Azacitidine pharmascience

Package leaflet: Information for the user

Azacitidine Pharmascience, 25 mg/ml, powder for suspension for injection
Azacitidinum
Please read all of this leaflet carefully before 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, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Leaflet contents

1. What Azacitidine Pharmascience is and what it is used for
2. What you need to know 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 anticancer medicine belonging to a group of drugs called "antimetabolites". Azacitidine Pharmascience contains the active substance called "azacitidine".
Why Azacitidine Pharmascience is used
Azacitidine Pharmascience is used in adults who are not eligible for haematopoietic stem cell transplantation, for the treatment of:

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

These diseases affect the bone marrow and may cause difficulties in the normal production of blood cells.
How Azacitidine Pharmascience works
Azacitidine Pharmascience works by preventing the growth of cancer cells.
Azacitidine is incorporated into the genetic material of cells [ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)]. Its mechanism of action is believed to involve altering the activation and deactivation of cellular genes, as well as interfering with the synthesis of RNA and DNA. These actions are thought to correct the impaired maturation and growth of young blood cells in the bone marrow that cause myelodysplastic disorders, and to kill cancer cells in leukaemia.
If you have any questions about how Azacitidine Pharmascience works or why this medicine has been prescribed for you, please consult your doctor or nurse.

2. Important information before using Azacitidine Pharmascience

When not to use Azacitidine Pharmascience

• if the patient is allergic (hypersensitive) to azacitidine or to any of the other ingredients of this medicine (listed in section 6),
• if the patient has advanced liver cancer,
• if the patient is breastfeeding.

Warnings and precautions
Before starting treatment with Azacitidine Pharmascience, discuss with your doctor,
pharmacist, or nurse if the patient:

• has low platelet counts, red blood cells, or white blood cells,
• has kidney disease,
• has liver disease,
• has previously had heart disease, myocardial infarction, or any lung disease.

Azacitidine Pharmascience may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Before starting treatment with Azacitidine Pharmascience and at the beginning of each treatment period (so-called "cycle"), blood tests will be performed. The purpose of these tests is to check whether the patient has sufficient blood cells, and whether the liver and kidneys are functioning properly.
Children and adolescents
Use of Azacitidine Pharmascience is not recommended in children and adolescents under 18 years of age.
Azacitidine Pharmascience and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take. Azacitidine Pharmascience may affect the way some other medicines work. Likewise,
some other medicines may affect the way Azacitidine Pharmascience works.
Pregnancy, breastfeeding, and effects on fertility
Pregnancy
Do not use Azacitidine Pharmascience during pregnancy, as it may be harmful to the unborn child.
Women who can become pregnant should use an effective method of contraception during treatment with Azacitidine Pharmascience and for 6 months after stopping treatment with this medicine. Inform your doctor immediately if pregnancy occurs during treatment with this medicine.
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding
Do not breastfeed while using Azacitidine Pharmascience. It is not known whether azacitidine passes into human breast milk.
Effect on fertility
Men should not father a child during treatment with Azacitidine Pharmascience.
Men should use an effective method of contraception during treatment with Azacitidine Pharmascience and for 3 months after stopping treatment with this medicine.
Patients should consult their doctor if they wish to store sperm before starting this treatment.
Driving and operating machinery
If adverse reactions such as fatigue occur, do not drive, use tools, or operate machinery.

3. How to use Azacitidine Pharmascience

Before administering Azacitidine Pharmascience to the patient, the doctor will give an additional medicine to prevent nausea and vomiting at the beginning of each treatment cycle.

• The recommended dose is 75 mg per m^2 of body surface area. The doctor selects the appropriate dose of Azacitidine Pharmascience for the patient depending on the patient's general condition, height and body weight. The doctor monitors the patient's progress during treatment and may adjust the dose if necessary.
• Azacitidine Pharmascience is administered daily for one week, followed by a rest period of 3 weeks. This "treatment cycle" is repeated every 4 weeks. Patients usually receive at least 6 treatment cycles.

Azacitidine Pharmascience is given as a subcutaneous injection by a doctor or nurse. It may be administered subcutaneously in the thigh, abdomen, or arm.
If you have any further questions about the use of this medicine, please consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although they do not occur in everyone.
You should tell your doctor immediately if the patient experiences any of the following adverse reactions:

• Drowsiness, tremors, jaundice, abdominal distension and easy bruising. These may be symptoms of liver failure and may be life-threatening.
• Swelling of the legs and feet, back pain, reduced urine output, increased thirst, rapid heartbeat, dizziness and nausea, vomiting or loss of appetite, and feelings of disorientation, anxiety or fatigue. These may be symptoms of kidney failure, which may be life-threatening.
• Fever. This may be due to infection resulting from a low white blood cell count, which may be life-threatening.
• Chest pain or shortness of breath, possibly accompanied by fever. This may be due to a lung infection called "pneumonia" and may be life-threatening.
• Bleeding. Such as blood in the stool due to gastrointestinal bleeding or bleeding inside the head. These may be symptoms of a low platelet count.
• Difficulty breathing, swelling of the lips, itching or rash. These may be due to an allergic (hypersensitivity) reaction.

