Etraga

Package leaflet: Information for the user

Etraga, 25 mg/mL, powder for suspension for injection
Azacitidinum
Please read all of this leaflet carefully before using this medicine because it contains
important information for you.
Keep this leaflet as you may need to read it again.
If you have any further questions, ask your doctor, pharmacist, or nurse.
If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse.
See section 4.
Leaflet contents:

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

1. What Etraga is and what it is used for

What Etraga is
Etraga is an anticancer medicine belonging to a group of drugs called "antimetabolites". Etraga contains an active substance called "azacitidine".
What Etraga is used for
Etraga 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 difficulties in the proper production of blood cells.
How Etraga works
Etraga 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 action involves 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 correct 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 Etraga works or why this medicine has been prescribed for you, please consult your doctor or nurse.

2. Important information before using Etraga

When not to use Etraga

• if the patient is allergic (hypersensitive) 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 Etraga, discuss this 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.

Etraga may cause a severe immune reaction called "differentiation syndrome" (see
section 4).
Blood tests
Before starting treatment with Etraga and at the beginning of each treatment period (so-called "cycle"), blood tests will be performed. The purpose of these tests is to check whether the patient has sufficient blood cell counts and to assess whether the liver and kidneys are functioning properly.
Children and adolescents
Etraga is not recommended for use in children and adolescents under 18 years of age.
Etraga 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. Etraga may affect the way some other medicines work. Likewise, some other medicines may affect the way Etraga works.
Pregnancy, breastfeeding, and fertility
Pregnancy
Do not use Etraga during pregnancy, as it may harm the unborn child. Women of childbearing potential should use an effective method of contraception during treatment with Etraga and for 6 months after stopping treatment with Etraga. Inform your doctor immediately if pregnancy occurs during treatment with Etraga.
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult her doctor or pharmacist before using this medicine.
Breastfeeding
Do not breastfeed while taking Etraga. It is not known whether this medicine passes into human milk.
Fertility
Men should not father a child while receiving treatment with Etraga. Men should use an effective method of contraception during treatment with Etraga and for 3 months after stopping treatment with Etraga.
The patient should consult their doctor if they wish to store sperm before starting this treatment.
Driving and operating machinery
If adverse effects such as fatigue occur, the patient should not drive, use tools, or operate machinery.

3. How to use Etraga

Before administering Etraga 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 of the medicine is 75 mg per m^2 of body surface area. The doctor selects the appropriate dose of Etraga based on the patient's general condition, height, and weight. The doctor monitors the patient's progress and may adjust the dose if necessary.
• Etraga is administered daily for one week, followed by a rest period of 3 weeks. This "treatment cycle" is repeated every 4 weeks. Patients usually receive at least 6 treatment cycles.

Etraga is given as a subcutaneous injection by a doctor or nurse. It can be injected under the skin of the thigh, abdomen, or arm.
If you have any further questions about the use of this medicine, please consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
You should immediately tell your doctor if you notice any of the following adverse reactions:

• Drowsiness, tremors, jaundice, abdominal bloating and tendency to bruise. These may be symptoms of liver failure, which may be life-threatening.
• Swelling of the feet and legs, back pain, reduced urine output, increased thirst, rapid heartbeat, dizziness and nausea, vomiting or loss of appetite, and feeling disoriented, anxious or fatigued. These may be symptoms of kidney failure, which 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, possibly accompanied by fever. This may be due to a lung infection called "pneumonia," which may be life-threatening.
• Bleeding. Such as blood in the stool due to bleeding in the stomach or intestine, 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 (hypersensitivity) reaction.

Other adverse reactions include:
Very common adverse reactions (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. Fever may occur. The patient is also more susceptible to infections.

• Low platelet count (thrombocytopenia). The patient has a tendency to bleed and bruise easily.

• Constipation, diarrhoea, nausea, vomiting.

• Pneumonia.

• 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.

• Difficulty sleeping (insomnia).

• Nosebleeds.

• Muscle pain.

• Weakness (asthenia).

• Weight loss.

• Low blood potassium levels.

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

• Intracranial haemorrhage.
• Bacterial blood infection (septicaemia). 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 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 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 (haematomas).
• 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 (haematomas), 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 congestion, 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.
• Drowsiness.
• 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.
• Bleeding at the catheter insertion site.
• Intestinal 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 adverse reactions (may affect up to 1 in 100 people)

• Hypersensitivity reaction (allergic reaction).
• 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 adverse reactions (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 the products of dying tumour cells and may include: changes in blood biochemistry; high levels of potassium, phosphate and 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 that spreads rapidly, causing damage to skin and tissue, 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 adverse reactions
If any adverse symptoms occur, including any not listed in this leaflet, you should 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
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Etraga

