Fludarabine Accord 25 mg/ml concentrate for solution for injection and for infusion

Patient Information Leaflet

Introduction

Patient Information Leaflet

Fludarabina Accord 25 mg/ml concentrate for solution for injection and infusion

Fludarabine phosphate

Read the entire leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only and must not be given to other people, even if they have the same symptoms as you, since it could harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are adverse effects not listed in this leaflet. See section 4.

Leaflet contents:

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

2. What you need to know before using Fludarabina Accord

3. How to use Fludarabina Accord

4. Possible side effects

5. How to store Fludarabina Accord

6. Contents of the container and other information

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

Fludarabine Accord contains the active substance fludarabine, which stops the growth of new cancer cells. All cells in the body produce new cells similar to themselves through division. Fludarabine Accord is taken up by cancer cells and halts their division.

In white blood cell cancers (such as chronic lymphocytic leukemia), the body produces many abnormal white blood cells, and lymph nodes begin to grow in various parts of the body. The abnormal growth of white blood cells prevents them from carrying out their normal disease-fighting functions and may displace healthy blood cells. This can result in infections, a decrease in the number of red blood cells (anemia), bruising, abnormally severe bleeding, or even organ failure.

Fludarabine Accord is used to treat B-cell chronic lymphocytic leukemia (B-CLL) in patients who have sufficient production of healthy blood cells.

Initial treatment of chronic lymphocytic leukemia with Fludarabine Accord alone should only be started in patients with advanced disease who have disease-related symptoms or evidence of disease progression.

2. What you need to know before using Fludarabine Accord

Do not use Fludarabine Accord:

• If you are allergic* to fludarabine phosphate or to 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 low red blood cell count due to a certain type of anemia (decompensated hemolytic anemia). Your doctor will have told you if you have this condition.

If you think any of these may apply to you**, inform your doctor.**

Warnings and precautions

Tell your doctor before using Fludarabine Accord

• If your bone marrow is not functioning properly or if your immune system is not working well or is suppressed, or if you have a history of serious infections.

Your doctor may decide not to give you this medicine, or may take preventive measures.

• If you feel very unwell, notice unusual bruising, increased bleeding after an injury, or if you seem to have frequent infections.

• If during treatment your urine becomes red or brownish, or you develop a rash or blisters on your skin.

These symptoms may be signs of a reduced number of blood cells, which can be caused either by the disease itself or by the treatment. This may last up to one year, regardless of whether you have previously been treated with this medicine. During treatment with Fludarabine Accord, your immune system may also attack different parts of your body, or your red blood cells (called "autoimmune disorders"). These problems can potentially be life-threatening. If this occurs, your doctor will stop treatment and you may receive other treatments such as transfusion of irradiated blood (see below) and adrenocorticosteroids.

You will have regular blood tests during treatment and will be closely monitored while receiving this medicine.

• If you notice any unusual symptoms affecting your nervous system such as vision changes, headache, confusion, or seizures.

If Fludarabine Accord is used over a long period, its effects on the central nervous system are unknown. However, patients treated with the recommended dose for up to 26 treatment cycles have been able to tolerate it.

When Fludarabine Accord is used at the recommended dose, following or concomitantly with other medicines, the following adverse effects have been reported: neurological disorders manifested by headache, dizziness (nausea) and vomiting, seizures, visual disturbances including loss of vision, changes in mental status (abnormal thinking, confusion, altered consciousness), and occasionally neuromuscular disorders manifested by muscle weakness in the limbs (including partial or complete irreversible paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or posterior reversible leukoencephalopathy syndrome (PRES)).

In patients receiving doses four times higher than recommended, blindness, coma, and death have been reported. Some of these symptoms appeared with a delay of about 60 days or more after stopping treatment. In some patients treated with Fludarabine Accord at doses higher than recommended, leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL), or posterior reversible leukoencephalopathy syndrome (PRES) have also been reported. The same symptoms of LE, ATL, or PRES described above could occur.

LE, ATL, and PRES could be irreversible, potentially fatal.

Whenever LE, ATL, or PRES is suspected, treatment with Fludarabine Accord should be stopped for further investigation.

