Beneflur 10 mg film-coated tablets

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Beneflur 10 mg film-coated tablets

Fludarabine phosphate

Read all of this leaflet carefully before you start taking 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 or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are side effects not listed in this leaflet. See section 4.

Contents of the leaflet

1. What Beneflur 10 mg tablets are and what they are used for
2. What you need to know before taking Beneflur 10 mg tablets
3. How to take Beneflur 10 mg tablets
4. Possible side effects
5. How to store Beneflur 10 mg tablets
6. Contents of the pack and other information

1. What Beneflur 10 mg film-coated tablets are and what they are used for

Beneflur 10 mg tablets contain 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. Beneflur 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 reduced number of red blood cells (anemia), bruising, abnormally severe bleeding, or even organ failure.

Beneflur 10 mg tablets are used for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients with sufficient production of healthy blood cells.

Initial treatment of chronic lymphocytic leukemia with Beneflur 10 mg tablets 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 starting to take Beneflur 10 mg film-coated tablets

Do not take Beneflur 10 mg film-coated tablets:

• If you are allergic to fludarabine phosphate or to any of the components of this medicine (listed in section 6).
• If you have severe kidney problems.
• If you are breastfeeding.
• If you have a low number of red blood cells due to a certain type of anemia (decompensated hemolytic anemia). Your doctor will have informed you if you have this condition.

If you think any of these may apply to you, inform your doctor before taking Beneflur 10 mg film-coated tablets.

Warnings and precautions

Consult your doctor before starting to take Beneflur 10 mg film-coated tablets.

Take special care with Beneflur 10 mg film-coated tablets:

• 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, more bleeding than usual after an injury, or if you seem to be getting frequent infections.

• 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 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 received treatment with Beneflur 10 mg film-coated tablets. During treatment with Beneflur 10 mg film-coated tablets, 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 occurs, your doctor will stop treatment, and you may receive other medications such as irradiated blood transfusions (see below) and adrenocorticosteroids.

You will have regular blood tests during treatment and will be closely monitored while being treated with Beneflur 10 mg film-coated tablets.

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

If Beneflur 10 mg film-coated tablets are 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 Beneflur is used at the recommended dose, following or concomitantly with other medications, the following adverse events have been reported:

neurological disorders manifesting 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 encephalopathy 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 discontinuation of treatment. In some patients treated with doses higher than the recommended dose of Beneflur, 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 Beneflur will be stopped for further investigation. If the diagnosis of LE, ATL, or PRES is confirmed, your doctor will permanently discontinue your treatment with Beneflur.

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

When your disease is very severe, your body may not be able to eliminate all waste products from cells destroyed by Beneflur. 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 it. He or she may decide that your treatment should begin in the hospital.

• if you need stem cell collection and are being treated with Beneflur 10 mg film-coated tablets (or have been).

• if you need a blood transfusion and are being treated with Beneflur 10 mg film-coated tablets (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 skin changes while receiving this medicine or after completing treatment.

• if you have or have had skin cancer, it may worsen or recur during or after treatment with Beneflur 10 mg film-coated tablets. You may develop skin cancer during or after treatment with Beneflur 10 mg film-coated tablets.

Other considerations while being treated with Beneflur 10 mg film-coated tablets:

• If you are pregnant, you must not take Beneflur 10 mg film-coated tablets unless clearly indicated by your doctor.

• Women: you must not become pregnant during treatment with Beneflur 10 mg film-coated tablets and must use an effective contraceptive method during treatment and for 6 months after the end of treatment, as Beneflur 10 mg film-coated tablets 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 Beneflur.

• 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 should discuss sperm preservation before treatment, as Beneflur 10 mg film-coated tablets may impair male fertility.

• Do not breastfeed while being treated with Beneflur 10 mg film-coated tablets.

• if you require any vaccination, consult your doctor, as vaccines containing live microorganisms must be avoided during and after treatment with Beneflur 10 mg film-coated tablets.

• if you have kidney problems or are over 65 years old, regular blood tests and/or laboratory tests will be performed to monitor kidney function. If your kidney problems are severe, this medicine will not be prescribed (see sections 2 and 3).

• Beneflur 10 mg film-coated tablets may cause more vomiting and nausea (feeling dizzy or unwell) than intravenous Beneflur. If this is a problem, your doctor will consider switching treatment to intravenous Beneflur.

