Zassida

Package leaflet: Information for the patient

Zassida, 25 mg/ml, powder for preparation of suspension for injection
Azacitidinum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. This medicine may harm others, even if their symptoms are the same.
• If you experience any adverse effects, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet

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

1. What Zassida is and what it is used for

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

What Zassida is used for
Zassida is used in adult patients who are not candidates 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 difficulties in the normal production of blood cells.

How Zassida works
Zassida works by preventing the growth of cancer cells. Azacitidine is incorporated into the genetic material of cells (ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]). It is believed that its mechanism of action involves altering the way genes are activated and deactivated within the cell, as well as interfering with RNA and DNA synthesis. These effects are thought to correct the impaired maturation and growth of blood cells in the bone marrow seen in myelodysplastic disorders, and to destroy cancer cells in leukaemia.

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

2. Important information before using Zassida

When not to use Zassida

• 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 Zassida, discuss with the doctor or pharmacist if the patient:

• has low platelet count, red blood cells, or white blood cells;
• has kidney disease;
• has liver disease;
• has had heart disease, myocardial infarction, or any lung disease in the past.

Zassida may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Blood tests will be performed before starting treatment with Zassida and at the beginning of each treatment period (called a cycle). These tests are to check whether the patient has sufficient blood cells and whether the liver and kidneys are functioning properly.
Children and adolescents
Zassida is not recommended for use in children and adolescents under 18 years of age.
Zassida and other medicines
Tell the doctor or pharmacist about all medicines the patient is currently taking, has recently taken, or plans to take. Zassida may affect the way some other medicines work. Likewise, some other medicines may affect the way Zassida works.
Pregnancy, breastfeeding, and fertility
Pregnancy
Zassida should not be used 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 Zassida and for 6 months after stopping treatment with Zassida.
If a patient becomes pregnant during treatment, she should consult her doctor immediately.
Breastfeeding
Breastfeeding must be avoided during treatment with Zassida. It is unknown whether this medicine passes into human breast milk.
Fertility
Men should not father a child during treatment with Zassida. An effective method of contraception must be used during treatment and for 3 months after the end of treatment with this medicine.
Patients should consult their doctor before starting treatment if they wish to preserve sperm.
Driving and operating machinery
If adverse effects such as fatigue occur, patients should not drive, operate tools, or handle machinery.

3. How to use Zassida

Before administering Zassida to the patient, the doctor will give 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. The treating physician will determine the dose based on the patient's general condition, height, and body weight. The doctor will monitor progress and may adjust the dose if necessary.
• Zassida is administered daily for one week, followed by a 3-week break. This 4-week treatment cycle is repeated. Usually, patients receive at least 6 treatment cycles.

This medicine is administered by a doctor or nurse as a subcutaneous injection. It can be injected subcutaneously into the thigh, abdomen, or upper 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 everyone will experience them.
You must inform the doctor immediately if the patient experiences any of the
following side effects:

• Drowsiness, tremor, jaundice, abdominal distension 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 fatigued. These may be symptoms of kidney failure and may be life-threatening.
• Fever. This may be due to infection caused by a low number of white blood cells and may be life-threatening.
• Chest pain or shortness of breath, possibly 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 gastrointestinal bleeding or bleeding inside the head. These may be symptoms of a 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 occur in more than 1 in 10 people)

• Decreased number of red blood cells (anaemia). The patient may feel tired and appear 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.
• Lung inflammation.
• Chest pain, shortness of breath.
• Fatigue.
• 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 problems (insomnia).
• Nosebleeds.
• Muscle pain.
• Weakness.
• Weight loss.
• Low blood potassium levels.

