Package Leaflet: Information for the User

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

Fludarabine phosphate

Read this 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, consult your doctor, pharmacist or nurse.

- If you experience any side effects, consult your doctor, pharmacist or nurse, even if they are not listed in this leaflet. See section 4.

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

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

3. How to use Fludarabine Teva 25 mg/ml

4. Possible side effects

5. Storage of Fludarabine Teva 25 mg/ml

6. Contents of the pack and additional information.

Fludarabina Teva 25 mg/ml contains the active ingredient fludarabine phosphate that stops the growth of new cancer cells. All cells in the body produce new cells similar to themselves through division. Fludarabina Teva 25 mg/ml is incorporated by cancer cells and paralyzes their division.

In leukemias of white blood cells (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 normal functions of fighting disease, and can displace healthy blood cells. This can result in infections, decrease in the number of red blood cells (anemia), bruises, abnormally severe bleeding or even organ failure.

Fludarabina Teva 25 mg/ml is used for the treatment of chronic lymphocytic leukemia of B cells (CLL-B), in patients with sufficient production of healthy blood cells.

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

Do not use Fludarabina Teva 25 mg/ml

• if you areallergicto 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 certain type of anemia (hemolytic anemia). Your doctor will have informed you if you have this disease.

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

Warnings and precautions

Consult your doctor before starting to use Fludarabina Teva 25 mg/ml.

Be particularly careful with Fludarabina Teva 25 mg/ml:

- if your bone marrow does not function properly or if your immune system does not work well or

is depressed or has 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, observe unusual bruising, more bleeding than usual after an injury, or if you think you have many infections.

??Inform your doctor if any of this is relevant before your treatment.

- if during treatment your urine is red or brown, or if you have a rash or blister on your skin.

??Inform your doctor immediately.

These symptoms may be signs of a decrease in the number of blood cells, which may be caused by the disease itself or by the treatment. This may last up to a year, regardless of whether you have received treatment with Fludarabina Teva 25 mg/ml before 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 potentially fatal.

If this happens, your doctor will interrupt 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 observe any unusual symptoms in your nervous system such as altered vision, headache, confusion, convulsions.

??Inform 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 treatment cycles 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 that manifest as headache, dizziness (nausea) and vomiting, convulsions, visual disturbances including loss of vision, changes in mental state (abnormal thinking, confusion, altered consciousness) and occasionally neuromuscular disorders manifested by muscle weakness in the limbs (including irreversible partial or complete paralysis) (symptoms of leucoencephalopathy, acute toxic leucoencephalopathy or reversible posterior leucoencephalopathy syndrome (RPLS)).

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

LE, LTA, and RPLS may be irreversible, life-threatening, or fatal.

Each time LE, LTA, or RPLS is suspected, treatment with Fludarabina Teva 25 mg/ml will be stopped for further investigation. If LE, LTA, or RPLS is confirmed, your doctor will permanently interrupt your treatment with Fludarabina Teva 25 mg/ml.

- if you notice any pain in the side, blood in the urine, or decrease in the amount of urine

??Inform your doctor immediately.

When 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 calledtumour lysis syndromeand may causekidney failure and heart problemsfrom the first week of treatment. Your doctor is aware of this and may administer other medicines to prevent it.

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

??Inform your doctor.

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

??Inform your doctor.

In the event that you need a blood transfusion, your doctor will ensure that you receive only irradiated blood. Severe complications, including death, have been reported from non-irradiated blood transfusions.

- if you observe any change in your skin while receiving this medicine or

after having completed the treatment

??Inform your doctor.

- if you have skin cancer or have had itit may worsen or reappear during treatment with Fludarabina Teva 25 mg/mlor later. You may develop skin cancer during or after treatment with Fludarabina Teva 25 mg/ml.

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

-Fludarabina Teva should not be administered if you are pregnant, unless your doctor has clearly indicated this.

-Women: Do not become pregnant during treatment with Fludarabina Teva and use an effective contraceptive methodduring treatment and for 6 months after its completion, as Fludarabina Teva may be harmful to the fetus. If you become pregnant during treatment, inform your doctor immediately. Your doctor will decide with you whether to continue taking Fludarabina Teva.

- Men: It is recommended not to father children and use an effective contraceptive methodduring treatment and for at least 3 months after its completion. You should inform about sperm conservation before treatment, as Fludarabina Teva may alter male fertility.

- Do not breastfeedwhile being treated with Fludarabina Teva.

- If you require any vaccination, consult your doctor, as live vaccines should be avoided during treatment with Fludarabina Teva 25 mg/mland after it.

- if you have kidney problems or are over 65 years old, regular blood tests and/or laboratory tests will be performed to monitor renal function

(see section 2 “Do not use Fludarabina Teva 25 mg/ml” and section 3. “How to use Fludarabina 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 very closely.

Children and adolescents

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

Use of Fludarabina Teva 25 mg/ml with other medicines

Inform your doctor or pharmacist if you are taking/using, have taken/used recently or may need to take/use any other medicine.

It is especially important to inform your doctor about:

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

Pregnancy, lactation, and fertility

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

Pregnancy

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

Lactation

Do not breastfeed while being treated with Fludarabina Teva.

