AZACITIDINE BETAPHARM 25 mg/mL POWDER FOR INJECTABLE SUSPENSION

Introduction

Package Leaflet: Information for the User

Azacitidine Betapharm 25 mg/ml powder for injectable suspension EFG

azacitidine

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

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

Contents of the pack

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

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

What is Azacitidine Betapharm

Azacitidine Betapharm is an anti-cancer agent that belongs to a group of medicines called “antimetabolites”. Azacitidine Betapharm contains the active substance “azacitidine”.

What is Azacitidine Betapharm used for

Azacitidine Betapharm 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 with the normal production of blood cells.

How Azacitidine Betapharm works

Azacitidine Betapharm 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 work 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.

Talk to your doctor or nurse if you have any questions about how Azacitidine Betapharm works or why you have been prescribed this medicine.

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

Do not use Azacitidine Betapharm

• 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 you start using Azacitidine Betapharm:

• 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 you start treatment with Azacitidine Betapharm 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

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

Other medicines and Azacitidine Betapharm

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines. This is because Azacitidine Betapharm may affect the way other medicines work. Similarly, other medicines may affect the way Azacitidine Betapharm works.

Pregnancy, breast-feeding, and fertility

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

Pregnancy

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

Use an effective method of contraception during treatment and for up to three months after treatment.

Tell your doctor immediately if you become pregnant during treatment.

Breast-feeding

Azacitidine Betapharm should not be used during breast-feeding. It is not known whether this medicine is excreted in breast milk.

Fertility

Men should not father a child while using Azacitidine Betapharm. Use an effective method of contraception during treatment and for up to three months after treatment with this medicine.

Talk to your doctor if you wish 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 Betapharm

Before you are given Azacitidine Betapharm, 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 Betapharm is given every day for a week, followed by a three-week rest period. This “treatment cycle” is repeated every four weeks. You will usually receive at least six 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 other 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)

• Low red blood cell count (anemia). You may feel tired and pale.
• Low 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.
• Sore throat and nose.
• 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, stomach, or intestine, or bleeding in the lower back due to hemorrhoids, 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.
• 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.
• Skin 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.
• 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).

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 national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Azacitidine Betapharm

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

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.

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 Betapharm 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 Betapharm 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 30 minutes before administration.

The suspension should be discarded if it contains large particles.

6. Package Contents and Additional Information

Azacitidina betapharm 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 (E 421).

Product Appearance and Package Contents

Azacitidina betapharm is a white or off-white powder for injectable suspension and is supplied in a glass vial containing 100 mg of azacitidine. Each package contains one vial.

Marketing Authorization Holder

betapharm Arzneimittel GmbH

Kobelweg 95

86156 Augsburg

Germany

Manufacturer

betapharm Arzneimittel GmbH

Kobelweg 95

86156 Augsburg

Germany

O

Dr. Reddy's Laboratories (UK) Limited

6 Riverview Road, East Riding Of Yorkshire

HU17 0LD Beverley

United Kingdom

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

Date of Last Revision of this Leaflet:

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.

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This information is intended for healthcare professionals only:

Recommendations for Safe Handling

Azacitidina betapharm 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

Azacitidina betapharm should be reconstituted with water for injectable preparations. The shelf-life 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 items should be assembled:

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

1. 4 ml of water for injectable preparations should be drawn up 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 azacitidine 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. Do not filter the suspension after reconstitution, as this could remove the active ingredient. It should be noted that some adapters, infusion 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 draw up 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.

1. 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. 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 withdraw the entire 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, 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 Azacitidina betapharm 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 properly 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 stored 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 properly 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 stored 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 properly and a new dose should be prepared.

The syringe loaded with the reconstituted suspension 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 more than 30 minutes, the suspension should be discarded properly and a new dose should be 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 presented only as an example for calculating individual doses of azacitidine, based on an average BSA of 1.8 m2.

Method of Administration

Do not filter the suspension after reconstitution.

Reconstituted Azacitidina betapharm 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

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