Azculem

Leaflet attached to the packaging: information for the user

Azculem, 25 mg/ml, powder for suspension for injection

Azacytidine

Read the leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet, you may need to read it again.
• In case of any doubts, consult a doctor, pharmacist, or nurse.
• If the patient experiences any side effects, including any side effects not listed in this leaflet, tell the doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet:

• 1. What is Azculem and what is it used for
• 2. Important information before using Azculem
• 3. How to use Azculem
• 4. Possible side effects
• 5. How to store Azculem
• 6. Contents of the packaging and other information

1. What is Azculem and what is it used for

What is Azculem

Azculem is an anti-cancer medicine that belongs to a group of medicines called "antimetabolites".
Azculem contains the active substance azacytidine.

What is Azculem used for

Azculem is used in adults who cannot receive a stem cell transplant, for the treatment of:

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

These are diseases that affect the bone marrow and can cause problems with the production of blood cells.

How Azculem works

Azculem works by slowing down the growth of cancer cells. Azacytidine is incorporated into the genetic material of cells [ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)].
It is thought that its action involves changing the way genes are activated and deactivated, as well as disrupting the production of new RNA and DNA.
These actions are believed to correct problems with the maturation and growth of young blood cells in the bone marrow that cause myelodysplastic disorders, and to kill cancer cells in leukemia.
If you have any questions about how Azculem works or why it has been prescribed for you, ask your doctor or nurse.

2. Important information before using Azculem

Do not use Azculem

• if you are allergic to azacytidine or any of the other ingredients of this medicine (listed in section 6);

• if you have advanced liver cancer;
• if you are breastfeeding.

Warnings and precautions

Before starting treatment with Azculem, discuss with your doctor, pharmacist, or nurse if:

• you have a low platelet count, red blood cell count, or white blood cell count;
• you have kidney disease;
• you have liver disease;
• you have had heart disease, heart attack, or any lung disease in the past.

Azculem may cause a severe immune reaction called "differentiation syndrome" (see section 4).
If you experience any symptoms of bleeding, fever, or decreased urine output, contact your doctor immediately.
Also, see section 4.
Blood tests
Before starting treatment with Azculem and at the beginning of each treatment period (called a "cycle"),
blood tests will be performed to check if you have enough blood cells and if your liver and kidneys are working properly.

Children and adolescents

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

Azculem and other medicines

Tell your doctor or pharmacist about all medicines you are taking, have recently taken, or might take.
Azculem may affect the way other medicines work, and some other medicines may affect the way Azculem works.

Pregnancy, breastfeeding, and fertility

Pregnancy
Azculem should not be used during pregnancy, as it may harm the baby.
Women who can become pregnant should use effective contraception during treatment with Azculem and for 6 months after stopping treatment with this medicine.
Tell your doctor immediately if you become pregnant during treatment.
If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Breastfeeding
Do not breastfeed while using Azculem. It is not known if the medicine passes into human milk.
Fertility
Men should avoid fathering a child during treatment with Azculem.
Men should use effective contraception during treatment with Azculem and for 3 months after stopping treatment with Azculem.
You should consult your doctor if you wish to father a child before starting this treatment.

Driving and using machines

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

3. How to use Azculem

Before administering Azculem, 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 determine the dose based on your overall condition, height, and weight.
  Your doctor will monitor your progress and may adjust the dose if necessary.
• Azculem is given daily for one week, followed by a 3-week rest period. This "treatment cycle" will be repeated every 4 weeks.
  Usually, you will receive at least 6 cycles of treatment.

This medicine will be given as an injection under the skin (subcutaneously) by your doctor or nurse.
The medicine 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, Azculem can cause side effects, although not everybody gets them.

Tell your doctor immediately if you experience any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal swelling, and easy bruising. These may be symptoms of liver failure, which 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, restlessness, or fatigue.
  These may be symptoms of kidney failure, which can be life-threatening.
• Fever. The cause may be an infection due to a low white blood cell count, which can be life-threatening.
• Chest pain or shortness of breath, which may be accompanied by fever.
  The cause may be a lung infection called pneumonia, which can be life-threatening.
• Bleeding. Such as blood in the stool due to bleeding from the stomach or intestines or bleeding in the head.
  These may be symptoms of a low platelet count.
• Difficulty breathing, swelling of the lips, itching, or rash.
  This may be caused by an allergic reaction (hypersensitivity).

