Document: leaflet MAH GENERIC_PL 14510-0009 change

• leaflet MAH GENERIC_PL 14510-0009
• leaflet SANDOZ_PL 14510-0009

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Sandoz Limited (Ebewe)
Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

PACKAGE LEAFLET: INFORMATION FOR THE USER

Fludarabine 25 mg/ml Concentrate for Solution for Injection or Infusion

Fludarabine phosphate

Read all of this leaflet carefully before you start taking this medicine.

-    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. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

-    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.

In this leaflet:

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

2.    Before you are given Fludarabine.

3.    How you are given Fludarabine.

4.    Possible side effects.

5.    How to store Fludarabine.

6.    Further information

1. WHAT FLUDARABINE IS AND WHAT IT IS USED FOR

Fludarabine is a cytotoxic (anti-cancer medicine) medicine that inhibits the growth of cancer cells.

Fludarabine is used to treat chronic B-cell lymphocytic leukaemia (B-CLL), in patients with sufficient healthy blood cells 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.

CLL is a cancer of the lymphocytes (white blood cells).

If you are diagnosed with CLL, too many lymphocytes are produced. They either don't 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 cells they push aside (displace) healthy blood cells in the bone marrow (where most new blood cells are formed). They also displace the healthy blood cells in the blood and organs. Without enough healthy blood cells, infections, anaemia, bruising, excessive bleeding (haemorrhaging) or even organ failure can result.

2. BEFORE YOU ARE GIVEN FLUDARABINE

Do not take Fludarabine :

-    If you are allergic (hypersensitive) to fludarabine phosphate or to any of the other ingredients (these are listed at the end of the leaflet).

-    If you are breast-feeding.

-    If your kidney function is severely reduced. Your doctor will decide, based on your kidney function whether Fludarabine may or may not be used.

-    If you have a specific type of anaemia (decompensated haemolytic anaemia; this is a shortage of red blood cells). Your doctor will have told you if you have this condition.

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

Take special care with Fludarabine

-    because the active substance of Fludarabine phosphate 25 mg/ml, fludarabine phosphate, is a very strong active substance.

Therefore, the side effects can be very serious and toxic (poisonous).

For these reasons, your doctor will watch you closely if he/she prescribed you Fludarabine phosphate 25 mg/ml. Therefore, it is very important that you report to your doctor all side effects which occur during the use of Fludarabine phosphate 25 mg/ml.

This concerns mainly the following adverse events:

-    You are not feeling well. This is especially important to report if your bone marrow is not working properly, if your immune system is not working well or if you are susceptible to infections.

-    After injury you notice unusual bruising or excessive bleeding. This can point to a reduction in healthy blood cells.

-    Changes of your skin, such as rash or blisters. This is especially important if you have or have had skincancer.

Your doctor may decide not to give you Fludarabine phosphate 25 mg/ml, or to give you this medicine with special precautions, if you experience one of the above mentioned side effects.

You will have regular blood checks during treatment.

-    if you are catching a lot of infections (if you have a poorly functioning or depressed immune system or a history of serious infections).

Your immune system may attack different parts of your body (called ‘autoimmune phenomenon’), and this may also be directed against your red blood cells (called ‘autoimmune hemolysis’). This condition can be life threatening and even lead to death. If you experience this condition you may receive further medication such as transfusion of blood (irradiated, see below) and adrenocorticoids.

-    when you receive a high dose. When Fludarabine phosphate 25 mg/ml is used in patients with acute leukaemia at very high doses (up to four times greater than the recommended dose for CLL) a third of patients experienced severe central nervous system effects (including blindness, coma and death). Symptoms appeared from 21 to 60 days from last dose. In patients receiving the recommended dose for CLL, coma, seizures or agitation are rare events. Confusion occasionally occurs. You should mention to your doctor any unusual symptoms you experience.

-    when you use Fludarabine for a lengthy period. The effect of long-term use of Fludarabine phosphate 25 mg/ml on the central nervous system is unknown. However, some people have endured the recommended dose for up to 26 courses of therapy.