If LE, ATL, or PRES is confirmed, your doctor will stop your treatment with Fludarabine Accord.

• If you notice any pain in your side, blood in your urine, or decreased urine output,

When your illness is very severe, your body may not be able to eliminate all waste products from cells destroyed by Fludarabine Accord. This is called tumor lysis syndrome and may cause kidney failure and heart problems within the first week of treatment. Your doctor is aware of this and may give you other medicines to prevent it.

• If you need stem cell collection and are being treated with Fludarabine Accord (or have been),

• If you need a blood transfusion and are being treated with Fludarabine Accord (or have been),

If you require a blood transfusion, your doctor will ensure that you receive only blood that has been irradiated. Serious complications, and even death, have occurred following transfusions of non-irradiated blood.

• If you notice any changes in your skin while receiving this medicine or after completing treatment,

• If you have skin cancer (or have had it), it may worsen or recur during or after treatment with Fludarabine Accord. You may develop skin cancer during or after treatment with Fludarabine Accord.

Other considerations while being treated with Fludarabine Accord:

• Men and women of childbearing potential must use effective contraception during treatment and for at least 6 months after. It cannot be ruled out that Fludarabine Accord may harm an unborn baby. Your doctor will carefully weigh the benefits of your treatment against the potential risk to the unborn child and, if you are pregnant, Fludarabine Accord will only be administered if strictly necessary.

• If you intend to breastfeed or are currently breastfeeding, you must not start or continue breastfeeding while being treated with Fludarabine Accord.

• If you require any vaccination, consult your doctor, as vaccines containing live microorganisms should be avoided during and after treatment with Fludarabine Accord.

• If you have kidney problems or are over 65 years of age, you will regularly have blood tests and/or laboratory tests to monitor kidney function (see also section 2 and 3.

Children and adolescents:

The safety and efficacy of Fludarabine Accord in children under 18 years of age have not been established. Therefore, the use of this medicine is not recommended in children.

Elderly patients and Fludarabine Accord:

If you are over 65 years of age, your kidney function will be regularly tested (see also section 3. How to use Fludarabine Accord). If you are over 75 years of age, you will be monitored very closely.

Other medicines and Fludarabine Accord:

Inform your doctor if you are taking, have recently taken, or might need to take any other medicines, including medicines obtained without a prescription.

It is especially important to inform your doctor about:

• Pentostatin (deoxycoformycin), also used to treat B-CLL. Taking these two drugs together may lead to serious pulmonary complications.
• Dipyridamole, used to prevent excessive blood clotting, or other similar medicines. These may reduce the effectiveness of Fludarabine Accord.
• Cytarabine (Ara-C), used to treat chronic lymphocytic leukemia. If Fludarabine Accord is combined with cytarabine, levels of the active form of Fludarabine Accord may increase in leukemic cells. However, overall blood levels and elimination from the blood have not been shown to change.

Pregnancy, breastfeeding, and fertility:

Pregnancy

Fludarabine Accord must not be given to women who are pregnant, as animal studies and limited human experience have demonstrated a potential risk of fetal abnormalities, early pregnancy loss, and premature births.

• If you are pregnant, think you may be pregnant, or are planning to become pregnant, inform your doctor immediately.

Your doctor will carefully weigh the benefits of treatment against the potential risk to the unborn child and, if you are pregnant, Fludarabine Accord will only be prescribed if strictly necessary.

Breastfeeding:

You must not start or continue breastfeeding during treatment with this medicine, as it may interfere with the growth and development of your baby.

Fertility:

Men and women who are fertile must use effective contraceptive methods during treatment and for at least 6 months after.

Driving and use of machines

Some people may feel tired, weak, experience vision disturbances, confusion, agitation, or have seizures while receiving treatment with Fludarabine Accord. Do not attempt to drive or operate machinery until you are certain it does not affect you.

Fludarabine Accord contains sodium

This medicine contains less than 23 mg (1 mmol) of sodium per dose, therefore it is considered essentially “sodium-free”.

3. How to use Fludarabine Accord

Follow exactly the instructions for administering this medicine as given by your doctor. If in doubt, consult your doctor again.

