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Fludaravis 50mg Lyophilisate For Solution For Injection Or Infusion

Fludarabine phosphate

In this leaflet:

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

2.    Before you use Fludarabine Actavis

3.    How to    use Fludarabine    Actavis

4.    Possible side effects

5.    How to    store Fludarabine    Actavis

6.    Further    information

1. WHAT FLUDARABINE ACTAVIS IS AND WHAT IT IS USED FOR

Fludarabine Actavis is an anti-cancer drug.

Fludarabine Actavis is used to treat chronic B-cell lymphocytic leukaemia (B-CLL) in 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 Actavis should only be started in 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 cell’ genetic material (DNA) must be copied and reproduced. Fludarabine Actavis works by hindering the production of new DNA. Therefore, when Fludarabine Actavis 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. BEFORE YOU USE FLUDARABINE ACTAVIS Do not use Fludarabine Actavis

-    if you are allergic (hypersensitive) to fludarabine phosphate or any of the other ingredients of Fludarabine Actavis.

-    if you are breast feeding

-    if your kidney function is severely impaired

-    if you have a low number of red blood cells (haemolytic anaemia). Your doctor will have told you if you have this condition.

Take special care with Fludarabine Actavis

-    If you are not feeling very well you should tell your doctor, as your doctor may decide not to give you this medicine, or may give you this medicine with caution. This is very important if your bone marrow is not working properly or if you are susceptible to infections.

-    If you notice any unusual bruising, excessive bleeding after injury or if you seem to be catching a lot of infections, tell your doctor. The number of normal blood cells may be reduced and so you will have regular blood tests during treatment.

-    The disease itself and the therapy may cause a reduction of the number of blood cells and your immune system may attack different parts of your body (autoimmune disorder). It may also be directed against your red blood cells (called ‘autoimmune haemolysis’). This condition can be life threatening. If this condition occurs you may receive further medication such as transfusion of blood (irradiated, see below) and corticosteroides.

-    If you need a blood transfusion and you are being (or have been) treated with this medicine, you should mention this to the doctor. Your doctor will ensure that you receive blood only, which has gone through a special treatment (irradiation). There have been severe complications and even death reported when non-irradiated blood has been given.

-    If you need to have stem cells collected and you are being (or have been) treated with this medicine, you should mention this to the doctor.

-    If your liver does not work properly, your doctor may give you this medicine with caution.

-    If you have any form of kidney disease, your kidney function should be checked regularly. If it is found that your kidneys do not work properly you may be given this medicine at a reduced dose. If your kidneys work at only a very low level you will not be given this medicine at all. Patients aged 65 years or older should have their kidney function checked before start of treatment.

-    There is little information on the effects of Fludarabine Actavis in patients aged 75 years and older. Your doctor will use it with caution if you are in this age group.

-    If you have very severe chronic lymphocytic leukaemia, your body may not be able to get rid of all the waste products from the cells destroyed by Fludarabine Actavis. This is called tumour lysis syndrome and may cause dehydration, kidney failure and heart problems. Your doctor will be aware of this and may give you other medicines to stop this happening.

-    If you experience any unusual symptoms from the nervous system you should mention it to your doctor. This is because when used in patients at doses four times greater than the recommended dose, severe central nervous system (brain and spinal cord) effects including blindness, coma and death have been reported.

-    Tell your doctor if you notice any changes to your skin either while you are receiving this medicine or after you have finished the course of therapy. The doctor should check the seriousness of the skin changes. If you have skin cancer, the damaged areas of your skin may become worse when you use this medicine.

-    Men and women who may still be fertile, must use a reliable form of contraception during and for at least 6 months after stopping treatment.

-    Check with your doctor about any vaccinations you may need, because live vaccinations should be avoided during and after treatment with Fludarabine Actavis.

Using other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is especially important if you are taking a drug called pentostatin or deoxycoformycin (also used to treat chronic lymphocytic leukaemia) as a combination with Fludarabine Actavis is not recommended.. Some drugs, e.g. dipyridamole (used to prevent excessive blood clotting) may reduce the effectiveness of Fludarabine Actavis.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Fudarabine treatment has the potential to harm the unborn child. You should not be given Fludarabine Actavis if you are pregnant unless clearly necessary and when the potential benefits justify the potential risks to the unborn child. If you are a woman who may still be fertile, you must avoid becoming pregnant during treatment and for at least 6 months after stopping treatment. However, if you do become pregnant inform your doctor immediately.

