Azacitidine delfarma

Package leaflet: Information for the user

Warning! Keep this leaflet. The information on the immediate packaging is in a foreign language.
Azacitidine Delfarma (Azacitidin Seacross), 25 mg/ml, powder for suspension for injection
Azacitidine
Azacitidine Delfarma and Azacitidin Seacross are different trade names for the same medicine.
Please read this leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• 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.

Leaflet contents:

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

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

What Azacitidine Delfarma is
Azacitidine Delfarma is an anticancer medicine belonging to a group of medicines called "antimetabolites". Azacitidine Delfarma contains the active substance called azacitidine.

Why Azacitidine Delfarma is used
Azacitidine Delfarma 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 the normal production of blood cells.

How Azacitidine Delfarma works
Azacitidine Delfarma works by inhibiting 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 act by altering the way genes are activated or deactivated, as well as by interfering with the formation of new RNA and DNA. These actions are thought to correct the impaired maturation and growth of blood cells in the bone marrow seen in myelodysplastic disorders, and to kill cancer cells in leukaemia.

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

2. Important information before using Azacitidine Delfarma

Do not use Azacitidine Delfarma

• if the patient is allergic 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 Delfarma, consult your 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.

Azacitidine Delfarma 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 your doctor immediately. See also section 4.

Blood tests
Before starting treatment with Azacitidine Delfarma and at the beginning of each treatment period (called a "cycle"), blood tests will be performed. These tests are intended to check whether the patient has an adequate number of blood cells and whether the liver and kidneys are functioning properly.

Children and adolescents
Use of Azacitidine Delfarma is not recommended in children and adolescents under 18 years of age.

Azacitidine Delfarma and other medicines
Tell your doctor or pharmacist about all medicines the patient is currently taking or has recently taken, as well as any medicines the patient plans to take. Azacitidine Delfarma may affect the action of other medicines. Some other medicines may also affect the action of Azacitidine Delfarma.

Pregnancy, breastfeeding, and effects on fertility

Pregnancy
Do not use Azacitidine Delfarma during pregnancy, as it may be harmful to the unborn child.
Women of childbearing potential should use an effective method of contraception during treatment with Azacitidine Delfarma and for 6 months after stopping treatment with this medicine.
Inform your 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 become pregnant, she should consult her doctor or pharmacist before using this medicine.

Breastfeeding
Do not breastfeed while taking Azacitidine Delfarma. It is not known whether the medicine passes into human milk.

Fertility
Men should avoid fathering a child during treatment with Azacitidine Delfarma.
Men should use an effective method of contraception during treatment with Azacitidine Delfarma and for 3 months after stopping treatment with Azacitidine Delfarma.
The patient should consult his doctor about sperm preservation before starting this treatment.

Driving and operating machinery
If the patient experiences adverse effects such as fatigue, the patient should not drive, use tools, or operate machinery.

3. How to use Azacitidine Delfarma

Before administering Azacitidine Delfarma, 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^2 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 patient's progress and, if necessary, may adjust the dose.
• Azacitidine Delfarma is administered daily for one week, followed by a rest period lasting 3 weeks. This "treatment cycle" will be repeated every 4 weeks. Typically, the patient will receive at least 6 treatment cycles.

This medicine will be given as a subcutaneous injection (under the skin) by a doctor or nurse. The medicine can be administered subcutaneously in the thigh, abdomen, or arm.
If you have any further questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
You should inform your doctor immediately if any of the following adverse reactions 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, nausea, vomiting or loss of appetite, and feelings of disorientation, restlessness or fatigue. These may be symptoms of kidney failure, which can be life-threatening.
• Fever. This may be due to infection resulting from 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. Such as 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 due to an allergic reaction (hypersensitivity).

Other adverse reactions:
Very common adverse reactions (may occur in 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 of fatigue.
• 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 the nose and throat.
• Dizziness.
• Headache.
• Sleep disturbances (insomnia).
• Nosebleeds.
• Muscle and bone pain (including back, bone and limb pain).
• Weakness (asthenia).
• Weight loss.
• Low blood potassium levels.

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

• Bleeding inside the skull.
• Blood infection caused by bacteria (septicaemia). This may result from a low number of white blood cells 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 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, bleeding from the stomach or intestines, bleeding from the anal area due to haemorrhoids, bleeding from the eye, bleeding under or into the skin (haematomas).
• 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 colour changes.
• Skin redness (erythema), purple spots on the skin (purpura), flat skin rash (maculopapular rash).
• Skin infection, inflammation of the subcutaneous connective tissue (cellulitis).
• Infection of the nose and throat or sore throat or throat inflammation (upper respiratory tract infection).
• Bronchitis.
• Nasal pain or runny nose (rhinitis), or sinus pain (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 of 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 skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).
• Muscle pain (myalgia).
• Increased serum creatinine levels (shown in laboratory tests).

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

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

Rare adverse reactions (may occur in 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, and uric acid, and low calcium levels, leading to kidney dysfunction, heart rhythm disturbances, seizures, and sometimes death.
• Necrosis at the injection site.

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

• Infection of deeper skin layers that spreads rapidly, causing damage to the skin and tissues, 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 the 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 symptoms occur, including any adverse symptoms not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of 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
By reporting adverse reactions, additional information on the safety of the medicine can be collected.

