Patient leaflet - Fludarabine 50 mg powder for solution for injection or infusion

1 What Fludarabine is and what it is used for

Fludarabine is an anti-cancer drug.

Fludarabine is used to treat chronic B-cell lymphocytic leukaemia (B-CLL) in adult patients with sufficient healthy blood cell production. This is a type of cancer of white blood cells (the cells are called lymphocytes).

First treatment for chronic lymphocytic leukaemia with Fludarabine should only be started in adult patients with advanced disease, having disease related symptoms or evidence of disease progression.

All cells of the body produce new cells like themselves by dividing. For this purpose, the cells’ genetic material (DNA) must be copied and reproduced. Fludarabine works by hindering the production of new DNA. Therefore, when Fludarabine is taken up by the cancer cells, it stops the growth of new cancer cells.

In cancers of the white blood cells (as chronic lymphocytic leukaemia) many abnormal lymphocytes are produced. The abnormal lymphocytes either do not work properly or are too young (immature) to carry out the normal disease fighting functions of white blood cells. If there are too many of these abnormal lymphocytes, they push aside healthy blood cells in the bone marrow where most of the new blood cells are formed. Without enough healthy blood cells, infections, anaemia, bruising, excessive bleeding or even organ failure can result.

2 What you need to know before you use Fludarabine

Do not use Fludarabine

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.

Warnings and precautions

Talk to your doctor before using Fludarabine. Take special care with Fludarabine:

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, tell your doctor immediately.
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 Fludarabine before. During treatment with Fludarabine, 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 Fludarabine.

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

If Fludarabine 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 Fludarabine 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 (abnormal thinking, 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 reversible posterior 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 Fludarabine doses higher than the recommended dose, leukoencephalopathy (LE), acute toxic leukoencephalopathy (ATL) or reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported. Symptoms of LE, ATL or RPLS as described above could occur.

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

Whenever LE, ATL or RPLS is suspected, your treatment with Fludarabine will be stopped for further investigations.

If the diagnosis of LE, ATL, or RPLS is confirmed, you doctor will permanently discontinue your treatment with Fludarabine.

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 Fludarabine. 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 Fludarabine (or have been).
if you need a blood transfusion and you are being treated with Fludarabine (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, including 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 Fludarabine therapy or afterwards. You may develop skin cancer during or after Fludarabine therapy.

Other things to consider while you are treated with Fludarabine:

Women of childbearing potential must use effective contraception during treatment and for at least 6 months afterwards. Men who are fertile must use effective contraception during treatment and for at least 3 months afterwards. It cannot be ruled out that Fludarabine may harm an unborn baby. Your doctor will carefully weigh the benefit of your treatment against a possible risk for an unborn child and, if you are pregnant, will only treat you with Fludarabine if clearly necessary.
if you consider or are breastfeeding you should not start it or continue while on treatment with Fludarabine.
if you need a vaccination, check with your doctor, because live vaccinations should be avoided during and after treatment with Fludarabine.
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).

Children and adolescents

The safety and effectiveness of Fludarabine in children below the age of 18 years has not been established. Therefore, Fludarabine is not recommended for use in children.

Older patients and Fludarabine: People over 65 will have regular tests for kidney function (see section 3 “How to use Fludarabine”).

People over 75 will be monitored especially closely.

Other medicines and Fludarabine

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 Fludarabine.
cytarabine (Ara-C) used to treat chronic lymphocytic leukaemia. If Fludarabine is combined with cytarabine, levels of the active form of Fludarabine 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, breast-feeding and fertility

Pregnancy

Fludarabine should not be given to women who are pregnant 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 you are pregnant or you think you may be pregnant, tell your doctor immediately. Your doctor will carefully weigh the benefit of your treatment against a possible risk for an unborn child and, if you are pregnant, will only prescribe Fludarabine if clearly necessary.

Breast-feeding

You must not start or continue breast-feeding during your treatment with Fludarabine, as this medicine may interfere with the growth and development of your baby.

Fludarabine 50mg Powder For Solution for

Injection or Infusion

Fludarabine phosphate

Instructions for use, handling and disposal

ANTINEOPLASTIC AGENT

A crossover from initial treatment with fludarabine phosphate to chlorambucil for non-responders to fludarabine phosphate should be avoided because most patients who have been resistant to fludarabine phosphate have shown resistance to chlorambucil.