Fludarabine Accord must be administered under the supervision of a qualified physician experienced in the use of anticancer therapy.

• For information on the preparation of the diluted solution, see section 6. Contents of the pack and other information.

How much Fludarabine Accord is administered:

The prescribed dose will depend on your body surface area. This is measured in square meters (m²) and is determined by your doctor based on your height and weight. The recommended dose is 25 mg of fludarabine phosphate per m² of body surface area.

How Fludarabine Accord is administered:

Fludarabine Accord is administered as an infusion solution either as an injection or, in most cases, as an intravenous infusion.

An infusion means that the medicine is delivered directly into the bloodstream via a drip into a vein.

An infusion lasts approximately 30 minutes.

Your doctor will ensure that Fludarabine Accord is not administered outside the vein (paravenously). However, if this occurs, no serious local adverse reactions have been reported.

How long Fludarabine Accord is administered:

The dose will be given once daily for 5 consecutive days.

This 5-day treatment cycle will be repeated every 28 days until your doctor decides that the optimal effect has been achieved (usually after 6 cycles).

The duration of treatment depends on the results obtained and your tolerance to Fludarabine Accord. The next cycle may be delayed if adverse effects are a concern.

You will have regular blood tests during your treatment. Your individual dose will be carefully adjusted according to your blood cell counts and your response to treatment.

The dosage may be reduced if adverse effects are problematic.

If you have kidney problems or are over 65 years old, you will have regular tests to check your kidney function. If your kidneys are not functioning properly, you may be given a lower dose of this medicine. If your kidney function is severely impaired, you will not be given this medicine at all (see also section 2).

If Fludarabine Accord solution is accidentally spilled:

If any of the Fludarabine Accord solution comes into contact with your skin or the mucous membranes of your nose or mouth, wash the area thoroughly with soap and water. If the solution gets into your eyes, rinse them thoroughly with plenty of tap water. Avoid any exposure by inhalation.

If you receive more Fludarabine Accord than you should:

If you receive an overdose, your doctor will stop treatment and treat any symptoms. High doses can lead to severely reduced blood cell counts.

For intravenous fludarabine, overdose has been reported to cause delayed blindness, coma, and even death.

If you forget a dose of Fludarabine Accord:

Your doctor will schedule the times at which you will receive this medicine. If you think you may have missed a dose, speak to your doctor as soon as possible.

If you stop treatment with Fludarabine Accord before the intended time:

You and your doctor may decide to discontinue your treatment with Fludarabine Accord solution if adverse effects become too severe.

If you have any further questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them. If you are unsure about what the adverse reactions described below mean, please ask your doctor to explain them to you.

Some serious adverse effects may potentially be life-threatening.

• If you experience difficulty breathing, have a stuffy nose, or have chest pain with or without fever. These may be signs of a lung infection.
• If you notice unusual bruising, increased bleeding after an injury, or feel you are suffering from frequent infections. These may be caused by a reduced number of blood cells. This may also lead to an increased risk of (serious) infections caused by organisms that normally do not cause disease in healthy individuals (opportunistic infections), including late reactivation of viruses, e.g. herpes zoster.
• If you notice any pain in your side, blood in your urine, or decreased urine output. These may be signs of tumor lysis syndrome (see section 2).
• If you observe a skin and/or mucosal reaction with redness, swelling, blisters, and tissue breakdown. These may indicate a severe allergic reaction (Lyell syndrome, Stevens-Johnson syndrome).
• If you have palpitations (if you suddenly become aware of your heartbeat) or chest pain. These may be signs of heart problems.

Contact your doctor immediately if you notice any of these effects.

The following is a list of possible adverse effects categorized by frequency. Rare adverse effects (less than 1 in 1,000 patients) were primarily identified from post-marketing experience.

Very common (may affect more than 1 in 10 people):

• Infections (some severe);
• Infections due to a suppressed immune system (opportunistic infections);
• Lung infection (pneumonia) with possible symptoms such as breathing difficulties and/or cough with or without fever;
• Reduction in blood cell count (thrombocytopenia), possibly leading to bruising and bleeding;
• Reduction in white blood cells (neutropenia);
• Reduction in red blood cells (anemia);
• Cough;
• Vomiting, diarrhea, general malaise (nausea);
• Fever;
• Feeling of tiredness (fatigue);
• Weakness.

