AZACITIDINE HIKMA 25 mg/mL POWDER FOR INJECTABLE SUSPENSION

2. What you need to know before you use Azacitidine Hikma

Do not use Azacitidine Hikma

• If you are allergic to azacitidine or any of the other ingredients of this medicine (listed in section 6).
• If you have advanced liver cancer.
• During breast-feeding.

Warnings and precautions

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

• If you have a low platelet count, red blood cells, or white blood cells.
• If you have kidney disease.
• If you have liver disease.
• If you have ever had heart disease or a heart attack, or have a history of lung disease.

Azacitidine Hikma may cause a severe immune reaction called "differentiation syndrome" (see section 4).

Blood tests

Before starting treatment with azacitidine and at the start of each treatment period (called a "cycle"), you will have blood tests. This is to check that you have enough blood cells and that your liver and kidneys are working 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 using, have recently used, or might use any other medicines. This is because azacitidine may affect the way other medicines work. Similarly, other medicines may affect the way azacitidine works.

Pregnancy, breast-feeding, and fertility

Pregnancy

Do not use azacitidine during pregnancy because it may harm the baby.

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

If you are pregnant or breast-feeding, think you may be pregnant, or plan to become pregnant, ask your doctor or pharmacist for advice before using this medicine.

Breast-feeding

Azacitidine must not be used during breast-feeding. It is not known if this medicine is excreted in breast milk.

Fertility

Men must not father a child while receiving treatment with Azacitidine Hikma. Men must use an effective contraceptive method while taking azacitidine and for 3 months after finishing treatment with this medicine.

Ask your doctor if you want to preserve your sperm before you are given this treatment.

Driving and using machines

Do not drive or use tools or machines if you experience side effects such as fatigue.

3. How to use Azacitidine Hikma

Before administering Azacitidine Hikma, your doctor will give you another medicine to prevent nausea and vomiting at the start of each treatment cycle.

• The recommended dose is 75 mg/m2 of body surface area. Your doctor will decide your dose of this medicine based on your general condition, height, and weight. Your doctor will monitor your progress and, if necessary, may change your dose.

• Azacitidine is given every day for a week, followed by a 3-week rest period. This "treatment cycle" is repeated every 4 weeks. You will usually receive at least 6 cycles of treatment.

A doctor or nurse will give you this medicine as an injection under the skin (subcutaneously). 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 side effects

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

Tell your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal swelling, and easy bruising. These may be symptoms of liver failure and can be life-threatening.
• Swelling of legs and feet, back pain, decreased urine output, increased thirst, rapid pulse, dizziness, and nausea, vomiting, or decreased appetite and feeling of confusion, restlessness, or fatigue.These may be symptoms of kidney failure and can be life-threatening.
• Fever. This may be due to an infection as a result of having low white blood cell counts, which can be life-threatening.
• Chest pain or difficulty breathing that may be accompanied by fever.This may be due to a lung infection known as "pneumonia" and can be life-threatening.
• Bleeding. For example, blood in the stool due to bleeding in the stomach or intestines, or bleeding in the head.
• Difficulty breathing, swelling of the lips, itching, or skin 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)

• Decreased red blood cell count (anemia). You may feel tired and 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.
• Fatigue (fatigue).
• Reaction at the injection site, including redness, pain, or skin rash.
• Loss of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Sleeping problems (insomnia).
• Nosebleeds (epistaxis).
• Muscle pain.
• Weakness (asthenia).
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding in the head.
• Blood infection caused by bacteria (sepsis). This may be due to low white blood cell counts in the blood.
• Bone marrow failure. This may cause low red and white blood cell counts and low platelet counts.
• A type of anemia where there is a decrease in red and white blood cells and platelets.
• Urinary tract infection.
• A viral infection that causes herpes-like lesions.
• Bleeding from the gums, stomach, or intestine, or bleeding around the rectum due to hemorrhoids (hemorrhoidal bleeding), bleeding in the eyes, bleeding under the skin or within the skin (hematoma).
• Blood in the urine.
• Ulcers in the mouth or tongue.
• Changes in the skin 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 the 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.
• A white coating on the tongue, inside of the cheeks, and sometimes the palate, gums, and tonsils (fungal infection in the mouth).
• Fainting.
• Decrease in blood pressure when standing up (orthostatic hypotension) that causes dizziness when standing up or sitting.
• Sleepiness, drowsiness (somnolence).
• Bleeding due to the catheter.
• A disease that affects the intestine that can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (shivering).
• Muscle spasms.
• Itchy skin rash (urticaria).
• Fluid around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Painful, large, and swollen purple spots on the skin and fever.
• Painful ulcers on the skin (pyoderma gangrenosum).
• Inflammation of the lining that surrounds the heart (pericarditis).

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

• Dry cough.
• Painless swelling of the fingertips (drumstick fingers).
• Tumor lysis syndrome - metabolic complications can occur during cancer treatment and sometimes even without treatment. These complications occur as a result of the product of dying tumor cells and can include: changes in blood biochemistry, high levels of potassium, phosphorus, uric acid, and low levels of calcium, which can cause changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known(cannot be estimated from the available data)

• Infection of the deep layers of the skin, which spreads rapidly damaging the skin and tissue, which can be life-threatening (necrotizing fasciitis).
• Severe immune reaction (differentiation syndrome) that can cause fever, cough, difficulty breathing, skin rash, decreased urine output, low blood pressure (hypotension), swelling of the arms or legs, and rapid weight gain.
• Inflammation of blood vessels in the skin that can cause skin rash (cutaneous vasculitis).

