Fludarabine Teva 25 mg/ml concentrate for solution for infusion or injection EFG

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Fludarabine Teva 25 mg/ml concentrate for solution for injection and infusion EFG

Fludarabine phosphate

Read the entire leaflet carefully before you start 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 questions, ask your doctor, pharmacist, or nurse.
• If you experience any adverse reactions, consult your doctor, pharmacist, or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents

1. What Fludarabine Teva 25 mg/ml is and what it is used for.
2. What you need to know before being given Fludarabine Teva 25 mg/ml.
3. How to use Fludarabine Teva 25 mg/ml.
4. Possible side effects.
5. How to store Fludarabine Teva 25 mg/ml.
6. Contents of the pack and other information.

1. What Fludarabine Teva 25 mg/ml is and what it is used for

Fludarabine Teva 25 mg/ml contains the active substance fludarabine phosphate, which stops the growth of new cancer cells. All cells in the body produce new cells similar to themselves through division. Fludarabine Teva 25 mg/ml 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 (lymphocytes), 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 Teva 25 mg/ml 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 Teva 25 mg/ml 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 Fludarabine Teva 25 mg/ml is administered to you

Do not use Fludarabine Teva 25 mg/ml

• 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 a low number of red blood cells due to a specific type of anemia (decompensated hemolytic anemia). Your doctor will have informed you if you have this condition.

Inform your doctor if you think any of the above may apply to you.

Warnings and precautions

Talk to your doctor before starting treatment with Fludarabine Teva 25 mg/ml.

Take special care with Fludarabine Teva 25 mg/ml:

• 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 be getting frequent infections.

??If any of these apply before your treatment, inform your doctor.

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

??Inform your doctor immediately.

These symptoms may be signs of a reduced number of blood cells, which may be caused either by the disease itself or by the treatment. This may last up to one year, regardless of whether you have previously received treatment with Fludarabine Teva 25 mg/ml. During treatment with Fludarabine Teva 25 mg/ml, your immune system may also attack different parts of your body or your red blood cells (called "autoimmune phenomena"). These problems can be potentially life-threatening.

If this occurs, your doctor will stop treatment and you may receive other treatments such as irradiated blood transfusion (see below) and adrenocorticosteroids.

You will have regular blood tests during treatment and will be closely monitored while being treated with Fludarabine Teva 25 mg/ml.

• if you notice any unusual neurological symptoms such as vision changes, headache, confusion, or seizures.

??Inform your doctor.

If Fludarabine Teva 25 mg/ml is used over a long period, the 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 is used at the recommended dose, either after or concurrently with other medications, the following adverse events have been reported: neurological disorders manifesting as 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 approximately 60 days or more after discontinuation of treatment. In some patients treated with doses higher than the recommended dose of Fludarabine Teva 25 mg/ml, leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL), or posterior reversible encephalopathy syndrome (PRES) have also been reported. The same symptoms of LE, ATL, or PRES described above could occur.

LE, ATL, and PRES can be irreversible, life-threatening, or fatal.

Whenever LE, ATL, or PRES is suspected, your treatment with Fludarabine Teva 25 mg/ml will be stopped for further investigation. If LE, ATL, or PRES is confirmed, your doctor will permanently discontinue your treatment with Fludarabine Teva 25 mg/ml.

• if you experience any flank pain, blood in the urine, or decreased urine output.

??Inform your doctor immediately.

When your disease is very severe, your body may not be able to eliminate all waste products from cells destroyed by Fludarabine Teva 25 mg/ml. 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 medications to prevent this from happening.

• if you need stem cell collection and are being treated with Fludarabine Teva 25 mg/ml (or have been recently),

??Inform your doctor.

• if you need a blood transfusion and are being treated with Fludarabine Teva 25 mg/ml (or have been recently),

??Inform your doctor.

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

• if you notice any skin changes while receiving this medicine or after completing treatment.

??Inform your doctor.

• if you have had or currently have skin cancer, it may worsen or recur during treatment with Fludarabine Teva 25 mg/ml or later. You may develop skin cancer during or after treatment with Fludarabine Teva 25 mg/ml.

Other considerations while being treated with Fludarabine Teva 25 mg/ml

• Fludarabine Teva should not be administered if you are pregnant, unless clearly indicated by your doctor.