Other side effects:
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 prone to infections.
• Low platelet count (thrombocytopenia). You are more likely to bleed and bruise.
• Constipation, diarrhea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Feeling tired.
• Reaction at the injection site, including redness, pain, or skin reaction.
• Loss of appetite, anorexia.
• Joint pain.
• Bruising.
• Rash.
• Purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Nose and throat pain.
• Dizziness.
• Headache.
• Difficulty sleeping (insomnia).
• Nosebleeds.
• Muscle and bone pain (including back, bone, and limb 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 brain.
• Blood infection caused by bacteria (sepsis). This may be caused by a low white blood cell count in the blood.
• Bone marrow failure. This may cause a decrease in the number of red and white blood cells and platelets.
• A type of anemia in which the number of red and white blood cells and platelets decreases.
• Urinary tract infection.
• Viral infection causing cold sores.
• Bleeding from the gums, stomach, or intestines, bleeding from the anus due to hemorrhoids, eye bleeding, bleeding under the skin or in the skin (hematoma).
• Blood in the urine.
• Inflammation of the mouth or tongue.
• Skin changes at the injection site. These include: swelling, hard lump, bruise, bleeding in the skin (hematoma), rash, itching, and skin color changes.
• Redness of the skin (erythema), purple spots on the skin (purpura), flat rash on the skin (maculopapular rash).
• Skin infection, inflammation of the tissue under the skin (cellulitis).
• Nose and throat infection or sore throat or tonsillitis (upper respiratory tract infection).
• Bronchitis.
• Nose or sinus pain (sinusitis), or runny nose (rhinitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath on exertion.
• Sore throat and larynx.
• Indigestion.
• Lethargy.
• General malaise.
• Anxiety.
• Disorientation.
• 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, lethargy.
• Bleeding at the catheter site.
• A disease that affects the intestines, which can cause fever, vomiting, and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• Raised, itchy rash on the skin (hives).
• Fluid accumulation around the heart (pericardial effusion)
• Muscle pain (myalgia).
• Increased creatinine levels in the blood (shown in laboratory tests).

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

• Allergic reaction (hypersensitivity).
• Liver failure.
• Large, purple, raised, painful spots on the skin with fever.
• Painful skin ulcers (necrotizing fasciitis).
• Inflammation of the tissue surrounding the heart (pericarditis).
• Coma, which can occur in severe cases of liver disease (progressive hepatic coma).
• A condition in which the body accumulates acid due to kidney failure to properly acidify the urine (renal tubular acidosis).

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

• Dry cough (interstitial lung disease).
• Tumor lysis syndrome - metabolic complications that can occur during cancer treatment, and sometimes even without treatment.
  These complications are caused by the breakdown 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.
• Necrosis at the injection site.

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

• Infection of the deeper layers of the skin, which can spread quickly, causing skin and tissue damage, which 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 side effects

If you experience any side effects, including any side effects not listed in the leaflet, tell your doctor or pharmacist, or nurse.
Side effects can be reported directly to the Department of Drug Safety, Ministry of Health: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: +48 22 49-21-301, fax: +48 22 49-21-309,
website: https://smz.ezdrowie.gov.pl
Side effects can also be reported to the marketing authorization holder.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azculem

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after "EXP".
The expiry date refers to the last day of the month stated.
Your doctor, pharmacist, or nurse is responsible for storing Azculem and for the proper disposal of any unused medicine.
No special precautions for storage are required for unopened vials of this medicine.
For immediate use
The reconstituted suspension should be administered within 45 minutes. The storage temperature should not exceed 25°C.
If more than 45 minutes have passed, the prepared suspension should be disposed of properly and a new dose prepared.
For later use
When reconstituted with unrefrigerated water for injection, the prepared suspension should be stored in the refrigerator (2°C to 8°C) immediately after preparation and for no more than 8 hours.
If more than 8 hours have passed, the suspension should be disposed of properly and a new dose prepared.
When reconstituted with refrigerated (2°C to 8°C) water for injection, the prepared suspension should be stored in the refrigerator (2°C to 8°C) immediately after preparation and for no more than 22 hours.
If more than 22 hours have passed, the suspension should be disposed of properly and a new dose prepared.
From a microbiological point of view, the reconstituted suspension should be used immediately.
If the product is not used immediately, the user is responsible for the storage time and conditions prior to administration, which should not exceed 8 hours at 2°C-8°C for the product prepared with unrefrigerated water for injection or 22 hours for the product prepared with refrigerated (2°C-8°C) water for injection.
Within 30 minutes before administration, the syringe containing the prepared suspension should be allowed to reach room temperature (20°C-25°C).
If more than 30 minutes have passed, the suspension should be disposed of properly and a new dose prepared.

6. Contents of the packaging and other information

What Azculem contains

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

What Azculem looks like and contents of the pack

Azculem is a white or off-white lyophilized powder for suspension for injection, supplied in a colorless glass vial closed with a gray rubber stopper and an aluminum cap with a green polypropylene ring, containing 100 mg of azacytidine.
Each vial is optionally covered with a thin transparent film.
Each pack contains one vial of Azculem.