5. How to store Azacitidine Delfarma

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the specified month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Delfarma.
They are also responsible for the correct preparation and disposal of unused Azacitidine Delfarma.
Unopened vials of this medicine – no special storage conditions required.

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

For later use
If the Azacitidine Delfarma suspension was prepared using unrefrigerated water for injections, the suspension must be immediately placed in a refrigerator (2°C – 8°C) after preparation and stored in the refrigerator for a maximum of 8 hours.
If the Azacitidine Delfarma suspension was prepared using refrigerated (2°C – 8°C) water for injections, the prepared suspension must be immediately placed 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 package and other information

What Azacitidine Delfarma 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 Azacitidine Delfarma looks like and contents of the pack
Azacitidine Delfarma is a white or almost white lyophilised powder for suspension for injection, supplied in a vial made of colourless type I glass, closed with a grey bromobutyl rubber stopper and an aluminium flip-off cap with a green polypropylene disc, containing 100 mg of azacitidine.
Each pack contains one vial of Azacitidine Delfarma.
For further information, please contact the responsible party or the parallel importer.
Marketing Authorisation Holder in Germany, the country of export:
Seacross Pharma (Europe) Limited
POD 13, The Old Station House
15A Main Street, Blackrock, A94 T8P8 Dublin, Ireland
Manufacturer:
Seacross Pharma (Europe) Limited
POD 13, The Old Station House
15A Main Street, Blackrock, A94 T8P8 Dublin, Ireland
Parallel Importer:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź, Poland
Repackaged by:
Delfarma Sp. z o.o.
ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź, Poland
German Marketing Authorisation Number (country of export): 2204002.00.00
Parallel Import Authorisation Number: 24/26

Information intended exclusively for healthcare professionals:

Safe handling recommendations
Azacitidine Delfarma is a cytotoxic medicine and, as with other potentially toxic compounds, caution must be exercised when handling azacitidine suspensions and during their preparation. Appropriate procedures for the preparation and disposal of antineoplastic medicinal products should be followed.
In case of contact of dissolved azacitidine with the skin, immediately wash the skin thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.

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

Reconstitution procedure
Azacitidine Delfarma should be dissolved in water for injections. The shelf life of the prepared medicine can be extended by dissolving it in cooled (2°C to 8°C) water for injections. Detailed storage information for the reconstituted medicine 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 all 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, then 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 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 remove the active substance. Note that some adapters, needles, and closed-system devices contain filters; therefore, such systems should not be used for administering the reconstituted medicinal product.

5. Clean the rubber stopper and insert a new syringe with a needle into the vial. Then invert the vial, ensuring the needle tip is below the fluid level. Pull back the plunger to withdraw the required volume of medicinal product for administration, making sure that all air has been expelled from the syringe.
   Then remove the syringe with the needle 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 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., a 150 mg dose = 6 ml, two syringes with 3 ml each. Due to retention in the vial and needle, it may not be possible to withdraw the entire suspension from the vial.

8. Immediately before administration, resuspend the contents of the dosing syringe. The temperature of the suspension at the time of injection should be approximately 20°C–25°C. To resuspend, roll the syringe vigorously between the palms until a uniform, cloudy suspension is obtained. Discard the product if large particles or aggregates are present.

Storage of the reconstituted product
For immediate use
The azacitidine Delfarma suspension may be prepared immediately before use, and the prepared suspension should be administered within 45 minutes. Storage temperature should not exceed 25°C. If more than 45 minutes have elapsed, the prepared suspension must be properly discarded and a new dose prepared.

For later use
When reconstituted with uncooled water for injections, the prepared suspension should be placed immediately in a refrigerator (2°C to 8°C) and stored for no longer than 8 hours. If more than 8 hours have elapsed during refrigerated storage, the suspension must be properly discarded and a new dose prepared.
When reconstituted with cooled water for injections (2°C to 8°C), the prepared suspension should be placed immediately in a refrigerator (2°C to 8°C) and stored for no longer than 22 hours. If more than 22 hours have elapsed during refrigerated storage, the suspension must be properly discarded and a new dose prepared.
From a microbiological standpoint, the reconstituted suspension should be used immediately. If not used immediately, the user is responsible for ensuring the storage conditions and duration prior to use, which must not exceed 8 hours at 2°C–8°C for product prepared with uncooled water for injections, or 22 hours for product prepared with cooled (2°C–8°C) water for injections.
For up to 30 minutes prior to administration, the syringe filled with the prepared suspension may be left to reach a temperature of approximately 20°C–25°C. If more than 30 minutes have elapsed, the suspension must be properly discarded 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) × BSA (m²)
The table below is merely an example of calculating individual azacitidine doses based on an average BSA of 1.8 m².

Route of administration
Do not filter the suspension after reconstitution.
The prepared Azacitidine Delfarma medication 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 separate injection sites.
Injection sites should be rotated. New injections should be administered at least 2.5 cm away from the previous injection site. Never inject into tender, bruised, erythematous, or hardened areas.
Any unused medication or waste material should be disposed of in accordance with local regulations for cytotoxic drugs.