Document: leaflet MAH GENERIC_PL 04569-1533 change

• leaflet MAH GENERIC_PL 04569-1533
• leaflet MAH GENERIC_PL 18727-0022

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Fludarabine Phosphate 50 mg powder for solution for injection or infusion

fludarabine phosphate

What is in this leaflet:

1.    What Fludarabine Phosphate is and what it is used for

2.    What you need to know before you use Fludarabine Phosphate

3.    How to use Fludarabine Phosphate

4.    Possible side effects

5.    How to store Fludarabine Phosphate

6.    Contents of the pack and other information

1. What Fludarabine Phosphate is and what it is used for What Fludarabine Phosphate is and how it works:

Fludarabine Phosphate is an anti-cancer medicine.

Fludarabine Phosphate is an intravenous injection or infusion that stops the growth of new cancer cells. All cells of the body produce new cells like themselves by dividing. Fludarabine Phosphate is taken up by the cancer cells and stops them dividing.

In cancers of the white blood cells (as chronic lymphocytic leukaemia), the body produces many abnormal white blood cells (lymphocytes) and lymph nodes start to grow in various parts of the body. The abnormal white blood cells cannot carry out the normal disease fighting functions and may push aside healthy blood cells. This can result in infections, a decrease in number of red blood cells (anaemia), bruising, severe bleeding or even organ failure.

What Fludarabine Phosphate is used for:

Fludarabine Phosphate is used in the treatment of B-cell chronic lymphocytic leukaemia (B-CLL) in patients with sufficient healthy blood cell production.

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

2. What you need to know before you use Fludarabine Phosphate Do not use Fludarabine Phosphate:

-    if you are allergic (hypersensitive) to fludarabine phosphate or any of the other ingredients of Fludarabine Phosphate (see section 6 Contents of the pack and other information)

-    if you have severe kidney problems

-    if you are breast-feeding

-    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:

-    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 if any of these apply before your treatment.

-    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 Phosphate before. During treatment with Fludarabine Phosphate 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 Fludarabine Phosphate.

-    If you notice any unusual symptoms of your nervous system such as disturbed vision,

► Tell your doctor.

If Fludarabine Phosphate 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. 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 has been stopped.

-    If you notice any pain in your side, blood in your urine or reduced amount of urine,

►    Tell your doctor immediately.

When your disease is very severe, your body may not be able to clear all the waste products from the cells destroyed by Fludarabine Phosphate. 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 Phosphate (or have been),

►    Tell your doctor.

-    If you need a blood transfusion and you are being treated with Fludarabine Phosphate (or have been),

►    Tell your doctor.

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,

►    Tell your doctor.

-    If you have or have had skin cancer it may worsen or flare up again with Fludarabine Phosphate therapy or afterwards. You may develop skin cancer during or after Fludarabine Phosphate therapy.

Other things to consider, while you are treated with Fludarabine Phosphate:

-    Men and women, who are fertile must use effective contraception during treatment and for at least 6 months afterwards. It cannot be ruled out that Fludarabine Phosphate 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 Phosphate if clearly necessary.

-    If you consider or are breast-feeding you should not start it or continue while on treatment with Fludarabine Phosphate.

-    If you need a vaccination, check with your doctor, because live vaccinations should be avoided during and after treatment with Fludarabine Phosphate.

-    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 also section 2, ‘Do not use Fludarabine Phosphate ’ and section 3 How to use Fludarabine Phosphate).

Other medicines and Fludarabine Phosphate:

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Ask your doctor or pharmacist for advice before taking any medicine.

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 substances.

They may reduce the effectiveness of Fludarabine Phosphate

•    cytarabine (Ara-C) used to treat chronic lymphatic leukaemia. If Fludarabine Phosphate is combined with cytarabine, levels of the active form of Fludarabine Phosphate in leukaemic cells may rise. However, the overall levels in the blood and its elimination from the blood were not shown to have changed.

Older patients and Fludarabine Phosphate:

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

People over 75, will be monitored especially closely.

Children:

The safety and effectiveness of Fludarabine Phosphate in children has not been established. Therefore, Fludarabine Phosphate is not recommended for use in children.

Pregnancy and breast-feeding:

Fludarabine Phosphate 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.

•    If you are a woman who could become pregnant, you must use effective contraceptive methods during treatment and for at least 6 months after treatment (see section 2 ‘What you need to know before you use Fludarabine Phosphate ’).

• Men who have been given Fludarabine Phosphate and who could become fathers must use reliable contraception during treatment and for at least 6 months afterwards.

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 Phosphate if clearly necessary.

Breast-feeding:

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

Ask your doctor for advice before taking any medicine.

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 Phosphate. Do not try to drive or operate machines until you are sure that you are not affected.

