicine may be extended by reconstituting with refrigerated (2 °C to 8 °C) water for injections. When Azacitidine Hikma is reconstituted using refrigerated (2 °C to 8 °C) water for injections, chemical and physical in-use stability of the reconstituted medicine has been demonstrated for 22 hours at 2 °C to 8 °C.

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

The suspension must be discarded if large particles are present.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

Composition of Azacitidine Hikma

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

Appearance of the product and contents of the pack

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

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó n.º 8, 8A and 8B, Fervença

2705-906 Terrugem SNT

Portugal

Manufacturer

Thymoorgan Pharmazie GMBH

Schiffgraben, 23, Vienenburg, Goslar, Lower Saxony

38690 - Germany

Further information about this medicine is available by contacting the local representative of the Marketing Authorisation Holder:

Hikma España, S.L.U.

Calle Anabel Segura nº11, Edificio A, 1st floor, office 2

28108 - Alcobendas, Madrid

Spain

This medicine is authorised in the European Economic Area member states and in the United Kingdom (Northern Ireland) under the following names:

Date of the most recent review of this leaflet: January 2024

Other sources of information

Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS) http://www.aemps.gob.es/

There are also links to other websites on rare diseases and orphan medicinal products.

This information is intended for healthcare professionals only:

Recommendations for safe handling

Azacitidine Hikma is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution must be exercised when handling and preparing azacitidine suspensions. Procedures for the proper handling and disposal of anticancer medicinal products 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. In case of contact with mucous membranes, they should be thoroughly rinsed with water.

Incompatibilities

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

Reconstitution procedure

Azacitidine Hikma must be reconstituted with water for injections. The shelf life of the reconstituted medicinal product can be extended by reconstituting it with refrigerated water for injections (between 2°C and 8°C). Information on storage of the reconstituted medicinal product 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.

1. Draw up 4 ml of water for injections into the syringe, ensuring that any air trapped in the syringe is purged.

2. Insert the needle of the syringe containing the 4 ml of water for injections through the rubber stopper of the azacitidine vial; then inject the water for injections into the vial.

3. 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 must not be used for administration of the medicinal product after reconstitution.

4. Clean the rubber stopper and insert a new syringe with a needle into the vial. Then 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 trapped in the syringe is purged. Then remove the syringe with the needle from the vial and discard the needle.

5. Next, firmly attach a new subcutaneous injection needle (25 gauge is recommended) to the syringe. The needle should not be purged before injection to reduce the incidence of local reactions at the injection site.

6. 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 into equal parts; for example, a 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.

7. 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 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 medicinal product

For immediate use

The azacitidine suspension may be prepared immediately before use, and the reconstituted suspension should be administered within 45 minutes. If the elapsed time exceeds 45 minutes, the reconstituted suspension must be properly discarded and a new dose prepared.

For later use

When reconstituted with unrefrigerated water for injections, the reconstituted suspension must be placed in a refrigerator (temperature between 2°C and 8°C) immediately after reconstitution and kept refrigerated for a maximum of 8 hours. If the elapsed refrigeration time exceeds 8 hours, the suspension must be properly discarded and a new dose prepared.

When 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 reconstitution and kept refrigerated for a maximum of 22 hours. If the elapsed refrigeration time exceeds 22 hours, the suspension must be properly discarded and a new dose prepared.

The syringe containing 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 the elapsed time exceeds 30 minutes, the suspension must 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 azacitidine doses, based on an average BSA of 1.8 m².

Route of administration

Do not filter the suspension after reconstitution.

Reconstituted Azacitidina Hikma must be injected subcutaneously (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 must be administered at least 2.5 cm away from the previous site and never into sensitive, bruised, red, or hardened areas.

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