Men who are treated with Fludarabine Actavis and can father a child must use a reliable form of contraception during, and for at least 6 months after stopping treatment.

It is not known if this medicine appears in the breast milk of women treated with Fludarabine Actavis. However, in animal studies the medicinal product was found in breast milk. Therefore you must not breast feed during your treatment with this medicine.

Driving and using machines

The effect of treatment with Fludarabine Actavis on the ability to drive or use machines has not been evaluated. Fludarabine Actavis may although influence the ability to drive and use machineries since side effects like tiredness, weakness, agitation, seizures and visual disturbances have been observed.

Importan information about some of the ingredients of Fludarabine Actavis

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

3. HOW TO USE FLUDARABINE ACTAVIS

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

The dose you are given depends on the size of your body. It varies with your body surface area. Technically this is measured in square metres (m²), but actually is worked out from your height and weight. The recommended dose is 25 mg/m² body surface. This will be given either as an injection or as an infusion (with a drip) into a vein once a day for 5 consecutive days every 28 days. This five day course of treatment will be repeated every 28 days until your doctor has decided that the best effect has been achieved.

The dosage may be decreased or the repeat course delayed if side effects are a problem. If you have kidney problems you will receive a reduced dose and you will have regular blood tests.

The safety of this drug in children and adolescents below age 18 has not been established and treatment is not recommended.

If any of the Fludarabine Actavis 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 lots of water. Try not to breathe in any fumes coming from the solution.

If you use more Fludarabine Actavis than you should

In the case of an overdose your doctor will stop the therapy and treat the symptoms.

Symptoms of an overdose can be blindness which may not appear until later, coma and death due to irreversible toxicity to the central nervous system. High doses can also lead to a severly reduced number of blood cells.

If you forget to use Fludarabine Actavis

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

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

4. POSSIBLE SIDE EFFECTS

Like all medicines, Fludarabine Actavis 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 2 ‘Take special care’).

-    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 means 1 or more in every 10 patients are likely to get these:

-    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 means between 1 and 10 in every 100 patients are likely to get these:

-    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 means between 1 and 10 in every 1,000 patients are likely to get these:

-    autoimmune disorder (see section 2, ‘Take special care’).

-    tumour lysis syndrome (see section 2, ‘Take special care’);

-    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 means less than 10 in every 10,000 patients are likely to get these:

-    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);

Frequency not know

-    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 side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

5. HOW TO STORE FLUDARABINE ACTAVIS

Keep out of the reach and sight of children.

Store below 25°C.

Do not use Fludarabine Actavis after the expiry date which is stated on the carton and vial after EXP.

6. FURTHER INFORMATION

What Fludarabine Actavis contains

-    The active substance is fludarabine phosphate

-    The other ingredients are mannitol and sodium hydroxide.

What Fludarabine Actavis looks like and contents of the pack

Each vial contains 50 mg 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 25 mg fludarabine phosphate.

Pack sizes

I    x 50 mg vial 5 x 50 mg vial

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Actavis Group PTC ehf Reykjavikurvegur 76-78 IS-220 Hafnarfjorbur Iceland

Manufacturer

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

II    Ion Michalache Blvd.

11171 Bucharest Romania

This leaflet was last revised in July 2012.

If you would like a leaflet with larger text, please contact 01271 311257.

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Actavis, Barnstaple, EX32 8NS, UK

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

Fludaravis 50mg Lyophilisate For Solution For Injection Or Infusion

Fludarabine phosphate

Instructions for use, handling and disposal

ANTINEOPLASTIC AGENT

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

Instructions for use

Reconstitution

Fludarabine Actavis should be prepared for parenteral use by aseptically adding sterile water for injection. When reconstituted with 2 ml of sterile water for injection, the powder should fully dissolve in 15 seconds or less. Each ml of the resulting solution will contain 25 mg of fludarabine phosphate, 25 mg 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 hours at 25°C ± 2°C/ 60% ± 5 %RH and for 7 days at 5°C ± 3°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 Actavis should not be used in case of a defective container.

Handling and disposal

Fludarabine Actavis 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 Actavis 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.

The 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.

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Actavis, Barnstaple, EX32 8NS, UK

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