Common side effects (may occur in less than 1 in 10 people):

• Bleeding inside the skull.
• Bacterial blood infection (sepsis). This may be due to a low number of white blood cells in the blood.
• Bone marrow failure. This may lead to low numbers of red blood cells, white blood cells and platelets.
• A type of anaemia in which the number of red blood cells, white blood cells and platelets is reduced.
• Urinary tract infection.
• Viral infection causing cold sores.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anal area due to haemorrhoids (haemorrhoidal bleeding), bleeding in the eye, bleeding under or into the skin (bruising).
• Blood in the urine.
• Mouth or tongue ulceration.
• Skin changes at the injection site. These include: swelling, hard lumps, bruising, bleeding into the skin (bruising), rash, itching and skin discoloration.
• Skin redness.
• Skin infection (cellulitis).
• Nose or throat infection or sore throat.
• Nose pain, nasal congestion or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Throat and larynx pain.
• Indigestion.
• Lethargy.
• General malaise.
• Restlessness, disorientation.
• Excessive hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside the cheeks, and sometimes on the palate, gums 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, lethargy.
• Bleeding at the catheter insertion site.
• A bowel disease that 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).

Uncommon side effects (may occur in less than 1 in 100 people):

• Hypersensitivity reaction (allergic reaction).
• Tremor.
• Liver failure.
• Large, raised, painful plum-coloured skin patches with fever.
• Inflammation of the membrane surrounding the heart (pericarditis).

Rare side effects (may occur in less than 1 in 1000 people):

• Dry cough.
• Painless swelling of the fingertips (clubbing).
• 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 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, irregular heartbeat, seizures, and sometimes death.

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

• Infection of deep skin layers that spreads rapidly, causing skin and tissue damage 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 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 any adverse reactions occur, including any adverse reactions not listed
in this leaflet, inform a doctor, pharmacist or nurse. Side effects 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
Adverse reactions can also be reported to the marketing authorisation holder or its representative.
Reporting side effects helps to provide more information on the safety of the medicine.

5. How to store the medicine Zassida

Keep the medicine out of sight and reach of children.
Do not use this medicine after the expiry date stated on the carton or label of the syringe following: EXP. The expiry date refers to the last day of the stated month.
The doctor, pharmacist, or nurse is responsible for storing Zassida medicine. They are also responsible for preparing Zassida medicine and properly disposing of any unused portions.
Unopened vials of this medicine – no special storage instructions are required.

For immediate use
After reconstitution, the suspension should be administered within 45 minutes.

For later use
If the Zassida suspension has been prepared using unrefrigerated 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 no longer than 8 hours.
If the Zassida suspension has been 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 no longer than 32 hours.
Before administration, allow the suspension to reach room temperature (20°C - 25°C) for up to a maximum of 30 minutes.
Do not use the medicine if large particles are visible in the suspension.

6. Contents of the Package and Other Information

What the medicinal product Zassida contains
The active substance is azacitidine.
Each vial contains 100 mg or 150 mg of azacitidine. After reconstitution with 4 ml or 6 ml of water
for injections, the suspension contains 25 mg/ml of azacitidine.
The other ingredient is: mannitol.

What Zassida looks like and contents of the pack
Zassida is a white powder for preparation of suspension for injection.
The powder is contained in a type I colourless glass vial with a bromobutyl rubber stopper coated with ETFE and an aluminium seal, containing 100 mg or 150 mg of azacitidine.
Each pack contains one vial.

Marketing Authorisation Holder
Zentiva k.s.
U kabelovny 130
Dolni Měcholupy
102 37 Prague 10
Czech Republic

Manufacturer/Importer
AqVida GmbH
Kaiser-Wilhelm-Strasse 89
20355 Hamburg, Germany

For further information about this medicinal product and its names in the Member States of the
European Economic Area, please contact the representative of the Marketing Authorisation Holder in Poland:
Zentiva Polska Sp. z o.o.
ul. Bonifraterska 17
00-203 Warsaw
tel: +48 22 375 92 00

Information intended exclusively for healthcare professionals:
Safe handling recommendations
Zassida is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution must be exercised during preparation and handling of the azacitidine suspension. Appropriate procedures for handling and disposal of antineoplastic medicinal products must be followed.
In case of contact of the prepared azacitidine with the skin, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned below (see "Preparation procedure").