Instructions for use

Reconstitution

Fludarabine should be prepared for parenteral use by aseptically adding sterile water for injection. When reconstituted with 2ml of sterile water for injection, the powder should fully dissolve in 15 seconds or less. Each ml

of the resulting solution will contain 25mg of fludarabine phosphate, 25mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. The pH range for the final product is 7.2 - 8.2.

Dilution

The required dose (calculated on the basis of the patient’s body surface) is drawn up into a syringe.

For intravenous bolus injection this dose is further diluted in 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 infused over approximately 30 minutes.

Fludarabine phosphate must not be mixed with other drugs.

Storage after reconstitution:

The physicochemical stability of the drug product after reconstitution in water for injections has been demonstrated for 8 The following information is intended for medical or healthcare professionals only:

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Fertility

Before treatment, patients planning pregnancy should seek genetic counselling. Women of childbearing potential must use effective contraception during treatment and for at least 6 months afterwards. Men, who are fertile, must use effective contraception during treatment and for at least 3 months afterwards.

Driving and using machines

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

Information on sodium content

This medicine contains less than 1 mmol sodium (23mg), i.e. essentially ‘sodium-free’.

3 How to use Fludarabine

Fludarabine should be administered under the supervision of a qualified doctor experienced in the use of anti-cancer therapy.

How much Fludarabine is given

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/m²body surface area.

How Fludarabine is given

Fludarabine 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 Fludarabine is not given beside the vein (paravenously). However, if this happens, no severe local adverse events have been reported.

How long Fludarabine is given for

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 Fludarabine. 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 Fludarabine solution is accidentally spilt

If any of the Fludarabine 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 too much Fludarabine is given

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

If a dose of Fludarabine is forgotten

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.

If you stop using Fludarabine

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

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

4 Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you are not sure what the side effects below are, ask your doctor to explain them to you.

Some side effects can be life-threatening.

Tell your doctor immediately if you:

have difficulty breathing, have a cough, or have chest pain with or without fever. These may be signs of an infection of the lungs.
notice any unusual bruising, more bleeding than usual after injury or if you seem to be catching a lot of 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 usually do not cause disease in healthy people (opportunistic infections) including a late reactivation of viruses, for example herpes zoster.
notice any pain in your side, blood in your urine, or reduced amount of urine. These may be signs of tumour lysis syndrome (see section 2).
notice any skin and/or mucous coat reaction with redness, inflammation, blistering and tissue break down. These may be signs of a severe allergic reaction (Lyell’s syndrome, Stevens-Johnson syndrome).
have palpitations (if you suddenly become aware of your heartbeat) or chest pain. These may be signs of heart problems.

Other possible side effects:

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, diarrhoea, 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 Iymphoproliferative disorder)
coma
seizures
agitation
blindness
inflammation or damage of the nerve of the eyes (optic neuritis; optic neuropathy)
heart failure
irregular heartbeat (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 (abnormal thinking, 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 reversible posterior 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).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: 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.

5 How to store Fludarabine

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

Store below 25°C.

Do not use this medicine after the expiry date which is stated on the carton and vial after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6 Contents of the pack and other information

What Fludarabine contains

The active substance is fludarabine phosphate
The other ingredients are mannitol and sodium hydroxide.

What Fludarabine looks like and contents of the pack

Each vial contains 50mg fludarabine phosphate as a powder for injection or infusion. The powder will be made up into a solution before it is given to you. 1 ml of reconstituted solution contains 25mg fludarabine phosphate.

Pack sizes

1 x 50mg vial

5 x 50mg vial

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord, Barnstaple, EX32 8NS, UK

Manufacturer

S. C. Sindan Pharma S.R.L.

11 Ion Michalache Blvd.

11171 Bucharest

Romania

This leaflet was last revised in April 2024

If you would like a leaflet with larger text, please contact 01271 385257.

hours at 25°C and for 7 days at 2-8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Inspection prior to use

The reconstituted solution is clear and colourless. It should be visually inspected before use. Only clear and colourless solutions without particles should be used. Fludarabine should not be used in the case of a defective container.

Handling and disposal

Fludarabine should not be handled by pregnant staff.

Procedures for proper handling should be followed according to local requirements for cytotoxic drugs. Caution should be exercised in the handling and preparation of the Fludarabine solution. The use of latex gloves and safety

glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.

If the solution comes into contact with the skin or mucous membranes, the area should be washed thoroughly with soap and water. In the event of contact with the eyes, rinse them thoroughly with copious amounts of water. Exposure by inhalation should be avoided.

This medicinal product is for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.