Other adverse reactions include:
Very common adverse reactions (may affect more than 1 in 10 people)

• Decreased number of red blood cells (anaemia). The patient may feel tired and appear pale.
• Decreased number of white blood cells. This may be accompanied by fever. The patient is also more susceptible to infections.
• Low platelet count (thrombocytopenia). The patient is more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Lung inflammation (pneumonitis).
• 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.
• Pain in nose and throat.
• Dizziness.
• Headache.
• Sleep disturbances (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness.
• Weight loss.
• Low blood potassium levels.

Common adverse reactions (may affect up to 1 in 10 people)

• Bleeding inside the skull.
• Bacterial blood infection (sepsis). This may be due to a low white blood cell count.
• Bone marrow failure. This may lead to low numbers of red blood cells, white blood cells and platelets.
• A type of anaemia in which the number of red blood cells, white blood cells and platelets is reduced.
• Urinary tract infection.
• Viral infection causing cold sores on the lip.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anal area due to haemorrhoids (haemorrhoidal haemorrhage), eye bleeding, bleeding under or into the skin (haematomas).
• Blood in the urine.
• Ulceration of the mouth or tongue.
• Skin changes at the injection site. These include: swelling, hard lumps, bruising, bleeding into the skin (haematomas), rash, itching and skin colour changes.
• Redness of the skin.
• Skin infection (cellulitis).
• Infection of the nose and throat or sore throat.
• Nasal pain or congestion, or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Sore throat and larynx.
• Indigestion.
• Lethargy.
• General malaise.
• Anxiety.
• Disorientation.
• Excessive hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside the cheeks, and sometimes on the palate, gums and tonsils (oral candidiasis).
• Fainting.
• Drop in blood pressure upon standing (orthostatic hypotension), leading to dizziness when changing to a standing or sitting position.
• Drowsiness.
• Bleeding at the catheter insertion site.
• Intestinal disease which may cause fever, vomiting and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle cramps.
• Raised, itchy skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).

Uncommon adverse reactions (may affect up to 1 in 100 people)

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, plum-coloured, raised, painful skin lesions with fever.
• Painful skin ulceration (pyogenic skin necrotising fasciitis).
• Inflammation of the outer layer of the heart (pericarditis).

Rare adverse reactions (may affect up to 1 in 1,000 people)

• Dry cough.
• Painless swelling of fingertips (clubbing).
• Tumour lysis syndrome – metabolic complications that may occur during cancer treatment, and sometimes even without treatment. These complications are caused by the products of dying tumour cells and may include: changes in blood chemistry; high levels of potassium, phosphate and uric acid, and low calcium levels, leading to kidney dysfunction, cardiac arrhythmias, seizures, and sometimes death.

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

• Infection of deep skin layers that spreads rapidly, causing skin and tissue damage which may be life-threatening (necrotising fasciitis).
• Severe immune reaction (differentiation syndrome), which may cause fever, cough, difficulty breathing, rash, reduced urine output, low blood pressure (hypotension), swelling of hands or feet, and sudden weight gain.
• Inflammation of blood vessels in the skin, which may lead to a rash (cutaneous vasculitis).

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Jerozolimskie Avenue 181c, 02-222 Warsaw, tel.: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl .
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of the 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 stated on the vial and the outer cardboard package. The expiry date refers to the last day of the specified month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Pharmascience. They are also responsible for the preparation of Azacitidine Pharmascience and the proper disposal of any unused remnants.
Unopened vials – no special storage conditions apply.

After reconstitution:
If the Azacitidine Pharmascience suspension has been prepared using unrefrigerated water for injections, the medicine has been shown to remain 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 reconstituted medicine can be extended by reconstituting it with refrigerated (2°C to 8°C) water for injections. If the Azacitidine Pharmascience suspension has been prepared using refrigerated (2°C to 8°C) water for injections, the medicine has been shown to remain chemically and physically stable at 2°C to 8°C for 32 hours.
From a microbiological standpoint, the reconstituted medicine should be used immediately. If not administered immediately, the responsibility for storage conditions and duration prior to use lies with the medical personnel, and must not exceed 8 hours at 2°C to 8°C after reconstitution using unrefrigerated water for injections, or no longer than 32 hours after reconstitution using refrigerated (2°C to 8°C) water for injections.
Allow the suspension to reach room temperature (20°C to 25°C) for a maximum of 30 minutes before administration.
If large particles are present in the suspension, discard it.

