FLUDARABINE TEVA 25 mg/ml CONCENTRATE FOR SOLUTION FOR INFUSION OR INJECTION

Introduction

Package Leaflet: Information for the User

Fludarabina Teva 25 mg/ml Concentrate for Solution for Injection and Infusion EFG

Fludarabine phosphate

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

Fludarabina 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 by division. Fludarabina Teva 25 mg/ml is taken up by the cancer cells and paralyses their division.

In white blood cell cancers (such as chronic lymphocytic leukaemia), the body produces many abnormal white blood cells (lymphocytes), and the lymph nodes start to grow in various parts of the body. The abnormal growth of white blood cells prevents the normal functions of fighting disease, and can displace healthy blood cells. This can result in infections, a decrease in the number of red blood cells (anaemia), bruising, abnormal bleeding or even organ failure.

Fludarabina Teva 25 mg/ml is used to treat chronic lymphocytic leukaemia of B cells (B-CLL) in patients with sufficient production of healthy blood cells.

The first treatment for chronic lymphocytic leukaemia with Fludarabina Teva 25 mg/ml should only be started in patients with advanced disease who have symptoms related to the disease or evidence of disease progression.

2. What you need to know before you are given Fludarabina Teva 25 mg/ml

Do not use Fludarabina Teva 25 mg/ml

• if you are allergic to fludarabine phosphate or any of the other ingredients of this medicine (listed in section 6).
• if you are breast-feeding.
• if you have severe kidney problems.
• if you have a low number of red blood cells due to a certain type of anaemia (uncompensated haemolytic anaemia). Your doctor will have told you if you have this disease.

Tell your doctor if you think any of these may apply to you.

Warnings and precautions

Consult your doctor before starting treatment with Fludarabina Teva 25 mg/ml.

Be particularly careful with Fludarabina Teva 25 mg/ml:

• if your bone marrow is not working properly or if your immune system is not working well or

you are depressed or have a history of severe infections.

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

• if you feel very unwell, notice unusual bruising, more bleeding than

usual after an injury, or if you seem to be getting many infections.

If any of these apply to you before your treatment, tell your doctor.

• if during treatment your urine is red or brown, or you have a rash or any

blistering of the skin.

Tell your doctor immediately.

These symptoms may be signs of a decrease in the number of blood cells, which can be caused by the disease itself or by the treatment. It can last up to one year, regardless of whether you have received treatment before with Fludarabina Teva 25 mg/ml or not. During treatment with Fludarabina 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 life-threatening.

If this happens, your doctor will stop the treatment and you may receive other medicines such as irradiated blood transfusions (see below) and corticosteroids.

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

• if you notice any unusual symptoms in your nervous system such as changes in

vision, headache, confusion, seizures.

Tell your doctor.

If Fludarabina Teva 25 mg/ml is used for a long period, its effects on the central nervous system are unknown. However, patients treated with the recommended dose for up to 26 cycles of treatment were able to tolerate it.

When fludarabine is used at the recommended dose, after treatment with another medicine or at the same time as another medicine, the following adverse events have been reported: neurological disorders manifesting as headache, feeling of 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 irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, toxic acute leukoencephalopathy or reversible posterior leukoencephalopathy syndrome (PRES)).

In patients with doses four times higher than recommended, blindness, coma, and death have been reported. Some of these symptoms appeared with a delay of around 60 days or more after stopping treatment. In some patients treated with doses higher than the recommended dose of Fludarabina Teva 25 mg/ml, leukoencephalopathy (LE), toxic acute leukoencephalopathy (TLE) or reversible posterior leukoencephalopathy syndrome (PRES) have also been reported. The same symptoms of LE, TLE or PRES described above may occur.

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

Whenever LE, TLE, or PRES is suspected, your treatment with Fludarabina Teva 25 mg/ml will be stopped for further investigation. If the diagnosis of LE, TLE, or PRES is confirmed, your doctor will permanently stop your treatment with Fludarabina Teva 25 mg/ml.

• if you notice any pain in your side, blood in your urine or a decrease in the

amount of urine

Tell your doctor immediately.

If your disease is very severe, your body may not be able to eliminate all the waste productsfrom the cells destroyed by Fludarabina Teva 25 mg/ml. This is called tumour lysis syndromeand can cause kidney failure and heart problemsfrom the first week of treatment. Your doctor is aware of this and may give you other medicines to prevent this from happening.

• if you need to have your stem cells removed and you are being treated with Fludarabina Teva 25 mg/ml (or have been),

Tell your doctor.

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

Tell your doctor.

If you need a blood transfusion, your doctor will make sure you only receive blood that has been treated with irradiation. Serious complications and even death have occurred from non-irradiated blood transfusions.

• if you notice any changes in your skin while you are receiving this medicine or

after you have finished treatment

Tell your doctor.

