Product Information for the User

Azacitidina betapharm25 mg/ml Powder for Injectable Suspension EFG

azacitidina

Read this entire product information carefully before starting to use this medication, as it contains important information for you.

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

What is Azacitidina betapharm

Azacitidina betapharm is an anticancer agent that belongs to a group of medications called “antimetabolites”. Azacitidina betapharm contains the active ingredient “azacitidina”.

What is Azacitidina betapharm used for

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

• High-risk myelodysplastic syndromes (SMD).
• Chronic myelomonocytic leukemia (LMMC).
• Acute myeloid leukemia (LMA).

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

How Azacitidina betapharm works

Azacitidina betapharm works by preventing the growth of cancer cells. Azacitidina incorporates into the genetic material of cells (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]). It is believed to act by altering the way cells activate or deactivate genes by interfering with the production of new RNA and DNA. It is believed that these actions correct the problems of maturation and growth of healthy blood cells in the bone marrow that cause myelodysplastic disorders, and that kill cancer cells in leukemia.

Consult a doctor or nurse if you have any questions about how Azacitidina betapharm works or why you have been prescribed this medication.

Do not use Azacitidina betapharm

• If you are allergic to azacitidina or any of the other components of this medication (listed in section 6).
• If you have advanced liver cancer.
• During lactation.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Azacitidina betapharm:

• If you have a decrease in platelet, red blood cell, or white blood cell count.
• If you have a kidney disease.
• If you have a liver disease.
• If you have ever had a heart disease or a myocardial infarction, or have a history of lung disease

Blood tests

Before starting treatment with Azacitidina betapharm and at the beginning of each treatment period (called "cycle") blood tests will be done. This is done to check that you have a sufficient number of blood cells and that your liver and kidneys are functioning correctly.

Children and adolescents

The use of Azacitidina betapharm is not recommended in children and adolescents under 18 years old.

Other medications and Azacitidina betapharm

Inform your doctor or pharmacist if you are using, have used recently, or may have to use any other medication. This is because Azacitidina betapharm may affect the way other medications work. Similarly, other medications may affect the way Azacitidina betapharm works.

Pregnancy, lactation, and fertility

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

Pregnancy

You should not use Azacitidina betapharm during pregnancy because it may be harmful to the baby.

Use an effective contraceptive method during treatment and for three months after treatment.

Inform your doctor immediately if you become pregnant during treatment.

Lactation

Azacitidina betapharm should not be used during breastfeeding. It is unknown whether this medication is excreted in breast milk.

Fertility

Males should not conceive a child while receiving treatment with Azacitidina betapharm. Use an effective contraceptive method during treatment and for three months after treatment with this medication.

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

Driving and operating machines

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

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/m2of body surface area. Your doctor will decide your dose of this medicine based on your overall condition, height, and weight. Your doctor will monitor your progress and, if necessary, may change your dose.

• Azacitidina betapharm is administered every day for one week, followed by a three-week rest period. This “treatment cycle” will be repeated every four weeks. You will generally receive at least six treatment cycles.

A doctor or nurse will administer this medicine as a subcutaneous injection under the skin. It can be administered under the skin of the thigh, abdomen, or arm (above the elbow).

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

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

Inform your doctor immediately if you observe any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal distension, and bruising.They may be symptoms of liver failure and can be potentially fatal.
• Swelling of the legs and feet, back pain, decreased urine output, increased thirst, rapid pulse, dizziness, and nausea, vomiting, or decreased appetite and a feeling of confusion, restlessness, or fatigue.They may be symptoms of kidney failure and can be potentially fatal.
• Fever.It could be due to an infection as a result of having low levels of white blood cells, which can be potentially fatal.
• Chest pain or difficulty breathing that may be accompanied by fever.It 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 in the head. These may be symptoms of having low levels of platelets in the blood.
• Difficulty breathing, swelling of the lips, itching, or skin rash.They 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. It may be accompanied by fever. You also have a higher probability of suffering from 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 (tiredness).
• Reaction at the injection site, which includes redness, pain, or skin rash.
• Loss of appetite.
• Joint pain.
• Bruising.
• Skin rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Sore throat and runny nose.
• Dizziness.