Preparation procedure
The medicinal product Zassida should be prepared using water for injections. The shelf life of the prepared medicinal product can be extended by using cooled (2°C - 8°C) water for injections. Details on storage of the prepared product are provided above.

1. Each pack contains one vial of azacitidine.
2. For the 100 mg vial – transfer 4 ml of water for injections into a syringe, ensuring that the syringe contains no air bubbles. For the 150 mg vial – transfer 6 ml of water for injections into a syringe, ensuring that the syringe contains no air bubbles.
3. Insert the syringe needle through the rubber stopper of the vial containing azacitidine and inject the 4 ml or 6 ml of water for injections into the vial.
4. After removing the syringe and needle, shake the vial vigorously until a homogeneous, cloudy suspension is obtained. After reconstitution, each ml of suspension contains 25 mg of azacitidine (100 mg/4 ml or 150 mg/6 ml). The prepared product should be a homogeneous suspension free from aggregates, large particles or foreign bodies. Discard the product if large particles or aggregates are present. Do not filter the suspension after preparation, as this may lead to removal of the active substance. Note that some adapters, spikes and closed system devices contain filters. Therefore, such devices should not be used for administration of the medicinal product after reconstitution.
5. Clean the rubber stopper and insert a new syringe with a needle into the vial. Then 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. Ensure that all air has been expelled from the syringe. Then withdraw the needle and syringe 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. For 150 mg = 6 ml dose – use the vial containing 150 mg. Due to retention in the vial and needle, complete withdrawal of the entire suspension from the vial may not be possible.
8. The contents of the syringe containing the dose must be resuspended immediately before administration. Prior to administration, allow the syringe filled with the prepared suspension to reach approximately 20°C–25°C. To resuspend, vigorously roll the syringe between the palms until a homogeneous, cloudy suspension is obtained.
   Discard the suspension if large particles or aggregates are present.

Storage of the prepared product
For immediate use
The medicinal product Zassida may be prepared immediately before administration and administered within 45 minutes. If more than 45 minutes elapse, the prepared suspension must be properly discarded and a new dose prepared.

For later use
If the product was prepared using uncooled water for injections, the prepared suspension must be placed immediately after reconstitution in a refrigerator at (2°C - 8°C) and stored in the refrigerator for no more than 8 hours. If more than 8 hours have elapsed during refrigerated storage, the suspension must be properly discarded and a new dose prepared.
If the product was prepared using cooled (2°C - 8°C) water for injections, the prepared suspension must be placed immediately after reconstitution in a refrigerator (2°C - 8°C) and stored in the refrigerator for no more than 32 hours. If more than 32 hours have elapsed during refrigerated storage, the suspension must be properly discarded and a new dose prepared.
Allow the syringe filled with the prepared suspension to reach approximately 20°C–25°C for up to 30 minutes before administration. If more than 30 minutes elapse, 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) x BSA (m²)
The table below is an example of how to calculate an individual azacitidine dose based on a body surface area of 1.8 m².

| Dose mg/m² | Total dose based on BSA 1.8 m² (mg) | Number of vials needed | Total volume of prepared suspension needed (ml) |
|------------|--------------------------------------|------------------------|--------------------------------------------------|
| 75 mg/m² (100%) | 135 mg | 1 vial of 150 mg | 5.4 ml |
| 37.5 mg/m² (50%) | 67.5 mg | 1 vial of 100 mg | 2.7 ml |
| 25 mg/m² (33%) | 45 mg | 1 vial of 100 mg | 1.8 ml |

Method of administration
The prepared Zassida product should be administered subcutaneously (insert the needle at an angle of 45–90º) using a 25G 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 never into irritated, bruised, red or hard areas.

Disposal
Any unused medicinal product or waste material must be disposed of in accordance with local regulations.