Fludarabine Accord

Leaflet accompanying the packaging: information for the user

Fludarabine Accord, 25 mg/ml, concentrate for solution for injection or infusion

for injection or infusion
Fludarabine phosphate

You should carefully read the contents of this leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, you should ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed specifically for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, including those not listed in this leaflet, you should tell your doctor, pharmacist, or nurse. See section 4.

Table of contents of the leaflet

• 1. What is Fludarabine Accord and what is it used for
• 2. Important information before using Fludarabine Accord
• 3. How to take Fludarabine Accord
• 4. Possible side effects
• 5. How to store Fludarabine Accord
• 6. Contents of the packaging and other information

1. What is Fludarabine Accord and what is it used for

Fludarabine Accord, 25 mg/ml, concentrate for solution for injection or infusion contains the active substance fludarabine phosphate, which inhibits the growth of new cancer cells. All body cells create new cells through their own division. Fludarabine Accord, taken up by cancer cells, inhibits their division. In patients with white blood cell cancer (e.g., chronic lymphocytic leukemia), the body produces many abnormal white blood cells (lymphocytes), resulting in the enlargement of lymph nodes in various parts of the body. Abnormal blood cells are not able to perform the normal defensive functions of the body and may displace healthy blood cells from the body. This can lead to infections, a decrease in the number of red blood cells (anemia), bruising, excessive bleeding (hemorrhage), and even organ failure. Fludarabine Accord is used to treat chronic lymphocytic leukemia with B-lymphocytes (B-CLL) in patients who have sufficient production of healthy blood cells. The first course of treatment for chronic lymphocytic leukemia with fludarabine phosphate can only be started in patients with advanced cancer who show symptoms related to it or significant disease progression.

2. Important information before using Fludarabine Accord

When not to use Fludarabine Accord

• If you are allergicto fludarabine phosphate or any of the other ingredients of this medicine (listed in section 6);
• If you are breastfeeding;
• If you have severe kidney problems;
• If you have a low number of red blood cellsdue to a specific type of anemia (uncompensated hemolytic anemia). Your doctor will inform you if you have this disease. You should inform your doctorif any of the above applies to you.

Warnings and precautions

When to talk to your doctor before using Fludarabine Accord

• If you have bone marrow problems or immune system problems or a history of severe infections.
• Your doctor may decide not to use this medicine or may take appropriate precautions.
• If you feel unwell, have unusual bruising, excessive bleeding after injury, or increased susceptibility to infections.
• If during treatment your urine turns red or brown or you experience skin changes in the form of a rash or blistersThese may be symptoms of a decrease in blood cells, caused by the disease itself or treatment. This condition can persist for up to a year, regardless of whether you have been treated with fludarabine before or not. During treatment with fludarabine, your immune system may attack different parts of your body or its red blood cells (so-called “autoimmune disorders”). This can be life-threatening. If you experience any of the above conditions, your doctor will discontinue the medicine and may introduce other treatments, such as irradiated blood transfusion (see below) and administration of corticosteroids. During treatment with fludarabine, you will have regular blood tests and will be under close observation.

Other considerations during treatment with Fludarabine Accord:

• Men and women of childbearing age must use effective contraceptionduring treatment and for at least 6 months after its completion. It cannot be excluded that Fludarabine Accord may have a harmful effect on the fetus. Your doctor will consider the benefit to the patient versus the risk to the fetus and will only recommend the use of fludarabine in pregnant women if it is absolutely necessary.
• Do not start or continue breastfeedingduring treatment with Fludarabine Accord.
• If you need to be vaccinated, you should consult your doctor, as live vaccines should be avoided during and after fludarabine treatment.
• If you have kidney problems or are over 65 years old,regular blood tests and/or laboratory tests will be performed to assess kidney function. If you have severe kidney problems, this medicine should not be used at all (see section 2 and 3).

Children and adolescents:

The efficacy and safety of fludarabine phosphate in children under 18 years of age have not been established, so this medicine should not be used in children.

Elderly:

Patients over 65 years oldwill have regular tests to assess kidney function (see also section 3: “How to take Fludarabine Accord”).
Patients over 75 years oldwill be monitored particularly closely.

Fludarabine Accord and other medicines

You should tell your doctor or pharmacist about all medicines you are taking or have recently taken, as well as any medicines you plan to take, including those available without a prescription.
It is especially important to tell your doctor about the following medicines.