• Headache.
• Difficulty falling asleep (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). It may be due to low levels of white blood cells in the blood.
• Bone marrow failure. It may cause low levels of red and white blood cells, and platelets.
• A type of anemia in which there is a decrease in red and white blood cells, and platelets.
• Urinary tract infection.
• A viral infection that causes herpes-like lesions.
• Bleeding gums, bleeding in the stomach or intestines, bleeding in the lower back due to hemorrhoidal bleeding, bleeding in the eyes, bleeding under the skin or inside 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.
• Skin redness.
• Skin infection (cellulitis).
• Throat and nasal infection, or sore throat.
• Nasal or sinus congestion.
• High or low blood pressure (hypertension or hypotension).
• Difficulty breathing when moving.
• Sore throat and laryngitis.
• Indigestion.
• Drowsiness (somnolence).
• Discomfort.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• A white coating on the tongue, the inside of the cheeks, and sometimes the palate, gums, and tonsils (fungal infection of the mouth).
• Fainting.
• Decreased blood pressure when standing (orthostatic hypotension) that causes dizziness when standing or sitting.
• Sleep, drowsiness (somnolence).
• Bleeding due to a catheter.
• A disease that affects the intestine and may cause fever, vomiting, and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills (rigors).
• Muscle spasms.
• Rash with itching (urticaria).
• Fluid around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).

• Tremors.
• Liver failure.
• Purple spots, large and swollen, on the skin and fever.
• Painful skin ulcers (pyoderma gangrenosum).
• Inflammation of the heart lining (pericarditis).

Rare side effects(may affect up to 1 in 1000 people)

• Dry cough.
• Swelling without pain of the fingertips (fingers like drumsticks).
• Tumor lysis syndrome – complications may 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 levels of potassium, phosphorus, and uric acid, and low levels of calcium, which cause changes in kidney function and heart rhythm, seizures, and sometimes death.

Frequency not known(cannot be estimated from available data)

• Deep skin infection that spreads quickly damaging the skin and tissue, which can be potentially fatal (necrotizing fasciitis).

Reporting side effects

If you experience any type of side effect, consult your doctor, pharmacist, or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the vial label and on the box. The expiration date is the last day of the month indicated.

Unopened vials of this medication do not require special conservation conditions.

If used immediately

The suspension must be administered within 45 minutes of its preparation.

If used later

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

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

Allow the suspension to reach an ambient temperature of 20 °C to 25 °C for up to 30 minutes before administration.

The suspension must be discarded if it contains large particles.

Composition of Azacitidina betapharm

• The active ingredient is azacitidina. A vial contains 100 mg of azacitidina. After reconstitution with 4 ml of water for injection, the reconstituted suspension contains 25 mg/ml of azacitidina..
• The other component is mannitol (E 421).

Appearance of the product and contents of the package

Azacitidina betapharm is a white or off-white powder for injection and is delivered in a glass vial containing 100 mg of azacitidina. Each package contains one vial.

Marketing Authorization Holder

betapharm Arzneimittel GmbH

Kobelweg 95

86156 Augsburg

Germany

Responsible for manufacturing

betapharm Arzneimittel GmbH

Kobelweg 95

86156 Augsburg

Germany

Or

Dr. Reddy's Laboratories (UK) Limited

6 Riverview Road, East Riding Of Yorkshire

HU17 0LD Beverley

United Kingdom

You can request more information about this medication by contacting the local representative of the marketing authorization holder:

Last review date of this leaflet:

The detailed information on this medicine is available on the website of the European Medicines Agency:http://www.ema.europa.eu/.There are also links to other websites on rare diseases and orphan medicines.