Children and adolescents

The safety and efficacy of Beneflur 10 mg film-coated tablets in children under 18 years of age have not been established. Therefore, the use of Beneflur 10 mg film-coated tablets is not recommended in children.

Elderly patients and Beneflur 10 mg film-coated tablets:

If you are over 65 years old, regular tests of your kidney function will be performed (see also section 3. How to take Beneflur 10 mg film-coated tablets).

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

Other medicines and Beneflur 10 mg film-coated tablets

Inform your doctor if you are taking, have recently taken, or might need to take any other medicines, including those 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 severe pulmonary complications.
• dipyridamole, used to prevent excessive blood clotting, or similar substances. These may reduce the effectiveness of Beneflur 10 mg film-coated tablets.
• cytarabine (Ara-C), used to treat chronic lymphocytic leukemia. If Beneflur 10 mg film-coated tablets are combined with cytarabine, levels of the active form of Beneflur 10 mg film-coated tablets 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

Women: you must not become pregnant during treatment with Beneflur 10 mg film-coated tablets because 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 Beneflur.

Breastfeeding

Do not breastfeed while being treated with Beneflur.

You must not start or continue breastfeeding during your treatment with Beneflur, as this medicine may interfere with your baby's growth and development.

Fertility in men and women

Women: an effective contraceptive method must be used during treatment and for 6 months after the end of treatment, as Beneflur 10 mg film-coated tablets 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 should discuss sperm preservation before treatment because Beneflur 10 mg film-coated tablets may impair male fertility.

Before starting treatment with Beneflur, both men and women who plan to have children after treatment are advised to speak with a doctor.

Driving and use of machines

Some people may feel tired, weak, have vision disturbances, confusion, agitation, or suffer seizures while receiving treatment with Beneflur 10 mg film-coated tablets. Do not attempt to drive or operate machinery until you are certain it does not affect you.

Beneflur 10 mg film-coated tablets contain lactose

This medicine contains lactose (a type of sugar). If your doctor has informed you that you have an intolerance to certain sugars, consult him before taking this medicine.

Beneflur 10 mg film-coated tablets contain sodium

This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

3. How to take Beneflur 10 mg film-coated tablets

Always take this medicine exactly as your doctor has told you. Consult your doctor or pharmacist if you are unsure.

How many tablets to take

The dose you should take depends 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 40 mg of fludarabine phosphate/m² of body surface area, once daily. The usual dose ranges between 3 and 10 tablets per day. Your doctor will calculate the exact number of tablets you should take.

How to take Beneflur 10 mg tablets

Swallow the tablet whole with water. Do not break or chew the tablets. You may take Beneflur 10 mg tablets either on an empty stomach or with food.

How long to take Beneflur 10 mg tablets

Take the dose prescribed by your doctor 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 Beneflur 10 mg tablets. The next cycle may be delayed if adverse effects are a concern.

You will have regular blood tests during treatment. Your individual dose will be carefully adjusted according to your blood cell counts and your response to treatment. If your blood cell counts are too low, your next treatment cycle may be postponed for up to two weeks, or your dose may be reduced. If adverse effects are problematic, the dose may be decreased.

If you have received two cycles of treatment and have not responded, but have also shown few signs of reduced blood cell counts, your doctor may decide to increase the dose.

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

If you have taken more than the prescribed amount of Beneflur 10 mg tablets

If you have taken too many Beneflur tablets, inform your doctor immediately.

High doses can lead to severely reduced blood cell counts.

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

If you forget to take Beneflur 10 mg tablets

If you think you may have missed a dose or if you vomit after taking the tablet, speak to your doctor as soon as possible.

Do not take a double dose to make up for forgotten tablets.

If you stop taking Beneflur 10 mg tablets

Do not stop taking Beneflur 10 mg tablets without consulting your doctor.

You and your doctor may decide to discontinue treatment with Beneflur 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 may cause adverse effects, although not everyone will experience them. If you are unsure about the adverse effects described below, please ask your doctor to explain them to you.

Some adverse effects may 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.

• you notice unusual bruising, excessive 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.

• 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).