• if you have had skin cancer or it has come back during treatment with Fludarabina Teva 25 mg/ml or later. You may develop skin cancer during or after treatment with Fludarabina Teva 25 mg/ml.

Other aspects to consider while you are being treated with Fludarabina Teva 25 mg/ml

• Fludarabina Teva must not be administered if you are pregnant, unless your doctor clearly indicates it.

• Women: you must not become pregnant during treatment with Fludarabina Teva and must use an effective contraceptive method during treatment and for 6 months after the end of treatment, as Fludarabina 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 you should continue taking Fludarabina Teva.

• Men: it is recommended not to father a child and to use an effective contraceptive method during treatment and for at least 3 months after the end of treatment. You must inform about sperm preservation before treatment, as Fludarabina Teva may affect male fertility.

• You must not breast-feed while you are being treated with Fludarabina Teva.

• If you need any vaccination, consult your doctor, as vaccines with live microorganisms must be avoided during treatment with Fludarabina Teva 25 mg/ml and after treatment.

Pregnancy, breast-feeding, and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy

Women: you must not become pregnant during treatment with Fludarabina Teva, as studies in animals and limited experience in humans have shown a possible risk of fetal abnormalities, as well as premature loss of pregnancy or premature birth. If you become pregnant during treatment, you must inform your doctor immediately. Your doctor will decide with you whether you should continue taking Fludarabina Teva.

Breast-feeding

You must not breast-feed while you are being treated with Fludarabina Teva.

Fertility in men and women

Women: you must use an effective contraceptive method during treatment and for 6 months after the end of treatment, as Fludarabina Teva may be harmful to the fetus.

Men: it is recommended not to father a child and to use an effective contraceptive method during treatment and for at least 3 months after the end of treatment. You must inform about sperm preservation before treatment, as Fludarabina Teva may affect male fertility.

It is recommended that both men and women who plan to have a child after treatment talk to a doctor before starting treatment with Fludarabina Teva.

Driving and using machines

Some people may feel tired, weak, have changes in vision, be confused, agitated, or have seizures while receiving treatment with Fludarabina Teva 25 mg/ml. Do not attempt to drive or operate machinery until you are sure that it does not affect you.

Fludarabina Teva 25 mg/ml contains sodium

This medicine contains less than 23 mg (1 mmol) of sodium per vial; this is essentially "sodium-free".

3. How to use Fludarabina Teva 25 mg/ml

Fludarabina Teva 25 mg/ml should be administered under the supervision of a qualified doctor with experience in the use of cancer 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 by injection or, in most cases, by infusion.

An infusion means that the medicine is administered directly into the bloodstream through a drip into a vein. An infusion lasts approximately 30 minutes.

Your doctor will make sure that Fludarabina Teva 25 mg/ml is not administered outside the vein (paravenously). However, if this happens, no serious local adverse events have been reported.

For how long Fludarabina Teva 25 mg/ml is administered

The dose will be administered once a day for 5 consecutive days.

This 5-day treatment cycle will be repeated every 28 days until your doctor decides that the best effect has been achieved. In general, this is after 6 cycles, i.e. after approximately 6 months.

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

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

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 working properly, you may be given this medicine at a lower dose. If your kidney function is severely reduced, you will not be given this medicine at all (see section 2).

If some of the Fludarabina Teva 25 mg/ml solution is accidentally spilled

If some 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 water and soap. 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 the symptoms.

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

For Fludarabina Teva 25 mg/ml administered intravenously, it has been reported that overdose can cause late blindness, coma, and even death.

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

Your doctor will decide when you will receive the medicine. If you think you may have missed a dose, talk to your doctor as soon as possible.

If you stop using Fludarabina Teva 25 mg/ml

You and your doctor may decide to stop your treatment with Fludarabina Teva 25 mg/ml if the adverse effects are becoming too severe.

If you have any further questions on 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 all people suffer from them.

If you are not sure what the following adverse reactions are, ask your doctor to explain them to you.

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

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

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

• if you notice unusual bruising, more bleeding than usual after a

wound or if you think you have many infections. These may be caused by a

decrease in the number of blood cells. This can also lead to an increased

risk of infections (serious) caused by organisms that normally do not cause

diseases in healthy people (opportunistic infections)including a late

reactivation of viruses, e.g. herpes zoster (very frequent adverse effect: may affect more than 1 in 10 people).

• if you notice any pain in the side, blood in the urine, or a decrease in the

amount of urine. These may be signs of tumor lysis syndrome

(see section 2 “Warnings and Precautions”) (uncommon adverse effect: may affect up to 1 in 100 people).