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 the outer cardboard
pack after EXP. The expiry date refers to the last day of the stated month.
The doctor, pharmacist, or nurse is responsible for the storage of Etraga. They are also
responsible for the preparation of Etraga and the proper disposal of any unused portions.
Unopened vials – no special storage requirements for the medicine.
After preparation:
For azacitidine prepared using unrefrigerated water for injections, chemical and physical in-use
stability of the prepared medicine has been demonstrated for 45 minutes at 25°C and for
8 hours at 2°C–8°C.
The in-use shelf life of the prepared medicine may be extended by preparing it with refrigerated
(2°C–8°C) water for injections. For azacitidine prepared using refrigerated (2°C–8°C) water for
injections, chemical and physical in-use stability of the prepared medicine has been demonstrated
for 32 hours at 2°C–8°C.
From a microbiological standpoint, the prepared medicine should be used immediately. If the
medicine is not used immediately, the user is responsible for the storage conditions and duration
prior to administration. However, it must not be stored for longer than 8 hours at 2°C–8°C for
the medicine prepared with unrefrigerated water for injections, or for longer than 32 hours for
the medicine prepared with refrigerated (2°C–8°C) water for injections.
Allow the suspension to reach room temperature (20°C–25°C) for a maximum of 30 minutes before
administration.
Do not use the medicine if large particles are present in the suspension.

6. Contents of the pack and other information

What Etraga contains
The active substance is azacitidine.
Each vial contains 100 mg or 150 mg of azacitidine. After reconstitution with water for
injections, the resulting suspension contains 25 mg/mL azacitidine.
Other ingredient: mannitol.

What Etraga looks like and contents of the pack
Etraga is a white powder for suspension for injection, supplied in a glass vial stoppered with a bromobutyl rubber closure and sealed with a plastic cap (white for the 100 mg vial and orange for the 150 mg vial), with an aluminium flip-off seal, packed in a cardboard carton.
Pack size:
1 vial – 150 mg

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
STADA Arzneimittel AG
Stadatrasse 2-18
61118 Bad Vilbel
Germany

Manufacturer:
AqVida GmbH
Kaiser-Wilhelm-Str. 89
20355 Hamburg
Germany
STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
Stada Pharm Sp. z o.o.
ul. Krakowiaków 44
02-255 Warsaw
Tel. +48 22 737 79 20

This medicinal product is authorised in the European Economic Area countries under the following names:
Iceland Etraga 25 mg/mL powder for injection suspension
Denmark Etraga
Sweden Etraga 25 mg/mL powder for injection suspension
Finland Etraga 25 mg/mL powder for injection suspension
Norway Etraga 25 mg/mL powder for injection suspension
Croatia Etraga
Hungary Etraga
Poland Etraga
Romania Etraga
Czech Republic Etraga
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Information intended exclusively for healthcare professionals:

Safe handling recommendations
Etraga 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 cytotoxic medicinal products should be followed.
In case of skin contact with prepared azacitidine, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse thoroughly with water.
Female healthcare personnel who are pregnant should not prepare or administer this medicinal product.
Pharmaceutical incompatibilities
The medicinal product must not be mixed with other medicinal products except as specified below (see "Preparation procedure").
Preparation procedure
The Etraga product should be prepared in water for injections. The stability period 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 below.

1. Gather the following materials: vial(s) of azacitidine, vial(s) of water for injections, non-sterile surgical gloves, alcohol swabs, syringe(s) with needle(s).
2. Withdraw the appropriate volume of water for injections (see table below) into the syringe and 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 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 milliliter of suspension contains 25 mg of azacitidine (100 mg/4 mL or 150 mg/6 mL). The prepared product is a uniform, cloudy suspension without agglomerates. Discard the suspension if it contains large particles or agglomerates. 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 components should not be used for administering the medicinal product after preparation.
5. Clean the rubber stopper and insert a new syringe with 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 remove the needle with 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 a dose of 150 mg = 6 mL, use the 150 mg vial. Due to retention in the vial and needle, it may not be possible to withdraw the entire suspension from the vial.
8. The suspension in the 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, roll the syringe vigorously between the palms until a uniform, cloudy suspension is obtained.
   Discard the suspension if it contains large particles or agglomerates.

After preparation:
For azacitidine prepared using unrefrigerated water for injections, chemical and physical in-use stability of the prepared medicinal product has been demonstrated for 45 minutes at 25°C and for 8 hours at 2°C–8°C.
The shelf life of the prepared medicinal product may be extended by preparing the product using refrigerated (2°C–8°C) water for injections. For azacitidine prepared using refrigerated (2°C–8°C) water for injections, chemical and physical in-use stability of the prepared medicinal product has been demonstrated for 32 hours at 2°C–8°C.
From a microbiological standpoint, the prepared product should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user. However, it should not be stored for longer than 8 hours at 2°C–8°C when prepared with unrefrigerated water for injections, or for longer than 32 hours when prepared with refrigerated (2°C–8°C) water for injections.
Allow the suspension to reach room temperature (20°C–25°C) for up to 30 minutes before administration. If more than 30 minutes elapses, the suspension should 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 how to calculate individual doses of azacitidine based on an average BSA of 1.8 m².

Method of administration
After reconstitution, the suspension should not be filtered.
The prepared medicinal product Etraga should be administered subcutaneously using a 25G needle
(needle should be inserted at an angle of 45-90º) into the arm, thigh, or abdomen.
Doses exceeding 4 mL should be evenly divided, using separate syringes, and administered at two
different 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 areas that are tender, bruised,
red, or hardened.
Any unused portions of the medicinal product or its waste should be disposed of in accordance
with local regulations.