Azacitidine msn

Package leaflet: Information for the user

Azacitidine MSN, 25 mg/mL, powder for suspension for injection
Azacitidinum
Please read all of this leaflet carefully before use, as it contains important information for the patient.
Keep this leaflet, as you may need to read it again.
If you have any questions, please consult your doctor, pharmacist, or nurse.
If you experience any side effects, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse.
See section 4.
Contents of the leaflet:

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

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

What Azacitidine MSN is
Azacitidine MSN is an anticancer medicine belonging to a group of medicines called "antimetabolites". Azacitidine MSN contains an active substance called "azacitidine".
What Azacitidine MSN is used for
Azacitidine MSN is used in adults who are not eligible for haematopoietic stem cell transplantation, for the treatment of:

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

These are diseases affecting the bone marrow and may cause difficulties in the normal production of blood cells.
How Azacitidine MSN works
Azacitidine MSN 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 way genes are activated and deactivated, as well as interfering with the synthesis of new RNA and DNA. These actions are thought to correct the impaired maturation and growth of young blood cells in the bone marrow, which underlies myelodysplastic disorders, and to kill cancer cells in leukaemia.
If you have any questions about how Azacitidine MSN works or why this medicine has been prescribed for you, please consult your doctor or nurse.

2. Important information before using Azacitidine MSN

When not to use Azacitidine MSN

• 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 Azacitidine MSN, 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, heart attack or any lung disease.

Azacitidine may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Before starting treatment with Azacitidine MSN and at the beginning of each treatment period (so-called "cycle"), the patient will undergo blood tests. 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
Azacitidine MSN is not recommended for use in children and adolescents under 18 years of age.
Azacitidine MSN 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 MSN may affect the action of certain other medicines. Likewise, certain other medicines may affect the action of Azacitidine MSN.
Pregnancy, breastfeeding and fertility
Pregnancy
Do not use Azacitidine MSN during pregnancy, as it may be harmful to the unborn child.
If the patient can become pregnant, she should use an effective method of contraception during treatment with Azacitidine MSN and for 6 months after completion of treatment with Azacitidine MSN. 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 baby, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding
Do not breastfeed while taking Azacitidine MSN. It is unknown whether this medicine passes into human milk.
Effect on fertility
Men should not father a child while being treated with Azacitidine MSN. Men should use an effective method of contraception during and for 3 months after completion of treatment with Azacitidine MSN.
The patient should consult with the doctor if he wishes to store sperm before starting this treatment.
Driving and operating machinery
If adverse effects such as fatigue occur, do not drive, use tools or operate machinery.

3. How to use Azacitidine MSN

Before administering Azacitidine MSN, 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 m^2 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 during treatment and may change the dose if necessary.
• Azacitidine MSN is given daily for one week, followed by a 3-week break. This "treatment cycle" is repeated every 4 weeks. You will usually receive at least 6 treatment cycles.

This medicine will be administered as a subcutaneous injection by a doctor or nurse. The medicine can be given subcutaneously in the thigh, abdomen, or upper arm.
If you have any further questions 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 everybody will experience them.
You should tell your doctor immediately if you notice any of the following side effects:

• Drowsiness, tremors, jaundice, abdominal bloating 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 feeling disoriented, restless or tired. These may be symptoms of kidney failure and may be life-threatening.
• Fever. This may be due to infection caused by a low white blood cell count, which may be life-threatening.
• Chest pain or shortness of breath, which may be 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 bleeding in the stomach or intestines, or bleeding inside the head. These may be symptoms of low platelet count.
• Difficulty breathing, swelling of the lips, itching or rash. This may be due to an allergic reaction (hypersensitivity).

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

• Decreased number of red blood cells (anaemia). The patient may feel tired and look 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.
• Pneumonia.
• Chest pain, shortness of breath.
• Fatigue (tiredness).
• 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 (epistaxis).
• Muscle 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 white blood cell count.
• Bone marrow failure. This may lead to low numbers of red and white blood cells and platelets.
• A type of anaemia in which there is a reduction in red and white blood cells and platelets.
• Urinary tract infection.
• Viral infection causing cold sores (herpes).
• Bleeding gums, bleeding in the stomach or intestines, bleeding from the anal area due to haemorrhoids (haemorrhagic haemorrhoids), bleeding in the eye, bleeding under the skin or in the skin (bruising).
• 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 (bruising), 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 runny nose, or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Sore throat and larynx.
• Indigestion.
• Apathy.
• General malaise.
• Anxiety.
• Disorientation.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside of cheeks, and sometimes on gums, palate and tonsils (oral thrush).
• 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.
• Intestinal disease which may cause 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).

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

• Allergic reaction (hypersensitivity).
• Tremor.
• Liver failure.
• Large, plum-coloured, raised, painful skin lesions accompanied by fever.
• Painful skin ulceration (pyogenic skin necrotizing fasciitis).
• Inflammation of the membrane surrounding the heart (pericarditis).

Rare side effects (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 products from 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, 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 (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 also 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
Side effects can also be reported directly to the marketing authorisation holder.
Reporting side effects helps to provide more information on the safety of the medicine.

