AZACITIDINE LORIEN 25 mg/mL POWDER FOR INJECTABLE SUSPENSION

2. What you need to know before you start using Azacitidine Lorien

Do not use Azacitidine Lorien

• 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 breastfeeding.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting 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.

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 done to check that you have enough blood cells and that your liver and kidneys are working properly.

Children and adolescents

Azacitidine Lorien is not recommended for use in children and adolescents under 18 years of age.

Other medicines and Azacitidine Lorien

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, breastfeeding, and fertility

Pregnancy

You should not use this medicine during pregnancy because it may harm the baby.

Use an effective contraceptive method during treatment and for up to three months after 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 should not be used during breastfeeding. It is not known whether this medicine is excreted in breast milk.

Fertility

Men should not father a child while receiving treatment with Azacitidine. Use an effective contraceptive method during treatment and for up to 3 months after treatment with this medicine.

Ask your doctor if you want to preserve your sperm before receiving 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 Lorien

Before administering Azacitidine, 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 administered 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 administer this medicine as an injection under the skin (subcutaneously). It can be administered under the skin of the thigh, abdomen, or arm (above the elbow).

If you have any other questions about using 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 potentially 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 potentially life-threatening.
• Fever. This could be due to an infection as a result of having low white blood cell counts, which can be potentially 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 potentially life-threatening.
• Bleeding. For example, blood in the stool, due to bleeding in the stomach or intestines, or bleeding in the head. These may be symptoms of having low platelet counts in the blood.
• 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 reaction.
• 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.
• Difficulty sleeping (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, bleeding from the stomach or intestine, bleeding in the lower back due to 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 be 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.
• Decreased 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.
• Muscle spasms.
• Itchy skin rash (urticaria).
• Fluid accumulation 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 1000 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 may include: changes in blood biochemistry, high potassium, phosphorus, uric acid, and low calcium levels, which in turn 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 potentially life-threatening (necrotizing fasciitis).
• 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 them directly through the Spanish Medicines Agency's website: https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidine Lorien

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. The expiry date is the last day of the month stated.

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.

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

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

If used immediately

The suspension should be administered within 45 minutes of preparation.

If used later

If the Azacitidine suspension is prepared using non-refrigerated water for injections, the suspension should be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and should be kept in the refrigerator for a maximum of 8 hours.

If the Azacitidine suspension is prepared using refrigerated water for injections (between 2°C and 8°C), the suspension should be placed in the refrigerator (between 2°C and 8°C) immediately after preparation and should be kept in the refrigerator for a maximum of 22 hours.

The suspension should be allowed to reach room temperature (20°C to 25°C) up to 45 minutes before administration.

The suspension should be discarded if it contains large particles.

6. Container Contents and Additional Information

Azacitidina Lorien Composition

• 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).

Product Appearance and Container Contents

Azacitidina Lorien is a white lyophilized powder for injectable suspension and is supplied in a glass vial containing 100 mg of azacitidine. Each container contains one vial of Azacitidina Lorien.

Marketing Authorization Holder

Laboratorios Lorien, S.L.

Av. Josep Tarradellas, 8

Ático 1ª

08029 Barcelona

Spain

Manufacturer

Laboratori FUNDACIO DAU

C/ De la letra C, 12-14,

Polígono Industrial de la Zona Franca,

08040 Barcelona, Spain

Or

SVUS Pharma a.s.

Smetanovo Nabrezi 1238/20a

500 02 Hradec Kralove

Czech Republic

Or

Oncomed Manufacturing A.S.

Karásek 2229/1b

621 00 Brno

Czech Republic

Date of Last Revision of this Leaflet: June 2024

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu/. 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

Azacitidina Lorien 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 azacitidina 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

Azacitidina 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 azacitidina; 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.
2. The needle of the syringe containing the 4 ml of water for injectable preparations should be inserted through the rubber stopper of the azacitidina vial; then, the water for injectable preparations should be injected into the vial.
3. 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, perfusion needles, and closed systems contain filters; therefore, such systems should not be used for the administration of the medicinal product after reconstitution.
4. 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. The plunger should then 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. The syringe with the needle should then be removed from the vial, and the needle should be discarded.
5. A new subcutaneous needle (25 gauge is recommended) should be firmly attached to the syringe. The needle should not be purged before injection to reduce the incidence of local reactions at the injection site.
6. If more than one vial is needed, all the above 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 the suspension from the vial.
7. 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, the syringe should be rolled vigorously 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 Azacitidina Lorien 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 Azacitidina Lorien should be injected subcutaneously (insert the needle at an angle of 45 to 90°), with a 25-gauge needle, in the upper 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.