• you notice a skin and/or mucous membrane reaction with redness, swelling, blisters, and tissue breakdown. These may be signs of a severe allergic reaction (Lyell syndrome, Stevens-Johnson syndrome).

• you have palpitations (if you suddenly become aware of your heartbeat) or chest pain. These may be signs of heart problems.

The following are possible adverse effects listed by frequency, based on intravenous use of Beneflur.

Very common adverse effects (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 difficulty breathing and/or cough with or without fever
• reduction in the number of platelets in the blood (thrombocytopenia), possibly leading to bruising and bleeding
• reduction in the number of white blood cells (neutropenia)
• reduction in the number of red blood cells (anemia)
• cough
• vomiting, diarrhoea, general feeling of discomfort (nausea)
• fever
• feeling of tiredness (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 were previously, simultaneously, or subsequently treated 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 discomfort

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

• autoimmune disorder (see section 2)
• tumour lysis syndrome (see section 2)
• confusion
• pulmonary toxicity; scarring of the lungs (pulmonary fibrosis), inflammation of the lungs (pneumonitis), difficulty breathing (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 (EBV)-associated lymphoproliferative disorder)
• coma
• seizures
• agitation
• blindness
• inflammation or damage to the optic nerve (optic neuritis; optic neuropathy)
• heart failure
• disturbances in heart rhythm (arrhythmias)
• skin cancer
• skin and/or mucous membrane reaction with redness, swelling, blisters, and tissue breakdown (Lyell syndrome, Stevens-Johnson syndrome)

Frequency not known (cannot be estimated from available data)

• bleeding in the brain
• neurological disorders manifesting 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 limb muscle weakness (including partial or complete irreversible paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy, or posterior reversible encephalopathy syndrome (PRES)).
• bleeding in the lungs
• inflammation of the bladder, which may cause pain during urination 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 may also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Beneflur 10 mg film-coated tablets

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

Do not use this medicine after the expiry date stated on the label of the bottle and the blister strip following "EXP". The expiry date refers to the last day of the month indicated.

Beneflur 10 mg tablets are a cytotoxic drug. It must always be stored in the original child-resistant packaging.

Do not store above 25°C. Do not refrigerate. Keep in the original packaging to protect from moisture.

Medicines must not be disposed of via wastewater drains or household waste. Dispose of unused medicines and their packaging at the SIGRE collection point in your pharmacy. If in doubt, ask your pharmacist how to dispose of medicines and packaging you no longer need. This will help protect the environment.

Return any unused tablets to your doctor or pharmacist. They will ensure that the disposal of Beneflur 10 mg film-coated tablets complies with local regulations for cytotoxic drugs.

6. Contents of the container and other information

Composition of Beneflur 10 mg tablets:

• The active substance is fludarabine phosphate. Each coated tablet contains 10 mg of fludarabine phosphate.

• The other components are:

• In the tablet core: cellulose (microcrystalline), lactose (monohydrate), silica (colloidal anhydrous), sodium croscarmellose, magnesium stearate;

• In the coating: hypromellose, talc, titanium dioxide (E171), iron oxide pigment (yellow (E172)), iron oxide pigment (red (E172)).

Appearance of Beneflur 10 mg tablets and contents of the pack:

Beneflur 10 mg tablets are salmon-coloured, oblong tablets, marked on one side with “LN” within a regular hexagon.

The tablets are presented in blisters of 5 tablets each. The blisters are made of thermoformable polyamide/aluminum/polypropylene film, with an aluminum foil lid. The blisters are contained in a polyethylene tablet bottle with a child-resistant screw cap.

Beneflur 10 mg tablets are available in packs containing:

• 15 tablets in 3 blisters in a child-resistant safety bottle.
• 20 tablets in 4 blisters in a child-resistant safety bottle.

Only some pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Sanofi B.V.

Paasheuvelweg 25

1105 BP Amsterdam

The Netherlands

Manufacturer

HVL Pharma UK LDT, 37 Hollands Road, Haverhill, CB9 8PU, United Kingdom

Or

SANOFI WINTHROP INDUSTRIE, 30-36, avenue Gustave Eiffel, 37100 Tours, France

Local representative

sanofi-aventis, S.A.

C/ Rosselló i Porcel, 21

08016 Barcelona

Spain

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

This patient information leaflet was approved in July 2023

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