• Women: You must not become pregnant during treatment with Fludarabine Teva and should use an effective method of contraception during treatment and for 6 months after completion, as Fludarabine Teva may be harmful to the fetus. If you become pregnant during treatment, you must inform your doctor immediately. Your doctor will decide with you whether to continue treatment with Fludarabine Teva.

• Men: It is recommended that you do not father children and should use an effective method of contraception during treatment and for at least 3 months after completion. You should seek advice about sperm preservation before treatment, as Fludarabine Teva may impair male fertility.

• You must not breastfeed while being treated with Fludarabine Teva.

• If you require vaccination, consult your doctor, as vaccines containing live microorganisms should be avoided during and after treatment with Fludarabine Teva 25 mg/ml.

• If you have kidney problems or are over 65 years old, you will regularly have blood tests and/or laboratory tests to monitor kidney function (see section 2 “Do not use Fludarabine Teva 25 mg/ml” and section 3 “How to use Fludarabine Teva 25 mg/ml”).

• If you have liver problems, your doctor should administer this medicine with caution.

• If you are over 75 years old, you will be monitored especially closely.

Children and adolescents

The safety and efficacy of this medicine have not been established in children under 18 years of age. Therefore, Fludarabine Teva 25 mg/ml is not recommended for use in children.

Use of Fludarabine Teva 25 mg/ml with other medicines

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines.

It is especially important to inform your doctor about:

• pentostatin (deoxycoformycin), also used to treat B-cell chronic lymphocytic leukemia (B-CLL). Taking these two drugs together may lead to severe pulmonary complications.
• dipyridamole, used to prevent excessive blood clotting, or other similar medicines. These may reduce the effectiveness of Fludarabine Teva 25 mg/ml.
• cytarabine (Ara-C), used to treat chronic lymphocytic leukemia. If Fludarabine Teva 25 mg/ml is combined with cytarabine, levels of the active form of cytarabine may increase. However, overall blood levels of cytarabine and its elimination from the blood have not been shown to change.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

Women: You must not become pregnant during treatment with Fludarabine Teva, as animal studies and very limited human experience have shown a potential risk of fetal abnormalities, as well as premature loss of pregnancy or preterm birth. If you become pregnant during treatment, inform your doctor immediately. Your doctor will decide with you whether to continue treatment with Fludarabine Teva.

Breastfeeding

You must not breastfeed while being treated with Fludarabine Teva.

Fertility in men and women

Women: You should use an effective method of contraception during treatment and for 6 months after completion, because Fludarabine Teva may be harmful to the fetus.

Men: It is recommended not to father children and to use an effective method of contraception during treatment and for at least 3 months after completion. You should seek advice about sperm preservation before treatment, as Fludarabine Teva may impair male fertility.

Both men and women planning to have a child after treatment are advised to speak with a doctor before starting treatment with Fludarabine Teva.

Driving and using machines

Some people may feel tired, weak, experience vision disturbances, confusion, agitation, or have seizures while receiving treatment with Fludarabine Teva 25 mg/ml. Do not attempt to drive or operate machinery until you are certain that you are not affected.

Fludarabine Teva 25 mg/ml contains sodium

This medicine contains less than 23 mg (1 mmol) of sodium per vial; hence, it is essentially “sodium-free”.

3. How to use Fludarabina Teva 25 mg/ml

Fludarabina Teva 25 mg/ml must be administered under the supervision of a qualified physician experienced in the use of anticancer therapy.

For instructions on dilution, handling, and disposal, see "The following information is intended for healthcare professionals only" at the end of this leaflet.

How much Fludarabina Teva 25 mg/ml 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/m² of body surface area.

How Fludarabina Teva 25 mg/ml is administered

Fludarabina Teva 25 mg/ml is administered as a solution either by injection or, in most cases, by 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 Fludarabina Teva 25 mg/ml is not administered outside the vein (paravenous administration). However, if this occurs, no serious local adverse events have been reported.

How long Fludarabina Teva 25 mg/ml 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. In general, this occurs after 6 cycles, in other words, after approximately 6 months.

The duration of treatment depends on the results obtained and your tolerance to Fludarabina Teva 25 mg/ml. The dose may be reduced or the next cycle delayed if adverse effects become problematic.