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. You can also report side effects directly through the Spanish Medicines Monitoring System for Human Use: https://www.notificaram.es. By reporting side 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 which is stated on the vial label and carton, after EXP. The expiry date is the last day of the month shown.

Your doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Hikma. They are also responsible for the proper preparation and disposal of unused medicine.

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

When Azacitidine Hikma is reconstituted using water for injectable preparations that has not been refrigerated, the chemical and physical stability of the reconstituted medicine has been demonstrated at 25 °C for 45 minutes and at 2 °C to 8 °C for 8 hours.

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

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

The suspension should be discarded if it contains large particles.

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. Container Contents and Additional Information

Composition of Azacitidine Hikma

• The active ingredient 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 Container Contents

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

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Hikma Farmacêutica (Portugal), S.A.

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

2705-906 Terrugem SNT

Portugal

Manufacturer

Thymoorgan Pharmazie GMBH

Schiffgraben, 23, Vienenburg, Goslar, Lower Saxony

38690- Germany

Further information on this medicinal product can be obtained from the local representative of the marketing authorization holder:

Hikma España, S.L.U.

Calle Anabel Segura nº11, Edificio A, planta 1ª, oficina 2

28108 - Alcobendas, Madrid

Spain

This medicinal product is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Date of last revision of this leaflet:January 2024

Other sources of information

Detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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

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 should be exercised when handling and preparing azacitidine suspensions. Procedures for the handling and disposal of anticancer medicinal products should be followed.

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

Incompatibilities

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

Reconstitution procedure

Azacitidine Hikma should be reconstituted with water for injectable preparations. The validity period of the reconstituted medicinal product can be extended by reconstituting it with refrigerated water for injectable preparations (between 2°C and 8°C). The following information is provided on the storage of the reconstituted medicinal product.

1. The following elements should be assembled:

Vials of azacitidine; vials of water for injectable preparations; non-sterile surgical gloves; alcohol-impregnated swabs; 5 ml syringes with needles.

1. 4 ml of water for injectable preparations should be drawn into the syringe,

ensuring that any trapped air is purged from the syringe.

1. The needle of the syringe containing the 4 ml of water for injectable preparations should be inserted through the rubber stopper of the azacitidine vial; then, the water for injectable preparations should be injected into the vial.
2. After removing the syringe and needle, the vial should be shaken vigorously until a uniform, turbid suspension is obtained. After reconstitution, each ml of suspension will contain 25 mg of azacitidine (100 mg/4 ml). The reconstituted product is a turbid and homogeneous suspension, without agglomerates. The suspension should be discarded if it contains large particles or agglomerates. The suspension should not be filtered after reconstitution, as this could remove the active ingredient. It should be noted that some adapters, infusion needles, and closed systems contain filters; therefore, these systems should not be used for the administration of the medicinal product after reconstitution.
3. The rubber stopper should be cleaned, and a new syringe with a needle should be inserted into the vial.

Then, the vial should be inverted, ensuring that the tip of the needle is below the level of the liquid. Next, the plunger should be pulled back to withdraw the required amount of medicinal product for the correct dose, ensuring that any trapped air is purged from the syringe. Then, the syringe with the needle should be removed from the vial, and the needle should be discarded.

1. Next, a new subcutaneous needle (25-gauge recommended) for injectables should be firmly attached to the syringe. The needle should not be purged before injection, in order to reduce the incidence of local reactions at the injection site.
2. If more than one vial is required, all the previous steps should be repeated for the preparation of the suspension. In the case of doses that require more than one vial, the dose should be divided into equal parts, for example, a dose of 150 mg = 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 of the suspension from the vial.

1. 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, vigorously roll the syringe between the palms of the hands until a uniform, turbid suspension is obtained. The suspension should be discarded if it contains large particles or agglomerates.

Storage of the reconstituted medicinal product

For immediate use

The Azacitidine Hikma suspension can be prepared immediately before use, and the reconstituted suspension should be administered within the next 45 minutes. If the time elapsed is more than 45 minutes, the reconstituted suspension should be discarded correctly, and a new dose should be prepared.

For later use

When reconstituted with non-refrigerated water for injectable preparations, the reconstituted suspension should be placed in a refrigerator (temperature between 2°C and 8°C) immediately after reconstitution and should be kept in the refrigerator for a maximum of 8 hours. If the time elapsed in the refrigerator is more than 8 hours, the suspension should be discarded correctly, and a new dose should be prepared.

When reconstituted with refrigerated water for injectable preparations (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 should be kept in the refrigerator for a maximum of 22 hours. If the time elapsed in the refrigerator is more than 22 hours, the suspension should be discarded correctly, and a new dose should be prepared.

The syringe loaded 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 the time elapsed is more than 30 minutes, the suspension should be discarded correctly, and a new dose should be prepared.

Calculation of an individual dose

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

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

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

Method of administration

Do not filter the suspension after reconstitution.

Reconstituted Azacitidine Hikma should be injected subcutaneously (insert the needle at an angle of 45 to 90°), with a 25-gauge needle, in the arm, thigh, or abdomen.

Doses greater than 4 ml should be injected at two separate sites.

Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous site and never in sensitive areas, with ecchymosis, redness, or induration.

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