-    if you need a blood transfusion and you are being (or have been) treated with Fludarabine phosphate 25 mg/ml, you should mention this to your 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 Fludarabine phosphate 25 mg/ml, tell your doctor that you have received Fludarabine phosphate 25 mg/ml.

-    when you need a vaccination; consult your doctor, because live virus vaccines should be avoided during and after treatment with Fludarabine phosphate 25 mg/ml.

-    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 phosphate 25 mg/ml. This may cause dehydration, reduced kidney function and heart problems. Your doctor will be aware of this and may give you other drugs to deal with this problem.

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

- if you have skin cancer, the damaged areas of your skin may become worse when you use this medicine. Tell your doctor if you notice any changes to your skin either while you are receiving this medicine or even after you have finished taking this medicine.

-    with children and adolescents. No data are available concerning the use of Fludarabine phosphate 25 mg/ml in children and adolescents.

-    men and women who may still be fertile must use a reliable form of contraception during treatment and for at least 6 months after stopping treatment. See also “Pregnancy and breast-feeding”.

- if you have any form of kidney disease or if you are over 65years old, your kidney function should be checked regularly. If your kidneys are found not to work properly you may be given Fludarabine phosphate 25 mg/ml at a reduced dose. If your kidneys work at only a very low level you will not be given this medicine at all.

- if you are over 75 years old, Fludarabine phosphate 25 mg/ml will be given with caution.

Consult your doctor if one of the above mentioned warnings is applicable to you, or has been in the past. Taking other medicines

Please tell your doctor if you are taking, or have recently taken any other medicines, including medicines obtained without prescription.

You should tell your doctor if you are taking or have taken any of the following medicines as they may interact with your Fludarabine:

-    If you are already taking a drug called pentostatin (= deoxycoformycin) (pentostatin is a chemotherapy drug that is given as a treatment for a special type of leukaemia [i.e. hairy cell leukaemia]) you must not use Fludarabine.

-    Some blood thinning medicines, such as dipyridamole (dipyridamole belongs to a group of medicines called anti-platelet agents that can help to prevent blood clotsforming) may reduce the effectiveness of Fludarabine.

-    An interaction can occur with this medicine when used together with cytarabine (Ara-C) which is used to treat chronic lymphatic leukaemia. If fludarabine phosphate is combined with cytarabine, levels of the active form of fludarabine phosphate in the cell may rise. However, the overall levels in the blood and its elimination from the blood were not shown to have changed.

Pregnancy and breast-feeding

You must not be given Fludarabine if you are pregnant unless your doctor tells you to. This is because animal studies and limited experience in humans have shown a possible risk of abnormalities in the developing foetus. If you are a woman of child-bearing potential, 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 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. However, in animal studies the medicinal product was found in breast milk. Therefore, you must not breast-feed during your treatment with this medicine.

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

Driving and using machines

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

If you feel Fludarabine affects your ability to drive or use machines, tell your doctor immediately. However, fludarabine phosphate may reduce the ability to drive and use machines, since e.g. fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.”

3. HOW YOU ARE GIVEN FLUDARABINE Children and adolescents

Fludarabine is not recommended for children and adolescents.

Dosage

The recommended dose is 25 mg/m² body surface.

The dose you are given depends on how big you are. It varies with your body surface area. This is measured in square metres (m²) and is worked out from your height and weight.

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

Methods and routes of administration

Fludarabine should be given by a doctor who has experience in the use of chemotherapy.

This will be given either as an injection (into a vein) or as an infusion (with a drip) once a day for 5 days.

Duration of treatment

This five-day course of treatment will be repeated every 28 days until your doctor has decided that the best effect has been achieved. In general this is after 6 cycles, in other words after approximately 6 months.

If you received too much Fludarabine:

There is no specific antidote for Fludarabine overdosage. If you received too much Fludarabine, the doctor will stop the therapy and treat the symptoms.

High doses of Fludarabine have been associated with irreversible central nervous system side effects characterised by delayed blindness, coma, and death.

High doses are also associated with severe reduction in the number of certain types of blood cells (severe thrombocytopenia (decreased number of platelets attended with bruises and bleeding) and neutropenia (decreased number of white blood cells attended with increased infection risk) due to decreased activity of the bone marrow (bone marrow suppression).

