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

1. What Fludara is and what it is used for
2. What you need to know before you are given Fludara
3. How to use Fludara
4. Possible side effects
5. How to store Fludara
6. Contents of the pack and other information

• 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 your red blood cell count is low, because of a type of anaemia (decompensated haemolytic anaemia). Your doctor will have told you if you have this condition

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

Talk to your doctor before using Fludara.

Take special care with Fludara:

• if your bone marrow is not working properly or if you have a poorly functioning or depressed immune system or a history of serious infections.

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

• if you feel very unwell, notice any unusual bruising, more bleeding than usual after injury, or if you seem to be catching a lot of infections.
• if during treatment you have a red to brownish urine, or have a rash or any blisters on your skin.

Tell your doctor immediately

These may be signs of a reduction in the number of blood cells, which may be caused either by the disease itself or the therapy. It can last for up to a year, independent of whether or not you had treatment with Fludara before. During treatment with Fludara also your immune system may attack different parts of your body, or your red blood cells (called ‘autoimmune disorders’). These conditions can be life-threatening.

If this occurs your doctor will stop your treatment and you may receive further medication such as transfusion of irradiated blood (see below) and adrenocorticoids.

You will have regular blood tests during treatment and you will be closely monitored while you are being treated with Fludara.

• if you notice any unusual symptoms of your nervous system such as disturbed vision, headache, confusion, seizures.

If Fludara is used for a long time, its effects on the central nervous system are not known. However patients treated with the recommended dose for up to 26 courses of therapy were able to tolerate it.

When Fludara is used at the recommended dose, following the treatment with some other medications or at the same time as some other medications, the following adverse events have been reported: neurological disorders manifested by headache, feeling sick (nausea) and vomiting, seizures, visual disturbances including vision loss, changes in mental status (thinking abnormal, confusion, altered consciousness) and occasionally neuromuscular disorders manifested by muscle weakness in your limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy or posterior reversible leukoencephalopathy syndrome (RPLS)).

In patients on doses four times greater than recommended blindness, coma and death have been reported. Some of these symptoms appeared delayed around 60 days or more after treatment had been stopped. In some patients receiving Fludara doses higher than the recommended dose, leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL) or posterior reversible leukoencephalopathy syndrome (RPLS) have also been reported. Same symptoms of LE, ATL or RPLS as above described could occur.

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

Whenever LE, ATL or RPLS is suspected, your treatment will Fludara will be stopped for further investigations. If the diagnosis of LE, ATL, or RPLS is confirmed, you doctor will permanently discontinue your treatment with Fludara.

• if you notice any pain in your side, blood in your urine or reduced amount of urine.

When your disease is very severe, your body may not be able to clear all the waste products from the cells destroyed by Fludara. This is called tumour lysis syndrome and can cause kidney failure and heart problems from the first week of treatment. Your doctor will be aware of this and may give you other medicines to help prevent it.

• if you need to have stem cells collected and you are being treated with Fludara (or have been).
• if you need a blood transfusion and you are being treated with Fludara (or have been).

In case you need a blood transfusion your doctor will ensure that you only receive blood that has been treated by irradiation. There have been severe complications and even death, from transfusions of non-irradiated blood.

• if you notice any changes to your skin either while you are receiving this medicine or after you have finished the therapy.
• if you have or have had skin cancer it may worsen or flare up again during Fludara therapy or afterwards. You may develop skin cancer during or after Fludara therapy.

• Fludara must not be administered if you are pregnant unless clearly indicated by your doctor
• Females: you must not become pregnant during treatment with Fludara and must use an effective method of contraception during and for 6 months after end of treatment, because Fludara may be harmful for the unborn baby. If pregnancy occurs during your treatment, you must immediately inform your doctor. Your doctor will decide with you whether you should carry on taking Fludara.
• Males: you are advised not to father a child and must use effective method of contraception during and at least for 3 months after end of treatment. You should advice on conservation of sperm prior to treatment because Fludara may alter male fertility.
• You must not breast-feed while you are treated with Fludara.
• - if you need a vaccination, check with your doctor, because live vaccinations should be avoided during and after treatment with Fludara.
• if you have kidney problems or if you are over 65, you will have regular blood and/or laboratory tests to check your kidney function. If your kidney problems are severe, you will not be given this medicine at all (see sections 2 and 3).

The safety and effectiveness of Fludara in children below the age of 18 years has not been established.

Therefore, Fludara is not recommended for use in children.

People over 65, will have regular tests for kidney function (see also section 3. How to use Fludara).

People over 75, will be monitored especially closely.

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

It is especially important to tell your doctor about:

• pentostatin(deoxycoformycin), also used to treat B-CLL. Taking these two drugs together can lead to severe lung problems.
• dipyridamole, used to prevent excessive blood clotting or other similar drugs. They may reduce the effectiveness of Fludara.
• cytarabine (Ara-C) used to treat chronic lymphatic leukaemia. If Fludara is combined with cytarabine, levels of the active form of Fludara in leukaemic cells may rise. However, the overall levels in the blood and its elimination from the blood were not shown to have changed.

Pregnancy

Females: you must not become pregnant during treatment with Fludara because animal studies and very limited experience in humans have shown a possible risk of abnormalities in the unborn baby as well as early pregnancy loss or premature delivery.. If pregnancy occurs during your treatment, you must immediately inform your doctor. Your doctor will decide with you whether you should carry on taking Fludara.