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.

If you have kidney problems or are over 65 years old, you will have regular tests to monitor 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 receive this medicine at all (see section 2).

If Fludarabina Teva 25 mg/ml solution is accidentally spilled

If any of the Fludarabina Teva 25 mg/ml 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 inhalation exposure.

If you are given more Fludarabina Teva 25 mg/ml than you should

If you receive an overdose, your doctor will stop the treatment and treat any symptoms.

High doses may also lead to a severely reduced number of blood cells.

For Fludarabina Teva 25 mg/ml administered intravenously, overdose has been reported to cause delayed blindness, coma, and even death.

If you miss a dose of Fludarabina Teva 25 mg/ml

Your doctor will determine the schedule for your medication. If you think you may have missed a dose, speak to your doctor as soon as possible.

If you stop using Fludarabina Teva 25 mg/ml

You and your doctor may decide to discontinue treatment with Fludarabina Teva 25 mg/ml if adverse effects become too severe.

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

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

If you are unsure about what the adverse reactions listed below are, please ask your doctor to explain them to you.

Some serious adverse effects can potentially be life-threatening. Contact your doctor immediately if:

• you have difficulty breathing, cough, or chest pain with or without fever.

These may be signs of a lung infection (very common adverse effect: may affect more than 1 in 10 people).

• you notice unusual bruising, increased bleeding after an injury, or feel like you are getting 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 (very common adverse effect: may affect more than 1 in 10 people).

• you experience any pain in your side, blood in your urine, or a decrease in the amount of urine. These may be signs of tumour lysis syndrome (see section 2 “Warnings and precautions”) (uncommon adverse effect: may affect up to 1 in 100 people).

• you notice a skin and/or mucosal membrane reaction with redness, swelling, blisters, and tissue breakdown. These may be signs of a severe allergic reaction (Lyell syndrome, Stevens-Johnson syndrome) (rare adverse effect: may affect up to 1 in 1,000 people).

• you have palpitations (if you suddenly become aware of your heartbeat) or chest pain. These may be signs of heart problems (rare adverse effect: may affect up to 1 in 1,000 people).

Other possible adverse effects:

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

• infections (some severe)
• reduced number of blood cells in the blood (thrombocytopenia), possibly leading to bruising and bleeding
• reduced number of white blood cells (neutropenia)
• reduced number of red blood cells (anemia)
• cough
• vomiting, diarrhoea, feeling unwell (nausea)
• fever
• feeling tired (fatigue)
• weakness

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

• other types of blood cancer (myelodysplastic syndrome, acute myeloid leukaemia). Most patients with these conditions had previously been treated, or were treated simultaneously or later, with other cancer drugs (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)
• altered vision
• inflammation of the mucous lining of the mouth (stomatitis)
• skin rashes
• swelling due to excessive fluid retention (oedema)
• inflammation of the mucous membranes of the digestive tract from mouth to anus (mucositis)
• chills
• general feeling of being unwell

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

• autoimmune disorder (see section 2 “Warnings and precautions”)
• confusion
• lung toxicity; scarring of the lungs (pulmonary fibrosis), inflammation of the lungs (pneumonitis), shortness of breath (dyspnoea)
• bleeding in the stomach or intestines
• abnormal levels of liver or pancreatic enzymes

Rare adverse effects (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 of the optic nerve (optic neuritis; optic neuropathy)
• heart failure
• changes in heart rhythm (arrhythmias)
• skin cancer

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

• bleeding in the brain (cerebral haemorrhage)
• neurological disorders presenting as 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 leukoencephalopathy syndrome (PRES))
• bleeding in the lungs (pulmonary haemorrhage)
• inflammation of the bladder, which may be painful when passing urine, and may lead to blood in the urine (haemorrhagic cystitis)

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, 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 Website: www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Fludarabine Teva 25 mg/ml

Keep this medicine out of 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.

Store in a refrigerator (between 2 °C and 8 °C).

Do not freeze.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of unused medicines and their containers. This will help protect the environment.

6. Contents of the pack and other information

Composition of Fludarabine Teva 25 mg/ml

• The active substance is fludarabine phosphate.

1 ml of concentrate contains 25 mg of fludarabine phosphate.

Each 2 ml vial contains 50 mg of fludarabine phosphate.