• Pentostatin(deoxycoformycin), also used to treat chronic lymphocytic leukemia B-cell. Concurrent use of these two medicines may lead to severe lung disease;
• Dipyridamole, a medicine that reduces blood clotting or other medicines with similar effects. They may reduce the effectiveness of fludarabine;
• Cytarabine(Ara-C) used to treat chronic lymphocytic leukemia. Concurrent use of fludarabine with cytarabine may increase the concentration of the active form of fludarabine in leukemia cells. However, no changes in overall blood concentration and elimination from the blood have been observed.

Pregnancy, breastfeeding, and fertility

Pregnancy
Fludarabine Accord should not be used if you are pregnant, as animal studies and limited human experience have shown possible risk of fetal malformations, as well as miscarriage and premature birth.

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child,

you should consult your doctor before using this medicine.
Your doctor will consider the benefit to the patient versus the risk to the fetus and will only recommend the use of this medicine in pregnancy if it is absolutely necessary.
Breastfeeding
Do not start or continue breastfeeding during treatment with Fludarabine Accord, as this medicine may affect the growth and development of the child.
Fertility
Male and female fertility patients must use effective contraception during treatment and for at least 6 months after its completion.

Driving and using machines

Some patients treated with Fludarabine Accord may experience fatigue, weakness, vision disturbances, confusion, agitation, and seizures. You should not attempt to drive or operate machinery until you are sure that you are not experiencing such effects.

Important information about some of the ingredients of Fludarabine Accord

This medicine contains less than 1 mmol of sodium per dose, i.e., it is essentially “sodium-free”.

3. How to take Fludarabine Accord

This medicine should always be taken exactly as your doctor or pharmacist has told you. If you are unsure, you should ask your doctor.
Fludarabine should be administered under the supervision of a qualified doctor experienced in the use of anticancer therapy.

• •Information on the preparation of dilutions of the solution, see section 6 “Contents of the packaging and other information”.

What dose of Fludarabine Accord should be given:

The dose of Fludarabine Accord depends on your body surface area. It is measured in square meters (m²) and is calculated by your doctor based on your height and weight.
The recommended dose is 25 mg of fludarabine phosphate/m² of body surface area.

How to administer Fludarabine Accord:

Fludarabine Accord is administered as a solution, either as an injection or, most commonly, as an intravenous infusion.
Intravenous infusion means that the medicine is administered directly into a vein in the form of a drip. One infusion lasts about 30 minutes.
Your doctor will ensure that Fludarabine Accord is not administered outside the vein. However, in the event of such administration, no serious local side effects have been reported.

How long to take Fludarabine Accord:

The recommended dose is administered once a day for 5 consecutive days.
This 5-day treatment cycle will be repeated every 28 daysuntil your doctor decides that the best possible treatment result has been achieved (usually after 6 treatment cycles).
The duration of treatment depends on its effectiveness and your tolerance. If side effects occur, the next treatment cycle may be delayed.

During treatment, you will have regular blood tests. Your individual dose

of the medicine will be carefully adjustedbased on your blood cell count and response to treatment.
If side effects occur, the dose may be reduced.
If you have kidney problems or are over 65 years old, you will have regular tests to assess kidney function. If your kidneys are not working properly, you may receive a lower dose of this medicine. This medicine should not be used if you have severe kidney problems (see section 2).

What to do in case of accidental spillage of Fludarabine Accord solution:

In case of contact between Fludarabine Accord solution and skin or mucous membranes of the nose or mouth, the area should be thoroughly rinsed with soap and water. If the solution gets into your eyes, they should be thoroughly rinsed with plenty of water. You should avoid inhaling the vapors emitted from the solution.

Use of a higher than recommended dose of Fludarabine Accord:

If you have received too much of the medicine, your doctor will stop treatment and administer treatment for the symptoms.
Using high doses may lead to a serious decrease in blood cells.
Overdose of Fludarabine Accord administered intravenously has caused delayed blindness, coma, and even death.

Missing a dose of Fludarabine Accord:

Your doctor will schedule the administration of the medicine. If you think you have missed a dose of the medicine, you should contact your doctor as soon as possible.
Do not take a double dose to make up for a missed dose.