Fertility in men and women

Women: Use an effective contraceptive method during treatment and for 6 months after its completion, as Fludarabina Teva may be harmful to the fetus.

Men: It is recommended not to father children and use an effective contraceptive method during treatment and for at least 3 months after its completion. You should inform about sperm conservation before treatment, as Fludarabina Teva may alter male fertility.

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

Driving and operating machines

Some people may feel tired, weak, have visual disturbances, be confused, agitated, or have convulsions while receiving treatment with Fludarabina Teva 25 mg/ml. Do not attempt to drive or operate machinery until you are sure 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; that is, it is essentially “sodium-free”.

Fludarabina Teva 25 mg/ml should be administered under the supervision of a qualified doctor with experience in the use of cancer therapy.

To obtain instructions on dilution, handling, and disposal, see "The following information is intended only for healthcare professionals" 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 from your height and weight.

The recommended dose is 25 mg of fludarabine phosphate/m2of body surface area.

How Fludarabina Teva 25 mg/ml is administered

Fludarabina Teva 25 mg/ml is administered as a solution as an injection or in most cases as an infusion.

An infusion means that the medication is administered directly into the circulatory system through 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). However, if this were to occur, no serious local adverse events have been reported.

For how long is Fludarabina Teva 25 mg/ml administeredFludarabina Teva 25 mg/ml

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. Generally, this is after 6 cycles, in other words, after approximately 6 months.

The duration of treatment depends on the results obtained and the 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 the number of your blood cells and your 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 do not function properly, you may be given this medication at a lower dose. If your kidney function is severely reduced, you will not be given this medication at all (see section 2).

If some 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 in 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 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 an overdose can cause late blindness, coma, and even death.

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

Your doctor will establish the times when you will receive the medication. If you think you may not have received a dose, speak with your doctor as soon as possible.

If you interrupt the use of Fludarabina Teva 25mg/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 other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

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

If you are unsure what adverse reactions are, ask your doctor to explain them to you.

Some serious side effects can be potentially fatal.Consult your doctor immediately:

- if you have difficulty breathing, coughing, or chest pain with or without fever.

These may be signs of a lung infection(very common side 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 are experiencing 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, for example herpes zoster(very common side effect: may affect more than 1 in 10 people).

- if you notice any chest pain, blood in the urine, or decreased urine output.

These may be signs oftumour lysis syndrome

(see section 2 “Warnings and precautions”)(rare side 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

(Lymphoma syndrome, Stevens-Johnson syndrome)(rare side 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 side effect: may affect up to 1 in 1,000 people).

Other possible side effects:

Very common side effects (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)

- coughing

- vomiting, diarrhea, general feeling of discomfort(nausea)

- fever

- feeling tired(fatigue)

- weakness.

Common side effects (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 treated at the same time or later with other cancer drugs(alkylating agents, topoisomerase inhibitors)

- spinal cord 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 eruptions

- swelling due to excessive fluid retention(edema)

- inflammation of the mucous membranes of the digestive system from the mouth to the anus (mucositis)

- chills

- general feeling of discomfort.

Rare side effects (may affect up to 1 in 100 people)

- autoimmune disorder (see section 2 “Warnings and precautions”)

- confusion

- pulmonary toxicity; lung scarring(pulmonary fibrosis), inflammation of

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

- bleeding in the stomach or intestines

- abnormal levelsof liver or pancreas enzymes

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

- lymphatic system disorders due to viral infection(lymphoproliferative disorder associated with VEB)

- coma

- seizures

- agitation

- blindness

- inflammation or damage to the optic nerve(optic neuritis; optic neuropathy)

- heart failure

- heart rhythm disturbances(arrhythmias)

- skin cancer.

?Unknown frequency(cannot be estimated from available data)

Reporting of side effects

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

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

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

Do not use this medication after the expiration date that appears on the carton and on the vial after “CAD”.The expiration date is the last day of the month indicated.

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

Do not freeze.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medicines that you no longer need. This will help protect the environment.

Fludarabine Teva 25 mg/ml Composition

- The active ingredient is fludarabine phosphate.

1 ml of concentrate contains 25 mg of fludarabine phosphate.

Each vial of 2 ml contains 50 mg of fludarabine phosphate.

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

Appearance of the product and contents of the pack

Fludarabine Teva 25 mg/ml is a transparent, colourless or yellowish-brown solution, essentially free of particles, in a colourless glass vial with a rubber stopper, aluminium seal, and plastic snap-off 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

Responsible Person

Pharmachemie B.V.

Swensweg 5

PO Box 552

2003 RN Haarlem

Netherlands

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

Last update of the summary of product characteristics: 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 should not be mixed with other medicinal products except those mentioned below.

Dilution

The required dose (calculated on the basis of the patient's body surface area) is aspirated into a syringe.

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

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

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

Inspection before use

Only solutions that are transparent and colourless without particles should be used. The product should not be used if the container is defective.

Storage after dilution

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

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

Handling and disposal

Fludarabine should not be handled by pregnant staff.

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

Care should be taken in 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 thoroughly washed with water and soap. In the event of eye contact, the eyes should be thoroughly flushed with plenty of water. Exposure to inhalation should be avoided.

The medicinal product is for single use only. Disposal of unused, spilled, and all materials that have come into contact with it should be carried out in accordance with local regulations for cytotoxic agents.