• The other components are mannitol (E421), sodium hydroxide (E524) to adjust pH, and water for injections.

Nature of the product and pack contents

Fludarabine Teva 25 mg/ml is a clear, colourless or yellowish-brown solution, essentially free from particles, in a colourless glass vial with a rubber stopper, aluminium seal, and plastic snap cap. Each pack contains one vial.

Marketing Authorisation Holder

Teva Pharma, S.L.U.

C/ Anabel Segura, 11. Edificio Albatros B, 1st floor

28108 Alcobendas, Madrid

Spain

Manufacturer

Pharmachemie B.V.

Swensweg 5

P.O. Box 552

2003 RN Haarlem

The Netherlands

This medicinal product is authorised in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) under the following names:

Belgium	Fludarabine Teva 25 mg/ml, concentrate for solution for injection/infusion Fludarabine Teva 25 mg/ml solution to be diluted for injection/perfusion Fludarabine Teva 25 mg/ml concentrate for the preparation of an injection/infusion solution
Czech Republic	Fludarabine-Teva
Denmark	Fludarabinphosphat Teva
France	FLUDARABINE TEVA 25 mg/mL, solution to be diluted for injectable solution/perfusion.
Germany	Fludarabinphosphat-GRY 25 mg/ml concentrate for the preparation of an injection/infusion solution
Iceland	Fludarabin Teva
Italy	Fludarabina Teva 25 mg/ml concentrate for injectable or infusion solution
Luxembourg	Fludarabine Teva 25 mg/ml solution to be diluted for injection/perfusion
Netherlands	Fludarabinefosfaat – PCH 25 mg/ml, concentrate for solution for infusion/injection
Norway	Fludarabin Teva
Slovenia	Fludarabin Teva 25 mg/ml concentrate for solution for injection/infusion
Spain	Fludarabina Teva 25 mg/ml concentrate for injectable and perfusion solution EFG
Sweden	Fludarabin Teva
United Kingdom (Northern Ireland)	Fludarabine Phosphate 25 mg/ml Concentrate for Solution for Injection/Infusion

Date of the most recent review of this summary: January 2025

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The following information is intended for healthcare professionals only:

Instructions for dilution, handling, and disposal

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned below.

Dilution

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

For intravenous bolus injection, this dose is further diluted with 10 ml of 0.9% sodium chloride.

Alternatively, for infusion, the required dose may be diluted in 100 ml of 0.9% sodium chloride and administered over approximately 30 minutes.

In clinical studies, fludarabine has been diluted in 100 ml or 125 ml of 5% dextrose injection or 0.9% sodium chloride.

Visual inspection before use

Only clear, colorless solutions free from particles should be used. The product must not be used if the container is damaged.

Storage after dilution

Chemical and physical in-use stability of the prepared solution for injection or infusion has been demonstrated:

Container	Solution	Concentration	Stability
PVC-free bag	sodium chloride 0.9%	0.3 - 6 mg/ml	5 days in refrigerator (2 °C - 8 °C) or at room temperature/light
glucose 5%	0.3 - 6 mg/ml	5 days in refrigerator (2 °C - 8 °C) or at room temperature/light
Glass vial	sodium chloride 0.9%	0.3 - 6 mg/ml	5 days in refrigerator (2 °C - 8 °C) or at room temperature/light
glucose 5%	0.3 mg/ml	5 days in refrigerator (2 °C - 8 °C) or at room temperature/light
6 mg/ml	5 days in refrigerator (2 °C - 8 °C) or 3 days at room temperature/light

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

Handling and disposal

Fludarabine must not be handled by pregnant personnel.

Procedures for proper handling must be followed in accordance with local requirements for the management of cytotoxic products.

Care must be taken when handling fludarabine solution. The use of latex gloves and safety goggles is recommended to avoid the risk of contact in the event of vial breakage or accidental spillage. If the solution comes into contact with the skin or mucous membranes, the affected area should be thoroughly washed with water and soap. In case of eye contact, the eyes should be thoroughly rinsed with copious amounts of water. Exposure by inhalation must be avoided.

The medicine is for single use only. Disposal of unused or spilled medication and of all materials that have come into contact with it must be carried out in accordance with local regulations for cytotoxic agents.