5. How to store Azacitidine MSN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and cardboard package after: EXP. The expiry date refers to the last day of the stated month.
Storage of Azacitidine MSN is the responsibility of the doctor, pharmacist, or nurse. They are also responsible for the proper preparation and disposal of unused Azacitidine MSN.
Unopened vials – no special storage instructions apply.
For immediate use
After reconstitution, the suspension should be administered within 60 minutes.
For later use
If the Azacitidine MSN suspension was prepared using unrefrigerated water for injections, the prepared suspension must be immediately stored in a refrigerator (2°C - 8°C) and may be stored refrigerated for up to 24 hours.
If the Azacitidine MSN suspension was prepared using refrigerated water for injections (2°C - 8°C), the prepared suspension must be immediately stored in a refrigerator (2°C - 8°C) and may be stored refrigerated for up to 36 hours when kept in the vial or up to 30 hours when kept in a syringe.
Before administration, allow the suspension to stand for up to 30 minutes to reach room temperature (20°C - 25°C).
If large particles are present in the suspension, it should be discarded.

6. Contents of the pack and other information

What Azacitidine MSN contains
The active substance is azacitidine. One vial contains 100 mg of azacitidine. After reconstitution
by adding 4 mL of water for injections, the prepared suspension contains 25 mg/mL of azacitidine.
The other ingredient is mannitol (E 431).

What Azacitidine MSN looks like and contents of the pack
Azacitidine MSN is a white powder for injection suspension, supplied in a 30 mL colourless, transparent
Type I borosilicate glass vial containing 100 mg of azacitidine. If necessary, vials may be placed in a
polypropylene overwrap or directly packed into a clean cardboard carton.
Each pack contains one vial of Azacitidine MSN.

Marketing Authorisation Holder:
MSN Labs Europe Limited
KW20A Corradino Park
Paola, PLA 3000
Malta
tel.: (+48) 699 711 147
{logo of the marketing authorisation holder}

Manufacturer/Importer:
Pharmadox Healthcare Limited
KW20A Kordin Industrial Park
Paola, PLA 3000
Malta
MSN Labs Europe Limited
KW20A Corradino Park
Paola, PLA 3000
Malta

This medicinal product is authorised in the European Economic Area countries under the following names:
Netherlands: Azacitidine Vivanta 25 mg/ml, poeder voor suspensie voor injectie
Poland: Azacitidine MSN
Hungary: Azacitidine MSN 25 mg/ml por szuszpenziós injekcióhoz
Czech Republic: Azacitidine MSN
Romania: Azacitidina MSN 25mg/ml pulbere pentru suspensie injectabilă

Information intended exclusively for medical professionals:

Safe handling recommendations
The medicinal product Azacitidine MSN is a cytotoxic drug, and as with other potentially toxic compounds, caution must be exercised when handling and preparing azacitidine suspension. Appropriate procedures for handling and disposal of antineoplastic medicinal products should be followed.
In case of contact of prepared azacitidine with skin, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, flush thoroughly with water.

Pharmaceutical incompatibilities
This medicinal product must not be mixed with other medicinal products except as specified below (see “Reconstitution procedure”).

Reconstitution procedure
The medicinal product Azacitidine MSN should be dissolved in Water for Injections. The shelf life of the reconstituted medicinal product can be extended by dissolving it in cooled (2°C to 8°C) Water for Injections.
Detailed information on storage 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).
2. Draw up 4 mL of Water for Injections into a syringe and ensure 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 azacitidine vial, 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 will contain 25 mg of azacitidine (100 mg/4 mL). The prepared product is a uniform, cloudy suspension free from agglomerates. Discard the product if it contains large particles or agglomerates. Do not filter the suspension after reconstitution, as this may result in removal of the active substance. Note that some adapters, spikes, and closed system transfer 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 to administer 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 new subcutaneous injection needle (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., a 150 mg dose = 6 mL, two syringes with 3 mL each. Due to sedimentation on vial walls and in the needle, it may not be possible to withdraw the entire suspension from the vial.
8. The syringe containing the dose must be resuspended immediately before administration. The filled syringe may be left for up to 30 minutes before administration to allow the suspension to reach approximately 20°C–25°C. If more than 30 minutes elapse, the suspension should be properly discarded and a new dose prepared. To resuspend, rotate the syringe vigorously between the palms until a uniform, cloudy suspension is obtained. Discard the product if it contains large particles or agglomerates.

Storage after reconstitution
For immediate use
The suspension of the medicinal product Azacitidine MSN may be prepared immediately before use, and the prepared suspension should be administered within 60 minutes. If more than 60 minutes have elapsed, the prepared suspension should be properly discarded and a new dose prepared.

For later use
If the product was prepared using uncooled Water for Injections, the prepared suspension should be placed immediately in a refrigerator (2°C to 8°C) after reconstitution and stored in the refrigerator for a maximum of 24 hours. If the refrigerated storage time exceeds 24 hours, the suspension should be properly discarded and a new dose prepared.
If the product was prepared using cooled (2°C to 8°C) Water for Injections, the reconstituted suspension should be placed immediately in a refrigerator (2°C to 8°C) after preparation and stored for a maximum of 36 hours when stored in the vial or 30 hours when stored in the syringe. If the refrigerated storage time exceeds 36 hours (when stored in the vial) or 30 hours (when stored in the syringe), the suspension should be properly discarded and a new dose prepared.
The syringe filled with the prepared suspension should be left at room temperature for up to 30 minutes before administration to allow it to reach approximately 20°C–25°C. If more than 30 minutes elapse, the suspension should be properly discarded and a new dose prepared.

Individual dose calculation
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 only an example of how to calculate individual doses of azacitidine based on an average BSA of 1.8 m².

Route of administration
Do not filter the suspension after reconstitution.
The medicinal product Azacitidine MSN, after reconstitution, should be administered subcutaneously (insert the needle at an angle of 45–90°) using a 25 G needle into the upper 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 from the previous injection site, and injections should never be given into tender, bruised, erythematous, or hardened areas.
Any unused medicinal product or waste material should be disposed of in accordance with local regulations.