• if you notice a skin and/or mucous membrane reaction with redness, inflammation,

blisters and tissue rupture.These may be signs of a severe

allergic reaction (Lyell's syndrome, Stevens-Johnson syndrome) (rare adverse effect: may affect up to 1 in 1,000 people).

• if 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:

Adverse effectsvery common (may affect more than 1 in 10 people)

• infections (some serious)
• reduction in the number of blood cells in the blood (thrombocytopenia) with

possibility of bruising and bleeding

• reduction in the number of white blood cells (neutropenia)
• reduction in the number of red blood cells (anemia)
• cough
• vomiting, diarrhea, feeling of general discomfort (nausea)
• fever
• feeling of tiredness (fatigue)
• weakness.

Adverse effects frequent (may affect up to 1 in 10 people)

• other types of blood cancer (myelodysplastic syndrome, acute myeloid

leukemia). Most patients with these diseases were previously treated

or at the same time or later with other cancer drugs (alkylating agents, topoisomerase inhibitors)or radiotherapy)

• bone marrow depression (myelosuppression)
• severe loss of appetite leading to weight loss (anorexia)
• numbness or weakness in limbs (peripheral neuropathy)
• altered vision
• inflammation of the mucous membrane lining of the mouth (stomatitis)
• skin rashes
• swelling due to excessive fluid retention (edema)
• inflammation of the mucous membranes of the digestive system from the mouth to the anus (mucositis)
• chills
• feeling of general discomfort.

Adverse effects uncommon (may affect up to 1 in 100 people)

• autoimmune disorder (see section 2 “Warnings and Precautions”)
• confusion
• pulmonary toxicity; scarring of the lungs (pulmonary fibrosis), inflammation of

the lungs (pneumonitis), shortness of breath (dyspnea)

• bleeding in the stomach or intestines
• abnormal levels of liver or pancreas enzymes

Adverse effects rare(may affect up to 1 in 1,000 people)

• lymphatic system disorders due to a viral infection (virus-associated

lymphoproliferative disorder)

• coma
• seizures
• agitation
• blindness
• inflammation or damage to the optic nerve (optic neuritis; optic neuropathy)
• heart failure
• heart rhythm disorders (arrhythmias)
• skin cancer.

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

• bleeding in the brain (cerebral hemorrhage)
• neurological disorders that manifest as headache, feeling of 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 irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, toxic acute leukoencephalopathy or posterior reversible encephalopathy syndrome (PRES))
• bleeding in the lungs (pulmonary hemorrhage)
• inflammation of the bladder, which can be painful when urinating, and can lead to blood in the urine (hemorrhagic cystitis).

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is not listed in this leaflet.

You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines Website: www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Fludarabine Teva 25 mg/ml

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date stated on the carton and vial after “EXP”. The expiration date is 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 the packaging and any unused medicine. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Fludarabine Teva 25 mg/ml

• The active ingredient 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 ingredients are mannitol (E421), sodium hydroxide (E524) for pH adjustment, and water for injectable preparations.

Appearance of the Product and Package Contents

Fludarabine Teva 25 mg/ml is a clear, colorless or brownish-yellow solution, essentially free of particles, in a colorless glass vial with a rubber stopper, aluminum seal, and plastic snap cap. Each package contains one vial.

Marketing Authorization Holder

Teva Pharma, S.L.U.

C/ Anabel Segura, 11. Edificio Albatros B, 1ª planta

28108 Alcobendas, Madrid

Spain

Manufacturer

Pharmachemie B.V.

Swensweg 5

PO Box 552

2003 RN Haarlem

Netherlands

This medicine is authorized in the Member States of the European Economic Areaand in the United Kingdom (Northern Ireland)with the following names:

Date of the last revision of this leaflet: January 2025

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The following information is intended only for healthcare professionals:

Instructions for Dilution, Handling, and Disposal

In the absence of compatibility studies, this medicine should not be mixed with other medicines except those mentioned below.

Dilution

The required dose (calculated based on the patient's body surface area) is aspirated 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 can be diluted in 100 ml of 0.9% sodium chloride and infused 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.

Inspection before use

Only clear, colorless solutions without particles should be used. The product should not be used if the package is defective.

Storage after dilution

The chemical and physical stability of the prepared solution for injection or infusion has been demonstrated:

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

Handling and disposal

Fludarabine should not be handled by pregnant personnel.

The procedures for the proper handling of this product should be followed, which will be carried out in accordance with local requirements for the handling of cytotoxic products.

Caution should be exercised when handling the fludarabine solution. The use of latex gloves and safety glasses 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 washed thoroughly with water and soap. In the event of eye contact, the eyes should be rinsed thoroughly with plenty of water. Inhalation exposure should be avoided.

The medicine is for single use only. The disposal of unused medicine, spills, and all materials that have come into contact with it will be carried out in accordance with local regulations for cytotoxic agents.