Azacitidine glenmark

Package leaflet: Information for the user

Azacitidine Glenmark, 25 mg/ml, powder for solution for injection
Azacitidinum
Please read all of 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 further questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

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

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

What Azacitidine Glenmark is used for
Azacitidine Glenmark is used in adults who are not eligible for stem cell transplantation to treat:

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

These diseases affect the bone marrow and may cause problems with the normal production of blood cells.

How Azacitidine Glenmark works
Azacitidine Glenmark 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 to work by altering the way genes in the cell are activated and deactivated, as well as interfering with the production of RNA and DNA. These actions are thought to lead to correction of the impaired 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 Azacitidine Glenmark works or why this medicine has been prescribed for you, please ask your doctor or nurse.

2. Important information before using Azacitidine Glenmark

When not to use Azacitidine Glenmark

• 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 Glenmark, discuss this with your doctor, pharmacist,
or nurse:

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

Azacitidine Glenmark may cause a severe immune reaction called "differentiation syndrome" (see section 4).
Blood tests
Before starting treatment with Azacitidine Glenmark and at the beginning of each treatment cycle, blood tests will be performed. The purpose of these tests is to check whether the patient has an adequate number of blood cells, and whether the liver and kidneys are functioning properly.
Children and adolescents
Azacitidine Glenmark is not recommended for use in children and adolescents under 18 years of age.
Azacitidine Glenmark 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. This is because Azacitidine Glenmark may affect the way some other medicines work. Likewise, some other medicines may affect the way Azacitidine Glenmark works.
Pregnancy, breastfeeding, and effects on fertility
Pregnancy
Do not use Azacitidine Glenmark 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 Glenmark and for 6 months after treatment has ended. 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 have a baby, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding
Do not breastfeed while receiving Azacitidine Glenmark. It is not known whether this medicine passes into human milk.
Effect on fertility
Men should not father a child while receiving treatment with Azacitidine Glenmark. Men should use an effective method of contraception during treatment with Azacitidine Glenmark and for 3 months after treatment with Azacitidine Glenmark has ended.
The patient should consult his 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 Glenmark

Before administering Azacitidine Glenmark to the patient, the doctor will give an additional 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 doctor will determine the appropriate dose of this medicine for the patient, depending on the patient's general condition, height and weight. The doctor will monitor the patient's progress during treatment and may adjust the dose if necessary.
• Azacitidine Glenmark is administered daily for one week, followed by a rest period of 3 weeks. This "treatment cycle" will be repeated every 4 weeks. The patient will usually receive at least 6 treatment cycles.

Azacitidine Glenmark is administered to the patient as a subcutaneous injection (subcutaneous administration) by a doctor or nurse. It may be injected subcutaneously into the thigh, abdomen, or upper arm.
If there are any further doubts regarding the use of this medicine, please consult the 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 the patient notices any of the following
side effects:

• Drowsiness, tremors, 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, as well as confusion, restlessness or fatigue. 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, 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. For example, blood in the stool due to bleeding in the stomach or intestine, or bleeding inside the skull. These may be symptoms of a low number of platelets.
• Difficulty breathing, swelling of the lips, itching or 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)

• 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 number of platelets (thrombocytopenia). The patient is more prone to bleeding and bruising.
• Constipation, diarrhoea, nausea, vomiting.
• Lung inflammation (pneumonitis).
• 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 (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.
• Bone marrow failure. This may lead to low numbers 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 herpes.
• Bleeding gums, bleeding in the stomach or intestine, bleeding from the anal area due to haemorrhoids (haemorrhoidal haemorrhage), 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 colour changes.
• Skin redness.
• Skin infection (cellulitis).
• Infection of the nose and throat or sore throat.
• Pain in the nose or nasal congestion, or sinus pain (sinusitis).
• High or low blood pressure (hypertension or hypotension).
• Shortness of breath during physical activity.
• Sore throat and larynx.
• Indigestion.
• Drowsiness.
• General malaise.
• Anxiety.
• Confusion.
• Hair loss.
• Kidney failure.
• Dehydration.
• White coating on the tongue, inside of cheeks, and sometimes on the palate, gums and tonsils (oral thrush).
• Fainting.
• Drop in blood pressure when standing up (orthostatic hypotension), leading to dizziness when changing to a standing or sitting position.
• Drowsiness, somnolence.
• Bleeding at the catheter insertion site.
• Bowel disease, 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).

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

• Allergic reaction (hypersensitivity).
• Tremors.
• Liver failure.
• Large, plum-coloured, raised, painful skin patches with fever.
• Painful skin ulceration (pyoderma gangrenosum).
• 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 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 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, heart rhythm disturbances, seizures, and sometimes death.

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

• Infection of deep skin layers, spreading rapidly and 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 any side effects occur, including any side effects not listed in this leaflet,
you should inform your doctor or pharmacist. Side effects can be reported directly to the Department of Monitoring of 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 to provide more information on the safety of this medicine.

