Azacitidine Pharmascience

Package Leaflet: Information for the User

Azacitidine Pharmascience, 25 mg/ml, Powder for Suspension for Injection

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 get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the Pack

• 1. What Azacitidine Pharmascience is and what it is used for
• 2. Before you use Azacitidine Pharmascience
• 3. How to use Azacitidine Pharmascience
• 4. Possible side effects
• 5. How to store Azacitidine Pharmascience
• 6. Contents of the pack and other information

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

What Azacitidine Pharmascience is

Azacitidine Pharmascience is an anti-cancer medicine belonging to a group of medicines called “antimetabolites”. Azacitidine Pharmascience contains the active substance called “azacitidine”.

What Azacitidine Pharmascience is used for

Azacitidine Pharmascience is used for the treatment of adults who are not eligible for stem cell transplantation, with:

• high-risk myelodysplastic syndromes (MDS),
• chronic myelomonocytic leukemia (CMML),
• acute myeloid leukemia (AML).

These diseases affect the bone marrow and can cause problems with normal blood cell production.

How Azacitidine Pharmascience works

Azacitidine Pharmascience works by preventing the growth of cancer cells. Azacitidine is incorporated into the genetic material of cells (RNA and DNA). It is thought to work by changing the way genes are activated and deactivated, as well as disrupting the production of RNA and DNA. It is believed that these actions repair the abnormalities in the maturation and growth of young blood cells in the bone marrow that cause myelodysplastic syndromes, and that they kill cancer cells in leukemia. If you have any questions about how Azacitidine Pharmascience works or why it has been prescribed for you, ask your doctor or nurse.

2. Before you use Azacitidine Pharmascience

When not to use Azacitidine Pharmascience

Warnings and precautions

Before starting treatment with Azacitidine Pharmascience, tell your doctor, pharmacist, or nurse if you:

• have a low platelet count, red or white blood cell count,
• have kidney disease,
• have liver disease,
• have a history of heart disease, heart attack, or any lung disease.

Azacitidine Pharmascience may cause a severe immune reaction called “differentiation syndrome” (see section 4). Blood tests will be done before starting treatment with Azacitidine Pharmascience and at the beginning of each treatment cycle to check if you have enough blood cells and if your liver and kidneys are working properly.

Children and adolescents

Azacitidine Pharmascience should not be used in children and adolescents under 18 years of age.

Azacitidine Pharmascience and other medicines

Tell your doctor or pharmacist about all medicines you are taking, or have recently taken, and those you plan to take. Azacitidine Pharmascience may affect the way other medicines work, and some other medicines may affect the way Azacitidine Pharmascience works.

Pregnancy, breastfeeding, and fertility

Pregnancy Do not use Azacitidine Pharmascience if you are pregnant, as it may harm your baby. Women who can become pregnant should use effective contraception during treatment with Azacitidine Pharmascience and for 6 months after stopping treatment with this medicine. If you become pregnant during treatment with this medicine, tell your doctor immediately. If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, ask your doctor or pharmacist for advice before using this medicine. Breastfeeding Do not breastfeed during treatment with Azacitidine Pharmascience, as it is not known whether azacitidine passes into breast milk. Fertility Men should not father a child during treatment with Azacitidine Pharmascience. Men should use effective contraception during treatment with Azacitidine Pharmascience and for 3 months after stopping treatment with this medicine. You should consult your doctor if you wish to preserve sperm before starting this treatment.

Driving and using machines

If you experience side effects such as fatigue, do not drive, use tools, or operate machinery.

3. How to use Azacitidine Pharmascience

Before administering Azacitidine Pharmascience to you, 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 per square meter of body surface area. Your doctor will choose the right dose of Azacitidine Pharmascience for you, based on your overall health, height, and weight. Your doctor will check your progress and may change your dose if necessary.
• Azacitidine Pharmascience is given daily for one week, followed by a rest period of three weeks. This treatment cycle is repeated every four weeks. You will usually receive at least six treatment cycles.

Azacitidine Pharmascience is given as a subcutaneous injection by a doctor or nurse. It can be injected under the skin of the thigh, abdomen, or arm. If you have any further questions about using this medicine, ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, Azacitidine Pharmascience 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 distension, and easy bruising.These may be signs of liver failure and can be life-threatening.
• Swelling of the feet and ankles, back pain, decreased urine output, increased thirst, rapid heartbeat, dizziness, and nausea, vomiting, or decreased appetite, as well as feelings of disorientation, anxiety, or fatigue.These may be signs of kidney failure and can be life-threatening.
• Fever. This may be due to an infection caused by a low white blood cell count, which can be life-threatening.
• Chest pain or shortness of breath, which may be accompanied by fever.This may be due to a lung infection called “pneumonia” and can be life-threatening.
• Bleeding, such as blood in the stool due to bleeding in the stomach or intestine, or bleeding in the head. These may be signs of a low platelet count.
• Difficulty breathing, swelling of the lips, itching, or rash.This 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 be pale.
• Decreased white blood cell count. This may be accompanied by fever. You are also more prone to infections.
• Low platelet count (thrombocytopenia). You are more prone to bleeding and bruising.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue.
• Reaction at the injection site, including redness, pain, or skin reaction.
• Loss of appetite.
• Joint pain.
• Bruising.
• Rash.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Sleep disturbances (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness.
• Weight loss.
• Low potassium levels in the blood.