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This information is intended solely for healthcare professionals:

Recommendations for safe handling

Azacitidina betapharm is a cytotoxic drug and, like other potentially toxic compounds, caution should be exercised when handling and preparing azacitidina suspensions. The procedures for correct handling and disposal of cancer drugs should be applied.

If azacitidina reconstituted 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 washed thoroughly with water.

Incompatibilities

This medicine should not be mixed with others, except as mentioned below (see "Reconstitution procedure").

Reconstitution procedure

Azacitidina betapharm should be reconstituted with water for injection. The shelf life of the reconstituted medicine can be extended by reconstituting it with refrigerated water for injection (between 2 °C and 8 °C). The following information is provided on the storage of the reconstituted medicine.

1. The following items should be mounted:

Vial(s) of azacitidina; vial(s) of water for injection; non-sterile surgical gloves; alcohol-moistened wipes; 5 ml injection syringes with needles.

1. 4 ml of water for injection should be drawn into the syringe, ensuring that any air trapped in the syringe is purged.
2. The needle of the syringe containing the 4 ml of water for injection should be inserted through the rubber stopper of the vial of azacitidina; the water for injection should then be injected into the vial.
3. After the syringe and needle have been removed, the vial should be shaken vigorously until a uniform, turbid suspension is obtained. After reconstitution, each ml of suspension will contain 25 mg of azacitidina (100 mg/4 ml). The reconstituted product is a uniform, turbid suspension without aggregates. The suspension should be discarded if it contains large particles or aggregates. Do not filter the suspension after reconstitution as this may remove the active ingredient. Note that some adapters, infusion needles, and closed systems contain filters; therefore, these systems should not be used for administering the medicine after reconstitution.The suspension should be discarded if it contains large particles or aggregates.
4. The rubber stopper should be cleaned and a new syringe with a needle should be inserted into the vial. The vial should then be inverted, ensuring that the tip of the needle is below the level of the liquid. The plunger should then be pulled back to draw out the required amount of medicine for the correct dose, ensuring that any air trapped in the syringe is purged. The syringe with the needle should then be removed from the vial and the needle should be discarded.

1. A new subcutaneous needle (a gauge 25 needle is recommended for injection) should be securely attached to the syringe. The needle should not be purged before injection to reduce the incidence of local reactions at the injection site.
2. If more than one vial is required, all the above steps should be repeated for the preparation of the suspension. For 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 draw out all the suspension from the vial.
3. 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 between 20 °C and 25 °C. To resuspend, the syringe should be vigorously rolled between the palms of the hands until a uniform, turbid suspension is obtained. The suspension should be discarded if it contains large particles or aggregates.The suspension should be discarded if it contains large particles or aggregates.

Storage of the reconstituted medicine

For immediate use

The azacitidina betapharm suspension can be prepared immediately before use and the reconstituted suspension should be administered within 45 minutes. If the time elapsed is greater 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 injection, the reconstituted suspension should be placed in a refrigerator (between 2 °C and 8 °C) immediately after reconstitution, and should be stored in the refrigerator for a maximum of 8 hours. If the time elapsed in the refrigerator is greater than 8 hours, the suspension should be discarded correctly and a new dose should be prepared.

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

The loaded syringe should be allowed to reach a temperature of approximately between 20 °C and 25 °C for a maximum of 30 minutes before administration. If the time elapsed is greater than 30 minutes, the suspension should be discarded correctly and a new dose should be prepared.

Calculation of an individual dose

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

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

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

Administration form

Do not filter the suspension after reconstitution.

Azacitidina betapharm reconstituted should be injected subcutaneously (insert the needle at an angle of 45° to 90°), with a gauge 25 needle, into the arm, thigh, or abdomen.

Doses greater than 4 ml should be injected in two separate locations.

The 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, ecchymoses, redness, or induration.

Elimination

The unused medicine and all materials that have come into contact with it should be disposed of in accordance with local regulations.