5. How to store Azacitidine Glenmark

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer carton or vial label following "EXP". The expiry date refers to the last day of the stated month.
The doctor, pharmacist, or nurse is responsible for the storage of Azacitidine Glenmark.
They are also responsible for the preparation of Azacitidine Glenmark and the proper disposal of any unused portions.
Unopened vials - no special storage conditions apply.
For immediate use
After reconstitution, the suspension should be administered within 45 minutes.
For later use
If the Azacitidine Glenmark suspension has been prepared using unrefrigerated Water for Injections, the reconstituted suspension must be placed immediately in a refrigerator (2°C−8°C) after preparation and stored in the refrigerator for no longer than 8 hours.
If the Azacitidine Glenmark suspension has been prepared using refrigerated Water for Injections (2°C−8°C), the reconstituted suspension must be placed immediately 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 stand for 30 minutes to reach room temperature (20–25°C).
If large particles are present in the suspension, it should be discarded.

6. Contents of the pack and other information

What Azacitidine Glenmark 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.

What Azacitidine Glenmark looks like and contents of the pack
Azacitidine is a white powder for the preparation of a suspension for injection, supplied in a vial made of colourless type I glass, with a butyl rubber stopper and an aluminium seal (white for 100 mg), packed in a cardboard box.
Pack size available:
1 vial containing 100 mg of azacitidine.

Marketing Authorisation Holder
Glenmark Pharmaceuticals s.r.o.
Hvězdova 1716/2b
140 78 Prague 4
Czech Republic

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

For further information, please contact the local representative of the Marketing Authorisation Holder:
Glenmark Pharmaceuticals Sp. z o.o.
ul. Osmańska 14
02-823 Warsaw

Information intended exclusively for healthcare professionals:

Safe handling recommendations
The medicinal product Azacitidine Glenmark is a cytotoxic medicinal product, and as with other potentially toxic compounds, caution must be exercised when preparing and handling 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, rinse thoroughly with water.
Female healthcare professionals who are pregnant should not prepare the medicinal product.

Pharmaceutical incompatibilities
Do not mix the medicinal product with other medicinal products except those listed below (see "Preparation procedure").

Preparation procedure
The medicinal product Azacitidine Glenmark should be prepared using Water for Injections. The shelf life of the prepared medicinal product can be extended if cooled (2°C–8°C) Water for Injections is used for preparation. Details on storage of the prepared medicinal product are provided below.

1. Gather the following items: Vial(s) of azacitidine; vial(s) of Water for Injections; non-sterile surgical gloves; alcohol swabs; syringe(s) with needle(s) for injection.
2. Draw the appropriate volume of Water for Injections into the syringe (see table below). Ensure that all air has been expelled from the syringe.

3. Insert the needle of the syringe containing water for injections through the rubber stopper of the vial containing azacitidine and then slowly inject the water for injections into the vial.

4. After removing the syringe and needle, vigorously shake the vial until a uniform, turbid suspension is obtained. After reconstitution, each milliliter of suspension contains 25 mg of azacitidine (100 mg/4 mL). The prepared product is a uniform, turbid suspension without agglomerates. Discard the suspension if it contains large particles or agglomerates. Do not filter the suspension after preparation, as this may result in removal of the active substance. Note that some adapters, transfer needles, and closed system transfer devices contain filters; therefore, such systems should not be used for administration of the medicinal product after preparation.

5. Clean the rubber stopper and insert a new needle with a syringe 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 amount of medicinal product for the appropriate dose. Ensure that all air has been expelled from the syringe. Then remove the needle with syringe from the vial and discard the needle.

6. A fresh subcutaneous injection needle (recommended 25 G) must be firmly attached to the syringe. Do not clean the needle before injection to reduce the frequency of injection site reactions.

7. Due to retention in the vial and needle, complete withdrawal of the entire suspension from the vial may not be possible.

8. The suspension in the dosing syringe must be resuspended immediately before administration. The temperature of the suspension at the time of injection should be approximately 20°C–25°C. To resuspend, vigorously roll the syringe between the palms until a uniform, turbid suspension is obtained. Discard the suspension if it contains large particles or agglomerates.

Storage after preparation
For immediate use
The suspension of the medicinal product Azacitidine Glenmark may be prepared immediately before use, and the prepared suspension must be administered within 45 minutes. If more than 45 minutes have elapsed, the prepared suspension must be properly discarded and a new dose prepared.
For later use
If unrefrigerated water for injections was used to prepare the product, the suspension must be placed in a refrigerator (2°C–8°C) immediately after preparation and stored in the refrigerator 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.
If refrigerated (2°C–8°C) water for injections was used to prepare the product, the prepared suspension must be placed in a refrigerator (2°C–8°C) immediately after preparation and stored in the refrigerator for no longer than 32 hours. If more than 32 hours have elapsed during refrigerated storage, the suspension must be properly discarded and a new dose prepared.
The suspension should be allowed to stand for 30 minutes before administration to reach room temperature (20–25°C). If more than 30 minutes have elapsed after removal from refrigeration, 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 only an example of how to calculate individual doses of azacitidine based on an average BSA of 1.8 m².

Method of administration
Do not filter the suspension after preparation.
The prepared medicinal product Azacitidine Glenmark 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, and injections should never be given into irritated, bruised, reddened, or hardened areas.
Any unused portions of the medicinal product or waste materials should be disposed of in accordance with local regulations.