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

• Bleeding in the brain.
• Blood infection caused by bacteria (sepsis). This may be due to a low white blood cell count in the blood.
• Bone marrow failure. This can lead to a low count of red and white blood cells and platelets.
• A type of anemia where the count of red and white blood cells and platelets is decreased.
• Urinary tract infection.
• Viral infection causing cold sores.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anus due to hemorrhoids (hemorrhoidal bleeding), eye bleeding, bleeding under the skin or in the skin (hematomas).
• Blood in the urine.
• Mouth or tongue ulcers.
• Skin changes at the injection site, including swelling, hard lumps, bruising, bleeding in the skin (hematomas), rash, itching, and skin discoloration.
• Redness of the skin.
• Skin infection (cellulitis).
• Nose and throat infection or sore throat.
• Nose or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath on exertion.
• Throat and larynx pain.
• Nausea.
• Indigestion.
• General feeling of being unwell.
• Anxiety.
• Disorientation.
• Excessive hair loss.
• Kidney failure.
• Dehydration.
• White patches on the tongue, inside the cheeks, and sometimes on the palate, gums, and tonsils (oral thrush).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension), leading to dizziness when changing position to standing or sitting.
• Drowsiness.
• Bleeding at the injection site.
• A disease affecting the intestines, which can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• A raised, itchy rash on the skin (hives).
• Fluid around the heart (pericardial effusion).

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

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, purple, raised, painful patches on the skin, with fever.
• Painful skin ulcers (necrotizing fasciitis).
• Inflammation of the outer layer of the heart (pericarditis).

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

• Dry cough.
• Painless swelling of the fingertips (clubbing).
• Tumor lysis syndrome - a complication of metabolism that can occur during cancer treatment, as well as sometimes without treatment. These complications are caused by the breakdown products of dying cancer cells and can include changes in blood chemistry; high levels of potassium, phosphorus, uric acid, and low levels of calcium, leading to kidney problems, heart rhythm disturbances, seizures, and sometimes death.

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

• Infection of the deep layers of the skin, which can spread quickly, causing skin and tissue damage, and can be life-threatening (necrotizing fasciitis).
• Severe immune reaction (differentiation syndrome), which can cause fever, cough, difficulty breathing, rash, decreased urine output, low blood pressure (hypotension), swelling of the hands or feet, and sudden weight gain.
• Inflammation of the blood vessels in the skin, which can cause a rash (cutaneous vasculitis).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in the “Further information” section. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidine Pharmascience

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 label and carton after EXP. The expiry date refers to the last day of that month. Your doctor, pharmacist, or nurse is responsible for storing Azacitidine Pharmascience and for preparing and disposing of any unused medicine. Unopened vials - no special storage precautions.

After preparation If the Azacitidine Pharmascience suspension was prepared using unrefrigerated water for injection, it has been shown to be chemically and physically stable at 25°C for 45 minutes and at 2°C to 8°C for 8 hours. The shelf-life of the prepared product can be extended by suspending it in refrigerated (2°C to 8°C) water for injection. If the Azacitidine Pharmascience suspension was prepared using refrigerated (2°C to 8°C) water for injection, it has been shown to be chemically and physically stable at 2°C to 8°C for 32 hours. From a microbiological point of view, the prepared product should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should not exceed 8 hours at 2°C to 8°C after preparation with unrefrigerated water for injection or 32 hours after preparation with refrigerated (2°C to 8°C) water for injection. Allow the suspension to reach room temperature (20°C to 25°C) for up to 30 minutes before administration. If more than 30 minutes have passed, the suspension should be discarded in accordance with local requirements and a new dose prepared.

6. Contents of the pack and other information

What Azacitidine Pharmascience contains

• The active substance is azacitidine.
• One ml of the prepared suspension contains 25 mg of azacitidine.
• One vial contains 100 mg or 150 mg of azacitidine.
• The other ingredient is mannitol.

What Azacitidine Pharmascience looks like and contents of the pack

Azacitidine Pharmascience is a white lyophilized powder for suspension for injection and is supplied in a vial made of colorless glass type I, closed with a bromobutyl rubber stopper coated with ETFE (the top of the stopper is also coated with siliconized polymeric material RB2-40) and an aluminum seal (white for 100 mg and orange for 150 mg). Pack sizes 1 vial containing 100 mg of azacitidine. 1 vial containing 150 mg of azacitidine. Not all pack sizes may be marketed.

