Azculem

Package leaflet: Information for the user

Azculem, 25 mg/ml, powder for the preparation of a suspension for injection
Azacitidine
Please read the entire leaflet carefully before use, as it contains important information for the patient.

• Keep this leaflet for future reference.
• If you have any questions, please consult your doctor, pharmacist, or nurse.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Table of contents:

1. What Azculem is and what it is 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 pack and other information

1. What Azculem is and what it is used for

What Azculem is
Azculem is an antineoplastic medicine belonging to a group of medicines called "antimetabolites".
Azculem contains the active substance called azacitidine.

What Azculem is used for
Azculem 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 are diseases that affect the bone marrow and may cause problems with normal blood cell production.

How Azculem works
Azculem works by inhibiting the growth of cancer cells. Azacitidine becomes incorporated into the genetic material of cells [ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)]. It is believed that its action involves altering the way genes in the cell are activated and deactivated, as well as interfering with the formation of new RNA and DNA. These effects are thought to correct the abnormalities in maturation and growth of young blood cells in the bone marrow that lead to myelodysplastic disorders, and to kill cancer cells in leukaemia.

If you have any questions about how Azculem works or why this medicine has been prescribed for you, please consult your doctor or nurse.

2. Information before using Azculem

Do not use Azculem

• if the patient is allergic to azacitidine or 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 Azculem, discuss with the doctor, pharmacist, or nurse if:

• the patient has low platelet counts, red blood cells, or white blood cells;
• the patient has kidney disease;
• the patient has liver disease;
• the patient has previously had heart disease, heart attack, or any lung disease.

Azculem may cause a severe immune reaction called "differentiation syndrome" (see
section 4).
If any signs of bleeding, fever, or reduced frequency of urination occur, contact the doctor immediately. See also 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. These tests are intended to verify whether the patient has sufficient blood cells and whether the liver and kidneys are functioning properly.
Children and adolescents
Use of Azculem is not recommended in children and adolescents under 18 years of age.
Azculem and other medicines
Inform the doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take. Azculem may affect the action of other medicines. Some other medicines may also affect the action of Azculem.
Pregnancy, breastfeeding, and effects on fertility
Pregnancy
Do not use Azculem during pregnancy, as it may be harmful to the unborn child.
Women of childbearing potential must use an effective method of contraception during treatment with Azculem and for 6 months after stopping treatment with this medicine. Inform the doctor immediately if the patient becomes pregnant during treatment.
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding
Do not breastfeed during treatment with Azculem. It is unknown whether the medicine passes into human milk.
Fertility
Men should avoid fathering a child during treatment with Azculem.
Men should use an effective method of contraception during treatment with Azculem and for 3 months after stopping treatment with Azculem.
The patient should consult the doctor if he wishes to store sperm before starting this treatment.
Driving and operating machinery
If the patient experiences adverse effects such as fatigue, he or she should not drive, use tools, or operate machinery.

3. How to use Azculem

Before administering Azculem, the doctor will give the patient another medicine to prevent nausea and vomiting at the beginning of each treatment cycle.

• The recommended dose is 75 mg per m of body surface area. The doctor will determine the dose of this medicine based on the patient's general condition, height and body weight. The doctor will monitor the progress of treatment and may adjust the dose if necessary.
• Azculem is administered daily for one week, followed by a rest period lasting 3 weeks. This "treatment cycle" will be repeated every 4 weeks. Usually, the patient will receive at least 6 treatment cycles.

This medicine will be administered as a subcutaneous injection (under the skin) by a doctor or nurse.
Azculem can be given 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 side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
You should contact your doctor immediately if any of the following side effects occur:

• Drowsiness, tremors, jaundice, abdominal distension and easy bruising. These may be symptoms of liver failure, which can 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 feeling disoriented, restlessness or fatigue. These may be symptoms of kidney failure, which can be life-threatening.
• Fever. This may be due to an infection caused by a low number of white blood cells, which can be life-threatening.
• Chest pain or shortness of breath, possibly accompanied by fever. This may be due to a lung infection called pneumonia, which can be life-threatening.
• Bleeding. For example, blood in the stool due to bleeding from the stomach or intestines, 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 caused by an allergic reaction (hypersensitivity).

Other side effects:
Very common side effects (may affect more than 1 in 10 people)

• Decreased number of red blood cells (anaemia). The patient may experience fatigue and paleness.
• 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.
• 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.
• Red or purple spots under the skin.
• Abdominal pain.
• Itching.
• Fever.
• Pain in nose and throat.
• Dizziness.
• Headache.
• Trouble sleeping (insomnia).
• Nosebleeds.
• Muscle and bone pain (including back, bone and limb pain).
• Weakness (asthenia).
• Weight loss.
• Low blood potassium levels.

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

• Bleeding inside the skull.
• Blood infection caused by bacteria (sepsis). This may be due to a low number of white blood cells in the blood.
• Bone marrow failure. This may cause a decrease in red and white blood cells and platelets.
• A type of anaemia in which the number of red and white blood cells and platelets is reduced.
• Urinary tract infection.
• Viral infection causing cold sores.
• Bleeding from the gums, stomach or intestines, from the anal area due to haemorrhoids, from the eye, or under the skin or into the skin (haemorrhages).
• Blood in the urine.
• Inflammation of the mucous membrane of the mouth or tongue.
• Skin changes at the injection site. These include: swelling, hard lump, bruising, bleeding into the skin (haematoma), rash, itching and skin discoloration.
• Skin redness (erythema), purple spots on the skin (purpura), flat skin rash (maculopapular rash).
• Skin infection, inflammation of the connective tissue under the skin (cellulitis).
• Infection of the nose and throat or sore throat or inflammation of the throat (upper respiratory tract infection).
• Bronchitis.
• Pain in the nose or runny nose (rhinitis), or sinus pain or sinusitis.
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Pain in the throat and larynx.
• Indigestion.
• Lethargy.
• General malaise.
• Anxiety.
• Disorientation.
• 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, somnolence.
• Bleeding at the catheter insertion site.
• Disease affecting the intestines, which may present with fever, vomiting and abdominal pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle cramps.
• Raised, itchy rash on the skin (urticaria).
• Fluid accumulation around the heart (pericardial effusion).
• Muscle pain (myalgia).
• Increased serum creatinine levels (shown in laboratory tests).