Common (may affect up to 1 in 10 people):

• Other types of blood cancers (myelodysplastic syndrome, acute myeloid leukemia). Most patients with these conditions had previously been treated, or were being treated simultaneously or later, with other cancer medicines (alkylating agents, topoisomerase inhibitors) or radiotherapy.
• Bone marrow suppression (myelosuppression);
• Severe loss of appetite leading to weight loss (anorexia);
• Numbness or weakness in limbs (peripheral neuropathy);
• Blurred vision;
• Inflammation of the lining of the mouth (stomatitis);
• Skin rashes;
• Swelling due to excessive fluid retention (edema);
• Inflammation of the mucous membranes of the digestive tract from mouth to anus (mucositis);
• Chills;
• General feeling of malaise.

Uncommon (may affect up to 1 in 100 people):

• Autoimmune disorder (see section 2 "Warnings and precautions").
• Tumor lysis syndrome (see section 2 "Warnings and precautions");
• Confusion;
• Pulmonary toxicity; scarring of the lungs (pulmonary fibrosis), lung inflammation (pneumonitis), difficulty breathing (dyspnea);
• Bleeding in the stomach or intestines;
• Abnormal levels of liver or pancreatic enzymes;

Rare (may affect up to 1 in 1,000 people):

• Lymphatic system disorders due to viral infection (Epstein-Barr virus-associated lymphoproliferative disorder);

• Coma;

• Seizures;

• Agitation;

• Blindness;

• Inflammation or damage to the optic nerve (optic neuritis; optic neuropathy);

• Heart failure;

• Changes in heart rhythm (arrhythmias);

• Skin cancer;

• Skin and/or mucosal reaction with redness, swelling, blisters, and tissue breakdown (Lyell syndrome, Stevens-Johnson syndrome).

• Not known (frequency cannot be estimated from available data): Bladder inflammation, which may cause painful urination and may lead to blood in the urine (haemorrhagic cystitis).

• Bleeding in the brain.

• Bleeding in the lungs.

• Neurological disorders manifested by headache, dizziness (nausea), vomiting, seizures, visual disturbances including loss of vision, changes in mental status (abnormal thinking, confusion, altered consciousness), and occasionally neuromuscular disorders manifested by muscle weakness in the limbs (including partial or complete irreversible paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or posterior reversible encephalopathy syndrome (PRES)).

Reporting of adverse effects

If you experience any type of adverse effect, talk to your doctor, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of 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 carton and vial after EXP. The expiry date refers to the last day of the month indicated.

• Unopened vials

Store in a refrigerator (2-8°C). Do not freeze.

• After dilution

Physical and chemical in-use stability has been demonstrated at concentrations of 0.2 mg/ml and 6.0 mg/ml after dilution with 0.9% sodium chloride and 5% glucose solution for 7 days at 2-8°C and 5 days at 20-25°C in non-PVC bags and glass bottles.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage times and conditions prior to administration are the responsibility of the user and should not exceed 24 hours at 2-8°C, unless dilution has been carried out under validated, controlled, aseptic conditions.

For information for physicians and healthcare professionals, see section 6. Pack contents and other information.

Do not use this medicine if you notice any visible signs of deterioration.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the container and other information

Composition of Fludarabina Accord:

• The active substance is fludarabine phosphate. Each ml contains 25 mg of fludarabine phosphate.
• The other components (excipients) are mannitol, disodium hydrogen phosphate dihydrate, and water for injections.

Fludarabina Accord is supplied in 2 ml glass vials.

Appearance of Fludarabina Accord and contents of the pack:

Fludarabina Accord is a clear, colourless or slightly yellowish-brown solution contained in a clear glass vial.

Fludarabina Accord is available in three pack sizes containing 1 vial, 5 vials or 10 vials.

Only some pack sizes may be marketed.

Marketing Authorization Holder:

Accord Healthcare S.L.U.