Marketing Authorization Holder

Pharmascience International Ltd. Lampousas 1 1095 Nicosia Cyprus

Manufacturer

AqVida GmbH Kaiser-Wilhelm-Str. 89 20355 Hamburg Germany

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Date of last revision of the leaflet:12/2023

Information intended for healthcare professionals only:

Handling precautions Azacitidine Pharmascience is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing the azacitidine suspension. Follow the procedures for the proper handling and disposal of anti-cancer medicinal products. If prepared azacitidine comes into contact with the skin, wash the area thoroughly with soap and water. If it comes into contact with the mucous membranes, rinse them with water. Female healthcare workers who are pregnant should not handle this medicinal product. Incompatibilities Do not mix this medicinal product with other medicinal products except those mentioned below (see “Preparation procedure”). Preparation procedure Azacitidine Pharmascience should be prepared using water for injection. The shelf-life of the prepared medicinal product can be extended by suspending it in refrigerated (2°C to 8°C) water for injection. Details on the storage of the prepared product are given below.

• 1. You will need the following: vial(s) of azacitidine, vial(s) of water for injection, non-sterile surgical gloves, alcohol swabs, and syringe(s) for injection with needle(s).
• 2. Draw up the appropriate volume of water for injection (see table below) into the syringe, ensuring that the air has been removed from the syringe.

• 3. Insert the needle of the syringe containing water for injection through the rubber stopper of the azacitidine vial and slowly inject the water for injection into the vial.
• 4. Withdraw the syringe and needle, and vigorously shake the vial until a uniform, cloudy suspension is obtained. After preparation, each ml of suspension contains 25 mg of azacitidine. The prepared product is a uniform, cloudy suspension without agglomerates. Discard the suspension if it contains large particles or agglomerates. Do not filter the prepared suspension, as this may remove the active substance. Note that some adapters, needleless devices, and closed systems contain filters. Such devices should not be used with this medicinal product after preparation.
• 5. Clean the rubber stopper with an alcohol swab and insert a new needle and syringe into the vial. Invert the vial and, ensuring that the needle is below the level of the liquid, withdraw the required volume of the azacitidine suspension to deliver the prescribed dose. Ensure that the air has been removed from the syringe. Then, withdraw the needle and syringe from the vial and discard the needle.
• 6. Attach a new sterile needle for subcutaneous injection (25 G recommended) firmly to the syringe. Do not flush the needle before injection to minimize the incidence of local reactions at the injection site.
• 7. If more than one vial is needed, repeat the above steps to prepare the suspension. Due to the overfill and needle retention, it may not be possible to withdraw the full volume of the suspension from the vial.

• 8. The contents of the syringe with the dose of the medicinal product must be resuspended immediately before administration. The temperature of the suspension at the time of injection should be between 20°C and 25°C. To resuspend, vigorously rotate the syringe between the palms until a uniform suspension is obtained. Discard the suspension if it contains large particles or agglomerates.

After preparation If the Azacitidine Pharmascience suspension was prepared using unrefrigerated water for injection, it has been shown to be chemically and physically stable at 25°C for 45 minutes and at 2°C to 8°C for 8 hours. The shelf-life of the prepared medicinal product can be extended by suspending it in refrigerated (2°C to 8°C) water for injection. If the Azacitidine Pharmascience suspension was prepared using refrigerated (2°C to 8°C) water for injection, it has been shown to be chemically and physically stable at 2°C to 8°C for 32 hours. From a microbiological point of view, the prepared medicinal product should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should not exceed 8 hours at 2°C to 8°C after preparation with unrefrigerated water for injection or 32 hours after preparation with refrigerated (2°C to 8°C) water for injection. Allow the suspension to reach room temperature (20°C to 25°C) for up to 30 minutes before administration. If more than 30 minutes have passed, the suspension should be discarded in accordance with local requirements and a new dose prepared. Individual dose calculation The total dose can be calculated based on body surface area (BSA) as follows: Total dose = Dose (mg/m2) x BSA (m2) The following table is an example of how to calculate individual doses of azacitidine based on an average BSA of 1.8 m2.

Administration Do not filter the suspension after preparation. The prepared Azacitidine Pharmascience suspension should be administered subcutaneously (insert the needle at an angle of 45 - 90°) using a 25 G needle in the arm, thigh, or abdomen.

Doses greater than 4 ml should be administered at two different injection sites.

Rotate the injection sites. Subsequent injections should be administered at least 2.5 cm from the previous injection site and never into areas that are tender, bruised, red, or hard. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.