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

3. How to use Fludarabine Phosphate

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

• For information for preparation of the reconstituted or diluted solution, see section 6 Contents of the pack and other information / information for medical or healthcare professionals.

How Fludarabine Phosphate is given:

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

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

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

For how long Fludarabine Phosphate is given:

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 Phosphate. 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.

Fludarabine Phosphate is not recommended for use in children.

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 also section 2, ‘Do not use Fludarabine Phosphate ’).

If any Fludarabine Phosphate solution is accidentally spilt:

If any of the Fludarabine Phosphate 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 more Fludarabine Phosphate is given than it should:

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

If a dose of Fludarabine Phosphate 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.

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

If you have any further questions on the use of this product, 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 adverse reactions below are, ask your doctor to explain them to you.

Some side effects can be life-threatening.

-    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.

-    If you 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 persons (opportunistic infections) including a late reactivation of viruses, for example herpes zoster.

-    If you 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 ‘Warnings and precautions’).

-    If you 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).

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

► Tell your doctor immediately, if you notice any of these effects.

Below we list possible side effects by how common they are. The rare side effects (less than

1 in every 1000 patients) were mainly identified from post-marketing experience.

Very common

-    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

-    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

-    autoimmune disorder (see section 2, ‘Warnings and precautions’).

-    tumour lysis syndrome (see section 2, ‘Warnings and precautions’);

-    confusion;

-    lung toxicity; scaring 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

-    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);

•    Frequencies not known

-    inflammation of the bladder, which can cause pain when passing urine, and can lead to blood in the urine (haemorrhagic cystitis).

-    bleeding in the brain.

-    bleeding in the lungs.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. How to store Fludarabine Phosphate

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

Do not use Fludarabine Phosphate 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.

The reconstituted solution is clean and colourless.

Only clear, colourless and particle free solutions should be used.

•    Storage of Fludarabine Phosphate as packed for sale Store in a refrigerator (2°C to 8°C). Do not freeze.

•    Storage of Fludarabine Phosphate after reconstitution

Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours at 25°C.

•    Storage of Fludarabine Phosphate after dilution

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 and would normally not be longer than 8 hours at 2 to 8°C and at 25°C.

For information for medical and healthcare professionals, see section 6 Contents of the pack and other information, information for medicinal and healthcare professionals.

6. Contents of the pack and other information

What Fludarabine Phosphate contains:

-    The active substance is fludarabine phosphate.

Each vial contains 50 mg fludarabine phosphate.

1 ml of reconstituted solution contains 25 mg fludarabine phosphate.

-    The other ingredients are mannitol and sodium hydroxide (for pH adjustment).

What Fludarabine Phosphate looks like and contents of the pack:

Fludarabine Phosphate 50 mg powder for solution for injection or infusion is a white lyophilized powder or plug for reconstitution.

The reconstituted solution is clear and colourless.

Fludarabine Phosphate is available in packs containing 1 or 5 10 ml vials.

Marketing Authorisation Holder:

Mylan

Potters Bar, Hertfordshire, EN6 1TL, United Kingdom Manufacturer:

Agila Specialties Polska Sp. z o.o.

10, Daniszewska Str 03-230 Warsaw Poland

This leaflet was last revised in 02/2015

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The following information is intended for medical or healthcare professionals only:

Fludarabine Phosphate 50 mg powder for solution for injection/infusion as other potential cytotoxic medicines should be prepared by qualified personnel in a designated area. Consideration should be given to handling and disposal according to guidelines used for cytotoxic drugs.

Incompatibilities

Must not be mixed with other drugs.

Instructions for use and handling Reconstitution

Fludarabine Phosphate should be prepared for use by aseptically adding sterile Water for Injections.

When reconstituted with 2 ml of sterile Water for Injections, the powder should fully dissolve in 60 seconds or less. Each ml of the resulting solution will contain 25 mg of fludarabine phosphate. The solution should be inspected visually. The reconstituted solution should be clear, colorless and without particles.

Dilution

The reconstituted solution draws up into a syringe. For intravenous bolus injection this dose is further diluted into 10 ml 0.9 % sodium chloride. For intravenous infusion the solution is diluted into 100 ml 0.9 % sodium chloride and infused over 30 minutes. In clinical studies, the product has been diluted in 100 ml or 125 ml of 5 % dextrose (for injection) or 0.9 % sodium chloride solution.

Storage

Unopened product

Store in a refrigerator (2°C to 8°C). Do not freeze.

After reconstitution

Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours at 25°C.

After dilution

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 and would normally not be longer than 8 hours at 2-8°C and at 25°C.

If any fludarabine phosphate solution is accidentally spilt:

If any of the fludarabine phosphate 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.