Marketing authorization holder and manufacturer

Marketing authorization holder:

Onkogen Kft.
1037 Budapest,
Bécsi Road 77-79.
Hungary

Importer:

Seacross Pharma (Europe) Limited
POD 13, The Old Station House
15A Main Street, Blackrock
Dublin, A94 T8P8
Ireland

This medicine is authorized in the European Economic Area under the following names:

Date of last revision of the leaflet: 11/12/2023

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Information intended for healthcare professionals only:

Recommendations for safe handling
Azculem is a cytotoxic medicinal product and, like other potentially toxic compounds, caution should be exercised when handling azacytidine suspensions and preparing them.
Procedures for the safe handling and disposal of anti-cancer medicinal products should be followed.
In case of contact with the reconstituted azacytidine solution and the skin, wash the skin immediately with soap and water.
In case of contact with the mucous membranes, rinse them thoroughly with water.
Incompatibilities
Do not mix this medicinal product with other medicinal products, except for those mentioned below (see "Reconstitution procedure").
Reconstitution procedure
Azculem should be reconstituted with water for injection.
The shelf-life of the reconstituted medicinal product is

can be extended by reconstituting it with refrigerated (2°C to 8°C) water for injection.
Detailed information on storage after reconstitution is given below.

• 1. Prepare the following materials: Vial(s) of azacytidine; vial(s) of water for injection; non-sterile surgical gloves; alcohol swabs; 5 ml syringe(s) for injection with needle(s).
• 2. Draw up 4 ml of water for injection into the syringe, ensuring that the syringe does not contain air.
• 3. Insert the needle of the syringe containing 4 ml of water for injection through the rubber stopper of the vial containing azacytidine and inject the water for injection into the vial.
• 4. Remove the syringe and needle, and vigorously shake the vial until a uniform, cloudy suspension is obtained.
  After reconstitution, each ml of suspension contains 25 mg of azacytidine (100 mg/4 ml).
  The reconstituted product is a uniform, cloudy suspension, without agglomerates.
  The product should be discarded if it contains large particles or agglomerates.
  Do not filter the suspension after reconstitution, as this may remove the active substance.
  It should be noted that some adapters, needles, and closed systems have filters, so these systems should not be used to administer the reconstituted product.
• 5. Clean the rubber stopper and insert a new syringe with a needle into the vial.
  Then, turn the vial upside down, ensuring that the needle tip is below the level of the liquid.
  Pull back the plunger to draw up the required amount of medicinal product to administer the correct dose, ensuring that the syringe does not contain air.
  Then, remove the syringe and needle from the vial and discard the needle.
• 6. Then, firmly attach a new needle for subcutaneous injection (25 G recommended) to the syringe.
  Do not flush the needle before 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.
  For doses requiring more than one vial, the dose should be evenly divided, e.g., 150 mg dose = 6 ml, 2 syringes of 3 ml each.
  Due to the retention in the vial and needle, it may not be possible to withdraw the entire suspension from the vial.
• 8. Immediately before administration, re-suspend the contents of the syringe.
  The temperature of the suspension at the time of injection should be around 20°C-25°C.
  To re-suspend, vigorously shake the syringe between the palms of your hands until a uniform, cloudy suspension is obtained.
  The product should be discarded if it contains large particles or agglomerates.

Storage of the reconstituted product
For immediate use
The reconstituted suspension of Azculem can be prepared immediately before use, and the prepared suspension should be administered within 45 minutes.
The storage temperature should not exceed 25°C.
If more than 45 minutes have passed, the prepared suspension should be disposed of properly and a new dose prepared.
For later use
When reconstituted with unrefrigerated water for injection, the prepared suspension should be stored in the refrigerator (2°C to 8°C) immediately after preparation and for no more than 8 hours.
If more than 8 hours have passed, the suspension should be disposed of properly and a new dose prepared.
When reconstituted with refrigerated (2°C to 8°C) water for injection, the prepared suspension should be stored in the refrigerator (2°C to 8°C) immediately after preparation and for no more than 22 hours.
If more than 22 hours have passed, the suspension should be disposed of properly and a new dose prepared.
From a microbiological point of view, the reconstituted suspension should be used immediately.
If the product is not used immediately, the user is responsible for the storage time and conditions prior to administration, which should not exceed 8 hours at 2°C-8°C for the product prepared with unrefrigerated water for injection or 22 hours for the product prepared with refrigerated (2°C-8°C) water for injection.
Within 30 minutes before administration, the syringe containing the prepared suspension should be allowed to reach room temperature (20°C-25°C).
If more than 30 minutes have passed, the suspension should be disposed of properly 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 (mg) = dose (mg/m2) x BSA (m2)
The following table is an example of the calculation of individual doses of azacytidine based on an average BSA of 1.8 m2.

Method of administration
Do not filter the reconstituted suspension.
The reconstituted Azculem should be injected subcutaneously (insert the needle at an angle of 45-90°) using a 25 G needle.
Doses greater than 4 ml should be injected at two different sites.
The injection site should be changed.
New injections should be given at a distance of at least 2.5 cm from the previous site and never in sensitive, bruised, red, or indurated areas.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicines.