Azacitidine Seacross

Package leaflet: Information for the user

Azacitidine Seacross 25 mg/mL powder for injectable suspension

Azacitidine
Equivalent medicine
Please read 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 questions, ask your doctor, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

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

1. What Azacitidina Seacross is and what it is used for

What Azacitidina Seacross is
Azacitidina Seacross is an anticancer agent belonging to a group of medicines called
"antimetabolites". Azacitidina Seacross contains the active substance "azacitidine".
What Azacitidina Seacross is used for
Azacitidina Seacross is used in adults who are not eligible for stem cell transplantation to treat:

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

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

How Azacitidina Seacross works
Azacitidina Seacross works by preventing cancer cells from growing. 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 cells switch genes on and off, and by interfering with the production of new RNA and DNA. These actions are thought to correct the abnormalities in the 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 Azacitidina Seacross works or why it has been prescribed for you, please speak to your doctor or nurse.

2. What you need to know before using Azacitidina Seacross

Do not use Azacitidina Seacross

• if you are allergic to azacitidine or to 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
Talk to your doctor, pharmacist, or nurse before using Azacitidina Seacross:

• if you have low platelet counts, low red blood cell counts, or low white blood cell counts;
• if you have kidney disease;
• if you have liver disease;
• if you have previously had heart disease, a heart attack, or a history of lung disease. If you notice signs of bleeding, develop a fever, or experience reduced urine output, inform your doctor immediately. See also section 4.

Blood tests
Before starting treatment with Azacitidina Seacross and at the beginning of each treatment cycle, blood tests will be performed to check whether you have an adequate number of blood cells and to ensure that your liver and kidneys are functioning normally.

Children and adolescents
The use of Azacitidina Seacross is not recommended in children and adolescents under 18 years of age.

Other medicines and Azacitidina Seacross
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This is because Azacitidina Seacross may affect how other medicines work. Likewise, other medicines may affect how Azacitidina Seacross works.

Pregnancy, breastfeeding and fertility

Pregnancy
You must not use Azacitidina Seacross during pregnancy, as it may harm the unborn child. Use an effective method of contraception during treatment and for up to 3 months after treatment ends. Inform your doctor immediately if you become pregnant during treatment.
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Breastfeeding
You must not breastfeed while using Azacitidina Seacross. It is not known whether this medicine passes into breast milk.

Fertility
Male patients must not father a child during treatment with Azacitidina Seacross. Use an effective method of contraception during treatment and for up to 3 months after treatment ends.
Consult your doctor if you wish to preserve sperm before starting this treatment.

Driving and using machines
Do not drive or operate tools or machinery if you experience side effects such as fatigue.

3. How to use Azacitidina Seacross

Before administering Azacitidina Seacross, your doctor will give you another medicine to prevent nausea and vomiting at the beginning of each treatment cycle.

• The recommended dose is 75 mg per m² of body surface area. Your doctor will determine the dose of this medicine based on your general condition, height, and body weight. Your doctor will monitor your progress and, if necessary, adjust the dose.
• Azacitidina Seacross is administered daily for one week, followed by a 3-week break. This "treatment cycle" will be repeated every 4 weeks. Generally, at least 6 treatment cycles are administered.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Contact your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremor, jaundice, abdominal swelling, and easy bruising. These may be symptoms of liver failure and can be life-threatening.
• Swollen legs and feet, back pain, reduced urine output, increased thirst, rapid pulse, dizziness, nausea, reduced appetite, confusion, restlessness, or fatigue. These may be symptoms 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, possibly accompanied by fever. This may be due to a lung infection called "pneumonia" and can be life-threatening.
• Bleeding. For example, blood in the stool due to bleeding in the stomach or intestine, or bleeding inside the head. These may be symptoms of low platelet levels in the blood.
• Difficulty breathing, swollen lips, itching, or skin rash. These may be due to an allergic reaction (hypersensitivity).

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

• Low red blood cell count (anaemia). You may feel tired and weak.
• Low white blood cell count. This may be accompanied by fever. You may also be more prone to infections.
• Low platelet count in the blood (thrombocytopenia). You may be more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue.
• Injection site reaction, including redness, pain, or skin reaction.
• Loss of appetite, anorexia.
• Joint pain.
• Bruising.
• Skin rash.
• Small red or purple spots under the skin.
• Stomach pain (abdominal pain).
• Itching.
• Fever.
• Irritation of nose and throat.
• Dizziness.
• Headache.
• Difficulty sleeping (insomnia).
• Nosebleeds (epistaxis).
• 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 inside the head.
• Blood infection due to bacteria (sepsis), which may be caused by a low white blood cell count.
• Bone marrow failure, which may lead to reduced numbers of red blood cells, white blood cells, and platelets.
• A type of anaemia with reduced red blood cells, white blood cells, and platelets.
• Urinary tract infection.
• Viral infection causing irritation (herpes).
• Bleeding gums, bleeding in the stomach or intestine, rectal bleeding due to haemorrhoids (haemorrhoidal haemorrhage), bleeding in the eye, bleeding under or into the skin (haematoma).
• Blood in the urine.
• Inflammation in the mouth or on the tongue (stomatitis).
• Skin changes at the injection site, including swelling, hard lump, bruising, bleeding into the skin (haematoma), rash, itching, and changes in skin colour.
• Skin redness (erythema), purple spots on the skin (purpura), flat skin rash (macular rash).
• Skin infection, inflammation of the subcutaneous connective tissue (cellulitis).
• Infection of the nose and throat, sore throat, or inflammation of the pharynx (upper respiratory tract infection).
• Bronchitis.
• Irritated nose or sinuses (rhinitis) or runny nose (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Throat and larynx pain.
• Indigestion.
• Lethargy.
• General feeling of being unwell.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating covering the tongue, inside of the cheeks, and sometimes the palate, gums, and tonsils (fungal mouth infection).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension), causing dizziness upon standing or sitting up.
• Drowsiness, numbness.
• Bleeding due to catheter.
• Illness affecting the intestine that may cause fever, vomiting, and stomach pain (diverticulitis).
• Fluid around the lungs (pleural effusion).
• Chills.
• Muscle spasms.
• Raised, itchy skin rash (urticaria).
• Fluid accumulation around the heart (pericardial effusion).
• Muscle pain (myalgia).
• Increased serum creatinine levels (shown by laboratory tests).

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

• Allergic reaction (hypersensitivity).
• Liver failure.
• Appearance of large, painful, raised plum-coloured skin patches with fever.
• Painful skin ulceration (pyoderma gangrenosum).
• Inflammation of the lining around the heart (pericarditis).
• Coma, which may occur in severe cases of liver disease (progressive hepatic coma).
• Medical condition involving accumulation of acid in the body due to the kidneys' inability to adequately acidify urine (renal tubular acidosis).

Rare side effects (may affect up to 1 in 1,000 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 breakdown products of dying cancer cells and may include the following: changes in blood parameters; high levels of potassium, phosphate, and uric acid; and low calcium levels, leading to changes in kidney function, heart rhythm, seizures, and sometimes death.
• Necrosis at the injection site.

Not known (frequency cannot be estimated from available data)

• Infection of the deeper layers of the skin that spreads rapidly, damaging skin and tissues, which may be fatal (necrotising fasciitis).

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Azacitidina Seacross

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 vial label and on the
carton after Exp. The expiry date refers to the last day of that month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidina Seacross,
as well as for the preparation and proper disposal of any unused Azacitidina Seacross.
For unopened vials of this medicine – no special storage conditions are required.
For immediate use
Once prepared, the suspension must be administered within 45 minutes and the storage temperature must not exceed 25°C.
For subsequent use
If the Azacitidina Seacross suspension is reconstituted with non-refrigerated water for injections, the suspension must be placed in a refrigerator (2°C - 8°C) immediately after preparation and stored in the refrigerator for a maximum of 8 hours.
If the Azacitidina Seacross suspension is reconstituted with refrigerated water for injections (2°C - 8°C), the reconstituted suspension must be placed in a refrigerator (2°C - 8°C) immediately after preparation and stored in the refrigerator for a maximum of 22 hours.
Before administration, allow up to 30 minutes for the suspension to reach room temperature (20°C – 25°C).
The suspension must be discarded if large particles are present.

6. Package contents and other information

What Azacitidina Seacross contains

• The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution with 4 mL of water for injection, the reconstituted suspension contains 25 mg/mL of azacitidine.
• The other component is mannitol (E421).

Description of the appearance of Azacitidina Seacross and package contents
Azacitidina Seacross is a white to almost white lyophilized powder for injectable suspension,
supplied in a colourless glass vial sealed with a grey bromobutyl rubber stopper and an aluminium ****crimp cap with a green polypropylene disc, containing 100 mg of azacitidine.
Each pack contains one vial of Azacitidina Seacross.
Marketing Authorisation Holder and Manufacturer
Seacross Pharma (Europe) Limited
Regus Dublin Airport
Skybridge House
Corballis Road North
Dublin Airport Swords
Co. Dublin, K67 P6K2
Ireland
This medicinal product is authorised in EEA Member States under the following names:

The following information is intended exclusively for healthcare professionals:

Recommendations for safe handling
Azacitidine Seacross is a cytotoxic medicinal product and, therefore, as with other potentially toxic compounds, caution must be exercised during handling and preparation of azacitidine suspensions.
Appropriate procedures for handling and disposal of antineoplastic medicinal products must be followed.
In case of skin contact with reconstituted azacitidine, wash immediately and thoroughly with water and soap. In case of mucous membrane contact, rinse thoroughly with water.

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned below (see section “Reconstitution procedure”).

Reconstitution procedure
Azacitidine Seacross must be reconstituted with Water for Injections. The shelf life of the reconstituted medicinal product can be extended if reconstitution is performed using refrigerated Water for Injections (2°C–8°C). Details on storage of the reconstituted medicinal product are provided below.

1. Prepare the following items: vial(s) of azacitidine; vial(s) of Water for Injections; non-sterile surgical gloves; alcohol swabs; 5 mL syringe(s) with needle(s).
2. Draw up 4 mL of Water for Injections into the syringe, ensuring that any air bubbles in the syringe are expelled.
3. Insert the needle of the syringe containing 4 mL of Water for Injections through the rubber stopper of the azacitidine vial and inject the Water for Injections into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a uniform, opaque suspension is formed. After reconstitution, each mL of suspension contains 25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, opaque suspension free from aggregates. The suspension must be discarded 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 systems contain filters; therefore, such systems must not be used for administration of the medicinal product after reconstitution.
5. Clean the rubber stopper and insert a new syringe with an attached needle into the vial. Invert the vial, ensuring that the tip of the needle is below the liquid level. Pull back the plunger to withdraw the required amount of medicinal product for the correct dose, ensuring that any air bubbles remaining in the syringe are expelled. Then remove the syringe with the needle from the vial and dispose of the needle.
6. At this point, securely attach a new subcutaneous injection needle (use of 25-gauge needles is recommended) to the syringe. The suspension should not be pushed into the needle prior to injection in order to reduce the incidence of local reactions at the injection site.
7. When more than one vial is required, repeat the steps described for suspension preparation. For doses requiring more than one vial, divide the dose equally (e.g., a 150 mg dose = 6 mL, into 2 syringes with 3 mL each). Due to retention in the vial and needle, it may not be possible to aspirate all the suspension from the vial.
8. The contents of the dosing syringe must be resuspended immediately before administration. The suspension temperature at the time of injection should be approximately 20°C–25°C. To resuspend, roll the syringe vigorously between the palms of the hands until a uniform, opaque suspension is obtained. The suspension must be discarded if large particles or aggregates are present.

Storage of the reconstituted medicinal product
For immediate use
The suspension of Azacitidine Seacross may be prepared immediately before use, and the reconstituted suspension must be administered within 45 minutes, with storage temperature not exceeding 25°C. If the elapsed time exceeds 45 minutes, the reconstituted suspension must be appropriately discarded and a new dose prepared.
For subsequent use
When reconstitution is performed using non-refrigerated Water for Injections, the reconstituted suspension must be stored immediately after reconstitution in a refrigerator (2°C–8°C) and kept refrigerated for a maximum of 8 hours. If the storage time in the refrigerator exceeds 8 hours, the suspension must be appropriately discarded and a new dose prepared.
When reconstitution is performed using refrigerated Water for Injections (2°C–8°C), the reconstituted suspension must be stored immediately after reconstitution in a refrigerator (2°C–8°C) and kept refrigerated for a maximum of 22 hours. If the storage time in the refrigerator exceeds 22 hours, the suspension must be appropriately discarded and a new dose prepared.
From a microbiological standpoint, the reconstituted product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage prior to use; storage must not exceed 8 hours at temperatures between 2°C and 8°C when reconstitution is performed with non-refrigerated Water for Injections, or must not exceed 22 hours when reconstitution is performed with refrigerated Water for Injections (2°C–8°C).
Prior to administration, allow up to 30 minutes for the filled syringe containing the reconstituted suspension to reach a temperature of approximately 20°C–25°C. If the elapsed time exceeds 30 minutes, the suspension must be discarded and appropriately disposed of, and a new dose must be prepared.

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

Method of administration
Do not filter the suspension after reconstitution.
The reconstituted solution of Azacitidina Seacross must be injected subcutaneously (insert the needle at an angle of 45–90°) into the upper arm, thigh, or abdomen, using a 25-gauge needle.
Doses exceeding 4 mL must be administered at two different injection sites.
Rotate injection sites regularly. Subsequent injections should be administered at least 2.5 cm away from the previous site and never into sensitive, bruised, reddened, or hardened areas.
Any unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations for cytotoxic agents.