World Trade Center

Moll de Barcelona, s/n

Edifici Est, 6th floor

08039 Barcelona

Spain

Manufacturer:

Accord Healthcare Polska Sp. z o.o.,

ul. Lutomierska 50, 95-200 Pabianice

Poland

Accord Healthcare single member S.A.

64th Km National Road Athens,

Lamia, Schimatari, 32009,

Greece

This medicinal product has been authorised in the following EEA countries under the following names:

Country	Proposed Name
Austria	Fludarabine Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Belgium	Fludarabine Accord Healthcare 25 mg/ml Concentrate for Solution for Injection or Infusion
Bulgaria	Fludarabine Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Cyprus	Fludarabine Accord 25 mg/ml, Concentrate for Solution for Injection or Infusion
Germany	Fludarabin Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Estonia	Fludarabine Accord 25 mg/ml
Spain	Fludarabina Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Finland	Fludarabine Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
France	Fludarabine Accord 25 mg/ml, Concentrate for Solution for Injection or Infusion
Hungary	Fludarabin Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Ireland	Fludarabine 25 mg/ml Concentrate for Solution for Injection or Infusion
Italy	Fludarabina Accord
Latvia	Fludarabine Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Lithuania	Fludarabine Accord 25 mg/ml Concentrate for Solution for Injection or Infusion
Malta	Fludarabine 25 mg/ml Concentrate for Solution for Injection or Infusion
Netherlands	Fludarabine Accord 25 mg/ml, Concentrate for Solution for Injection or Infusion
Portugal	Fludarabina Accord
Sweden	Fludarabine Accord
United Kingdom	Fludarabine phosphate 25 mg/ml Concentrate for Solution for Injection or Infusion

Date of the most recent review of this leaflet: May 2023

Detailed and up-to-date information on this medicine is available on the website of the Spanish Agency of Medicines and Medical Devices (Agencia Española de Medicamentos y Productos Sanitarios - AEMPS) http://www.aemps.gob.es

The following information is intended for healthcare professionals only

Fludarabine Accord, like other potentially cytotoxic medicinal products, must be prepared by trained personnel in a designated area. Handling and disposal procedures must be carried out in accordance with guidelines for cytotoxic medicinal products.

For intravenous use only.

Incompatibilities

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

Dilution

The required dose (calculated based on the patient's body surface area) should be drawn into a syringe.

For intravenous bolus injection, this dose should be further diluted with 10 mL of sodium chloride 9 mg/mL (0.9%). Alternatively, for infusion, the required dose may be diluted in 100 mL of sodium chloride 9 mg/mL (0.9%) and administered by infusion over approximately 30 minutes.

In clinical studies, the product has been diluted in 100 mL or 125 mL of 5% dextrose injection solution or 0.9% sodium chloride solution.

Storage

Marketing authorization holder's packaging: 2 years.

Physical and chemical stability in use has been demonstrated at concentrations of 0.2 mg/mL and 6.0 mg/mL after dilution with 0.9% sodium chloride or 5% glucose solution for 7 days at 2–8°C and for 5 days at 20–25°C in non-PVC bags and glass bottles.

From a microbiological standpoint, the product should be used immediately. If not used immediately, storage in use prior to administration is the responsibility of the user and should not exceed 24 hours at 2–8°C unless the dilution has been carried out under validated, controlled aseptic conditions.

Inspection before use

The diluted solution should be transparent, colourless or slightly brownish-yellow. It should be visually inspected before use.

Only solutions that are transparent, colourless or slightly brownish-yellow, and free from particles should be used. Fludarabine Accord must not be used if the container is damaged.

Handling and disposal

Fludarabine Accord must not be handled by pregnant women.

Appropriate procedures for safe handling must be followed, in accordance with local requirements for cytotoxic medicinal products.

Care must be taken during the handling and preparation of the Fludarabine Accord solution. The use of latex gloves and safety goggles is recommended to avoid the risk of contact in case of vial breakage or accidental spillage. If the solution comes into contact with skin or mucous membranes, the affected area should be thoroughly washed with soap and water. In case of eye contact, the eyes should be rinsed thoroughly with abundant water. Inhalation exposure should also be avoided.

This medicinal product is for single use only. Any unused medicine and all materials that have come into contact with it must be disposed of in accordance with local regulations.