Stopping treatment with Fludarabine Accord:

If severe side effects occur, your doctor will decide to stop treatment.
If you have any further questions about the use of this medicine, you should ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you are unsure about any of the following side effects, you should ask your doctor for an explanation.
Some side effects can be life-threatening.

If you have difficulty breathing, cough or chest pain with fever or

without.These may be symptoms of a lung infection.

If you notice unusual bruising, excessive bleeding after injury, or increased susceptibility to

infections.These symptoms may be caused by a decrease in blood cells. This can lead to an increased risk of (severe) infections caused by microorganisms that do not normally cause disease in healthy people (opportunistic infections), including late reactivation of viruses, e.g., shingles.

If you experience pain in your side, notice blood in your urine, or a decrease in the amount of

urine produced.These may be signs of tumor lysis syndrome(see section 2).

If you notice skin changes and/or mucous membrane changes in the form of

redness, inflammation, blisters, and tissue damage.These may be symptoms of a severe allergic reaction (Lyell's syndrome, Stevens-Johnson syndrome).

• If you have an irregular heartbeat (palpitations) or chest pain.These may be symptoms of heart problems. You should contact your doctor immediately if you experience any of the above side effects.The following side effects have been reported according to their frequency.
• Very common(occurring in more than 1 in 10 patients):
• infections (including severe);
• infections caused by immune system suppression (opportunistic infections);
• lung infections (pneumonia), with symptoms such as difficulty breathing and/or cough with fever or without;
• decrease in platelet count (thrombocytopenia), which may be accompanied by bruising and bleeding;
• decrease in white blood cell count (neutropenia);
• decrease in red blood cell count (anemia);
• cough;
• vomiting, diarrhea, nausea;
• fever;
• fatigue;
• weakness.

Common(occurring in less than 1 in 10 patients):

• other blood cancers (myelodysplastic syndrome, acute myeloid leukemia). Most patients who developed these diseases had been treated previously or concurrently with other anticancer medicines (alkylating agents, topoisomerase inhibitors)or radiation therapy;
• decrease in bone marrow cells (myelosuppression);
• severe loss of appetite leading to weight loss (anorexia);
• numbness or weakness in the limbs (peripheral neuropathy);
• vision disturbances;
• inflammation of the mouth;
• skin rash;
• swelling due to excessive fluid retention;
• inflammation of the mucous membranes in the digestive system from the mouth to the anus (mucositis);
• chills;
• general feeling of being unwell.
• Uncommon(occurring in less than 1 in 100 patients):
• autoimmune diseases (see section 2 “Warnings and precautions”);
• tumor lysis syndrome (see section 2 “Warnings and precautions”);
• feeling disoriented;
• lung damage; scarring of the lungs (pulmonary fibrosis), lung inflammation, shortness of breath;
• bleeding in the abdomen or intestines;
• abnormal liver or pancreatic enzyme activity.
• Rare(occurring in less than 1 in 1000 patients):
• immune system problems due to viral infections (lymphoproliferative disease associated with EBV infection);
• coma;
• seizures;
• anxiety;
• loss of vision;
• inflammation or damage to the optic nerve, optic neuropathy;
• heart failure;
• irregular heartbeat (arrhythmia);
• skin cancer;
• skin and/or mucous membrane changes in the form of redness, inflammation, blisters, and tissue damage (Lyell's syndrome, Stevens-Johnson syndrome);
• Frequency not known(cannot be estimated from the available data):
• inflammation of the bladder, which can cause pain when urinating and blood in the urine (hemorrhagic cystitis);
• bleeding into brain tissue (cerebral hemorrhage),
• bleeding into lung tissue (pulmonary hemorrhage).
• Neurological disorders in the form of headache, nausea (vomiting), vomiting, seizures, vision disturbances, including loss of vision, changes in mental state (confusion, disorientation, changes in consciousness), as well as occasional neurological disorders in the form of muscle weakness in the limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or reversible posterior leukoencephalopathy syndrome (RPLS)).