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

• Allergic reaction (hypersensitivity).
• Liver failure.
• Large, purple, raised, painful skin lesions with fever.
• Painful skin ulceration (pyogenic granuloma).
• Inflammatory condition of the membrane surrounding the heart (pericarditis).
• Coma, which may occur in severe cases of liver disease (progressive hepatic coma).
• A condition in which there is an accumulation of acid in the body due to kidney failure to adequately acidify urine (renal tubular acidosis).

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

• Dry cough (interstitial lung disease).
• 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, uric acid, and low calcium levels, leading to kidney dysfunction, irregular heart rhythm, seizures, and sometimes death.
• Necrosis at the injection site.

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

• Infection of deeper skin layers, spreading rapidly and causing damage to skin and tissues, which may be life-threatening (necrotizing 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 side effects
If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: 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 authorisation holder.
Reporting side effects helps provide more information on the safety of this medicine.

5. How to store Azculem

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 outer carton after the abbreviation "EXP". The expiry date refers to the last day of the stated month.
The doctor, pharmacist, or nurse is responsible for the storage of Azculem. They are also responsible for the proper preparation and disposal of any unused Azculem.
Unopened vials of this medicine – no special storage conditions apply.

For immediate use
After preparing the suspension, it should be administered within 45 minutes, and the storage temperature should not exceed 25°C.

For later use
If the Azculem suspension has been prepared using unrefrigerated water for injections, the suspension must be placed immediately in a refrigerator (2°C – 8°C) after preparation and stored in the refrigerator for a maximum of 8 hours.
If the Azculem suspension has been prepared using refrigerated (2°C – 8°C) water for injections, the prepared suspension must be placed immediately in a refrigerator (2°C – 8°C) after preparation and stored in the refrigerator for a maximum of 22 hours.
Approximately 30 minutes before administration, allow the suspension to warm to room temperature (20°C – 25°C).
Do not use the prepared suspension if large particles are present in it.

6. Contents of the pack and other information

What Azculem contains

• The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution by adding 4 ml of water for injections, the resulting suspension contains 25 mg/ml of azacitidine.
• The other ingredient is mannitol (E 421).

What Azculem looks like and contents of the pack
Azculem is a white or almost white lyophilized powder for suspension for injection,
supplied in a colourless glass vial closed with a grey bromobutyl rubber stopper and
an aluminium cap with a green polypropylene flip-off seal, containing 100 mg of azacitidine.
Each vial may optionally be covered with a thin transparent film.
Each pack contains one vial of Azculem.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Onkogen Kft.
1037 Budapest,
Bécsi út 77-79.
Hungary
Importer:
Seacross Pharma (Europe) Limited
POD 13, The Old Station House
15A Main Street, Blackrock
Dublin, A94 T8P8
Ireland
This medicinal product is authorised in the European Economic Area under the
following names:

Information intended exclusively for healthcare professionals:

Safe handling recommendations
Azculem is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling azacitidine suspensions and preparing them. Appropriate procedures for the preparation and disposal of antineoplastic medicinal products must be followed.
In case of contact of dissolved azacitidine with the skin, the skin should be immediately and thoroughly washed with soap and water. In case of contact with mucous membranes, flush thoroughly with water.

Pharmaceutical incompatibilities
Do not mix this medicinal product with other medicinal products except those mentioned below (see "Reconstitution procedure").

Reconstitution procedure
The medicinal product Azculem should be dissolved in water for injections. The shelf life of the prepared medicinal product can be extended by dissolving it in cooled (2°C to 8°C) water for injections. Detailed storage information after reconstitution is provided below.

1. Prepare the following materials: vial(s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol-impregnated swabs; 5 ml syringe(s) with needle(s) for injection.
2. Draw 4 ml of water for injections into the syringe, ensuring that air has been expelled from the syringe.
3. Insert the needle of the syringe containing 4 ml of water for injections through the rubber stopper of the vial containing azacitidine, and then inject the water into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a uniform, cloudy suspension is obtained. After reconstitution, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml). The resulting product is a uniform, cloudy suspension free from aggregates. Discard the product if large particles or aggregates are present. Do not filter the suspension after reconstitution, as this may result in removal of the active substance. Note that some adapters, needles, and closed system devices contain filters; therefore, such systems should not be used for administration of the reconstituted medicinal product.
5. Clean the rubber stopper and insert a new syringe with needle into the vial. Invert the vial, ensuring that the tip of the needle is below the fluid level. Pull back the plunger to withdraw the required volume of medicinal product for the appropriate dose, ensuring that air has been expelled from the sy游戏副本

Method of administration
Do not filter the suspension after reconstitution.
The reconstituted medicinal product Azculem 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 exceeding 4 ml should be administered at two different injection sites.
Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous injection site, and injections should never be given into tender, bruised, erythematous, or hardened areas.
Any unused portions of the medicinal product or waste materials should be disposed of in accordance with local regulations for cytotoxic drugs.