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 lyophilised powder for reconstitution to form a suspension for
injection, supplied in a vial made of colourless type I glass, closed with a bromobutyl rubber stopper
coated with ETFE (the stopper top is additionally coated with polymerised silicone RB2-40) and
aluminium 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 Authorisation Holder
Pharmascience International Ltd.
Lampousas 1
1095 Nicosia
Cyprus
Manufacturer
AqVida GmbH
Kaiser-Wilhelm-Str. 89
20355 Hamburg
Germany
This medicinal product is authorised in the European Economic Area countries under the following names:

Information intended exclusively for healthcare professionals:

Safe handling recommendations
Azacitidine Pharmascience is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution must be exercised when preparing and handling azacitidine suspension. Appropriate procedures for handling and disposal of antineoplastic medicinal products should be followed.
In case of skin contact with prepared azacitidine, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, flush thoroughly with water.
Personnel – pregnant women should not handle this medicinal product.
Pharmaceutical incompatibilities
Do not mix the medicinal product with other medicinal products except those mentioned below (see "Preparation procedure").
Preparation procedure
Azacitidine Pharmascience should be prepared using water for injections. The stability of the prepared medicinal product may be extended by suspending the substance in cooled (2°C to 8°C) water for injections. Details regarding storage of the prepared product are provided below.

1. Gather the following supplies: vial(s) of azacitidine, vial(s) of water for injections, non-sterile surgical gloves, alcohol swabs, syringe(s) with needle(s).
2. Draw the appropriate volume of water for injections into the syringe (see table below), ensuring that all air has been expelled from the syringe.

3. Insert the needle of the syringe containing water for injections through the rubber stopper of the vial containing azacitidine and then slowly inject the water for injections into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a uniform, cloudy suspension is obtained. After preparation, each milliliter 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 lead to removal of the active substance. Note that some caps, vial adapters, and closed-system devices contain filters. Therefore, such components should not be used for administration of the medicinal product after preparation.
5. Clean the rubber stopper and insert a new needle with syringe into the vial. Then invert the vial, ensuring that the tip of the needle is below the fluid level. Pull back the plunger to withdraw the appropriate amount of the medicinal product suspension to ensure the correct dose. Ensure that all air has been expelled from the syringe. Then remove the needle and syringe from the vial and discard the needle.
6. Firmly attach a fresh subcutaneous injection needle (recommended 25 G) to the syringe. Do not flush the needle prior to injection to reduce the frequency of local reactions at the injection site.
7. If more than one vial is required, repeat all the above steps to prepare the suspension. Due to retention in the vial and needle, it may not be possible to withdraw the entire volume of suspension from the vial.
8. The suspension in the syringe containing the medicinal product dose 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 re-establish the appropriate suspension, roll the syringe vigorously 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 medicinal product suspension has been prepared using unrefrigerated water for injections, it has been shown to maintain chemical and physical stability 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 using refrigerated (2°C to 8°C) water for injections. If the Azacitidine Pharmascience medicinal product suspension was prepared using refrigerated (2°C to 8°C) water for injections, it has been shown to maintain chemical and physical stability at 2°C to 8°C for 32 hours.
From a microbiological standpoint, the prepared medicinal product should be used immediately. If not administered immediately, responsibility for the storage time and conditions prior to use lies with the medical personnel and must not exceed 8 hours at 2°C to 8°C after preparation using unrefrigerated water for injections, or no longer than 32 hours after preparation using refrigerated (2°C to 8°C) water for injections.
Allow the suspension to reach room temperature (20°C to 25°C) for up to a maximum of 30 minutes before administration. If more than 30 minutes has elapsed, the suspension should be discarded according to applicable local regulations and a new dose prepared.

Calculation of individual dose
The total dose can be calculated based on body surface area (BSA) as follows:
Total dose = Dose (mg/m²) × BSA (m²)
The table below is merely an example of how individual azacitidine doses are calculated based on an average BSA of 1.8 m².

Method of administration
Do not filter the suspension after preparation.
The prepared suspension of Azacitidine Pharmascience product should be administered subcutaneously
(insert the needle at an angle of 45 - 90°) using a 25 G needle into the arm, thigh, or abdomen.
Doses greater than 4 ml should be administered at two different injection sites.
Injection sites should be rotated. Subsequent injections should be administered at least 2.5 cm
from the previous injection site, and never inject into irritated, bruised, erythematous,
or hardened areas.
Any unused remnants of the medicinal product or waste materials should be disposed of in accordance
with local regulations.