Reporting side effects

If you experience any side effects, including those not listed in this leaflet, you should tell your doctor or pharmacist. Side effects can be reported directly to the Department of Drug Safety Monitoring 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
e-mail: ndl@urpl.gov.pl
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Fludarabine Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the ampoule/vial label and carton after EXP.
The expiry date refers to the last day of the month.
Storage conditions for the product (unopened vials):
Store in a refrigerator (2-8°C).
Do not freeze.
Storage conditions for the product after dilution:
Chemical and physical stability of solutions with a concentration of 0.2 mg/ml and 6 mg/ml after dilution in 0.9% NaCl and 5% glucose has been demonstrated for 7 days at 2-8°C and 5 days at 20-25°C in a non-PVC infusion bag and glass bottle.
From a microbiological point of view, this medicinal product should be used immediately. If not used immediately, the user is responsible for the storage time and conditions, which should not normally exceed 24 hours at 2°C to 8°C, provided that the dilution has been made in controlled and validated aseptic conditions.
Information intended for healthcare professionals only:
Fludarabine Accord, as a cytotoxic medicine, should be prepared by qualified personnel in a designated area. Handling of the medicinal product should be in accordance with local guidelines for cytotoxic medicinal products.

6. Contents of the packaging and other information

What Fludarabine Accord contains

The active substance of the medicine is fludarabine phosphate. 1 ml of the concentrate contains 25 mg of fludarabine phosphate.
The other ingredients are mannitol, disodium phosphate dihydrate, and water for injections.
Fludarabine Accord is packaged in glass vials with a volume of 2 ml.

What Fludarabine Accord looks like and contents of the packaging

Fludarabine Accord is a sterile, clear, colorless or slightly brownish-yellow solution in a vial made of colorless glass.
Fludarabine Accord is available in three packaging sizes: 1, 5, or 10 vials per package.
Not all packaging sizes may be marketed.

Marketing authorization holder

Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warsaw

Manufacturer/importer

Accord Healthcare Polska Sp.z o.o.
ul. Lutomierska 50
95-200 Pabianice
Accord Healthcare B.V.
Winthontlaan 200
3526 KV Utrecht
Netherlands

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Date of last revision of the leaflet: August 2022

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Information intended for healthcare professionals only:
Fludarabine Accord, as a cytotoxic medicine, should be prepared by qualified personnel in a designated area. Handling of the medicinal product should be in accordance with local guidelines for cytotoxic medicinal products.
This medicinal product is intended for intravenous use only.

Incompatibilities

Due to the lack of compatibility studies, this medicinal product should not be mixed with other medicinal products.

Dilution

The required dose (calculated based on the patient's body surface area) is drawn into a syringe.
In the case of direct intravenous injection (bolus), this dose is then diluted in 10 ml of 0.9% (9 mg/ml) sodium chloride injection solution. Alternatively, for infusion, the required dose can be diluted in 100 ml of 0.9% (9 mg/ml) sodium chloride solution and administered over approximately 30 minutes.
In clinical studies, the product was diluted in 100 ml or 125 ml of 5% dextrose solution or 0.9% sodium chloride solution (9 mg/ml).

Storage

Shelf life (unopened vials): 2 years
Chemical and physical stability of solutions with a concentration of 0.2 mg/ml and 6 mg/ml after dilution in 0.9% NaCl and 5% glucose has been demonstrated for 7 days at 2-8°C and 5 days at 20-25°C in a non-PVC infusion bag and glass bottle.
From a microbiological point of view, this medicinal product should be used immediately. If not used immediately, the user is responsible for the storage time and conditions, which should not normally exceed 24 hours at 2°C to 8°C, provided that the dilution has been made in controlled and validated aseptic conditions.

Visual inspection

The diluted solution is clear, colorless, or slightly brownish-yellow.
It should be inspected before use.
Only a clear and colorless or slightly brownish-yellow solution without visible particles should be used.

Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

Disposal of the medicinal product

Pregnant women should not come into contact with fludarabine phosphate.
Handling of the medicinal product should be in accordance with local guidelines for cytotoxic medicinal products.
When handling the solution, caution should be exercised. It is recommended to use latex gloves and protective eyewear to avoid exposure in case of breakage of the vial or accidental spillage of the contents. If the solution comes into contact with the skin or mucous membranes, the area should be thoroughly rinsed with soap and water. If the solution gets into the eyes, they should be thoroughly rinsed with plenty of water. You should avoid inhaling the vapors emitted from the solution.
This medicinal product is intended for single use only. Any unused product or waste material should be disposed of in accordance with local regulations.