Breast-feeding:

You must not breast-feed while you are treated with Fludara.

Fertility in males and females

Females: you must use an effective method of contraception during and for 6 months after end of treatment, because Fludara may be harmful for the unborn baby.

Males: You are advised not to father a child and must use an effective method of contraception during and at least for 3 months after end of treatment. You should seek advice on conservation of sperm prior to treatment because Fludara may alter male fertility.

Both men and women who are planning to have a child after treatment are advised to talk to a doctor before start of Fludara treatment.

Some people get tired, feel weak, have disturbed vision, become confused, or agitated or have seizures while they are treated with Fludara. Do not try to drive or operate machines until you are sure that you are not affected.

This medicine contains less than 1mmol sodium per dose, i.e, essentially sodium free.

The dose you are given depends on your body surface area. This is measured in square metres (m²) and is worked out by the doctor from your height and weight.

The recommended dose is 25 mg fludarabine phosphate/m² body surface area.

Fludara is given in the form of a solution as an injection or mostly as an infusion.

An infusion means that the medicine is given directly into the blood stream by a drip through a vein.

One infusion takes approximately 30 minutes.

Your doctor will make sure that Fludara is not given beside the vein (paravenously). However, if this happens, no severe local adverse events have been reported.

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

This 5-day course of treatment will be repeated every 28 days until your doctor has decided that the best effect has been achieved (usually after 6 courses).

How long the treatment lasts depends on how successful your treatment is and how well you tolerate Fludara. The repeat course may be delayed if side 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 the therapy. The dosage may be decreased if side effects are a problem.

If you have kidney problems or if you are over the age of 65, you will have regular tests to check your kidney function. If your kidneys do not work 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 any of the Fludara solution comes into contact with your skin or the lining of your nose or mouth, wash the area thoroughly with soap and water. If the solution gets into your eyes, rinse them thoroughly with plenty of tap water. Avoid any exposure by inhalation.

If you may have received an overdose your doctor will stop the therapy and treat the symptoms. High doses can lead to a severely reduced number of blood cells.

For Fludara given intravenously it has been reported, that overdose can cause delayed blindness, coma and even death.

Your doctor will set the times at which you are to receive this medicine. Talk to your doctor as soon as possible, if you think you may have missed a dose.

You and your doctor may decide to stop your treatment with Fludara if the side effects are becoming too severe.

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

• infections (some serious)
• infections due to depressed immune system (opportunistic infections)
• infection of the lungs (pneumonia) with possible symptoms like breathing difficulties and / or cough with or without fever
• reduction in the number of blood platelets (thrombocytopenia) with the possibility of bruising and bleeding
• lowered white blood cell count (neutropenia)
• lowered red blood cell count (anaemia)
• cough
• vomiting, diarrhea, feeling sick (nausea)
• fever
• feeling tired (fatigue)
• weakness

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

• other blood related cancers (myelodysplastic syndrome, acute myeloid leukaemia). Most patients with these conditions were previously, or at the same time or later treated with other cancer drugs (alkylating agents, topoisomerase inhibitors) or radiation therapy.
• bone marrow depression (myelosuppression)
• severe loss of appetite leading to weight loss (anorexia)
• numbness or weakness in limbs (peripheral neuropathy)
• disturbed vision
• inflammation of the inside of the mouth (stomatitis)
• skin rash
• swelling due to excessive fluid retention (oedema)
• inflammation of the mucous coat of the digestive system from the mouth to the anus (mucositis)
• chills
• generally feeling unwell

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

• autoimmune disorder (see section 2)
• tumour lysis syndrome (see section 2)
• confusion
• lung toxicity, scarring throughout the lungs (pulmonary fibrosis), inflammation of the lungs (pneumonitis), shortness of breath (dyspnoea)
• bleeding in the stomach or intestines
• abnormal levels of the liver or pancreas enzymes

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

• disorders of the lymph system due to a viral infection (EBV-associated lymphoproliferative disorder)
• coma
• seizures
• agitation
• blindness
• inflammation or damage of the nerve of the eyes (optic neuritis; optic neuropathy)
• heart failure
• irregular heart beat (arrhythmia)
• skin cancer
• skin and/or mucous coat reaction with redness, inflammation, blistering and tissue break down (Lyell's syndrome, Stevens-Johnson syndrome)

Not known (frequency cannot be estimated from available data)

• bleeding in the brain
• neurological disorders manifested by headache, feeling sick (nausea) and vomiting, seizures, visual disturbances including vision loss, changes in mental status (thinking abnormal, confusion, altered consciousness), and occasionally neuromuscular disorders manifested by muscle weakness in your limbs (including irreversible partial or complete paralysis) (symptoms of leukoencephalopathy, acute toxic leukoencephalopathy or posterior reversible leukoencephalopathy syndrome (RPLS)).
• bleeding in the lungs
• inflammation of the bladder, which can cause pain when passing urine, and can lead to blood in the urine (haemorrhagic cystitis)

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

• The active substance is fludarabine phosphate. Each vial contains 50 mg fludarabine phosphate. 1 millilitre of reconstituted solution contains 25 mg fludarabine phosphate.
• The other ingredients are mannitol and sodium hydroxide.

Fludara is a sterile white powder for solution for injection or infusion provided in 10 ml glass vials.

The powder is reconstituted with water for injection and further diluted. The reconstituted solution is clear and colourless.

Fludara is available in packs containing 5 vials.

Marketing Authorisation Holder

Manufacturer