If administration of Fludarabine is forgotten:

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.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Fludarabine can cause side effects, although not everybody gets them.

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.

Tell your doctor immediately:

•    If you have difficulty breathing, have a cough, or have chest pain with or without fever

•    If you notice any unusual bruising, more bleeding than usual after injury or if you seem to be catching a lot of infections

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

•    If you notice any skin and / or mucous coat reaction with redness, inflammation blistering and tissue break down

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

• If you have palpitations (if you suddenly become aware of your heart beat) or chest pain

Below we list possible side effects by how common they are.

Very common side effects: occurs in more than 1 out of 10 patients

Common side effects: occurs in more than 1 out of 100 patients, but in less than 1 out of 10 patients

Uncommon side effects: occurs in more than 1 out of 1,000 patients, but less than 1 out of 100 patients

Rare side effects: occurs in more than 1 out of 10,000 patients, but less than 1 out of 1,000 patients

Very rare side effects: occurs in less than 1 out of 10,000 patients

The following side effects have been reported:

Very common side effects

•    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

•    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

•    autoimmune disorder (including a condition in which the immune system attacks the red blood cells [autoimmune hemolytic anemia], immune-mediated hemolytic anemia concurrent with immune-mediated thrombocytopenia [Evans syndrome], haemorrhages in the skin, mucous membranes, and elsewhere associated with a marked reduction in the numbers of blood platelets [thrombocytopenic purpura], a bleeding disorder characterized by autoantibodies directed against a coagulation factor [acquired haemophilia], and immune-mediated skin diseases characterized by groups of itching blisters [pemphigus]);

• tumour lysis syndrome (a group of complications caused by the break-down products of dying cancer cells and include high levels of potassium, phosphate and uric acid as well as low levels of calcium in the blood, and the presence of excessive amounts of uric acid in the urine. It may possibly lead to acute uric

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

acid nephropathy and kidney failure). If you notice any pain in your side, decreased urination or blood in your urine, tell your doctor immediately;

•    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 side effects:

•    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)

Side effects with 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.

All medicines can cause allergic reactions although serious allergic reactions are very rare. Any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body) should be reported to a doctor immediately.

If you suffer from any of these side effects or others not mentioned in this information leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE FLUDARABINE

Keep out of the reach and sight of children.

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

Storage of Fludarabine as packed for sale in a refrigerator (2°C - 8°C).

Storage of Fludarabine after dilution - see section 6. Further information; information for medical and healthcare professionals.

6. FURTHER INFORMATION What Fludarabine contains

- The active substance is fludarabine phosphate 25 mg/ml. One ml contains 25 mg fludarabine phosphate.

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

- The other ingredients are disodium phosphate.dihydrate, sodium hydroxide, and water for injection. What Fludarabine looks like and contents of the pack

Fludarabine concentrate for solution for injection or infusion is a clear, colourless or almost colourless solution.

This medicine is presented in glass containers called vials.

Each 2ml vial contains 50 mg fludarabine phosphate.

It is available in packs containing 1 vial, 5 vials and 10 vials with or without a protective plastic overwrap (ONCO-SAFE).

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

This leaflet was last revised in 04/2014

The following information is intended for medical or healthcare professionals only: Fludarabine 25 mg/ml - concentrate for solution for injection or infusion Instructions for use and handling and disposal

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 sodium chloride 9 mg/ml (0.9%) solution for injection. Alternatively, for infusion, the required dose may be diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solution for injection-and infused over approximately 30 minutes.

Inspection prior to use

Only clear and colourless solutions without particles should be used. The product should not be used in case of a defective container.

Handling and disposal

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Fludarabine 25 mg/ml concentrate for solution for injection or infusion	PL 14510/0009

Pregnant women should be excluded from handling fludarabine phosphate. The Regulations concerning proper handling and disposal must be followed considering guidelines for proper handling and disposal of cytotoxic medicinal products. Any spilled or unused material may be eliminated by incineration.

Caution should be exercised during handling and preparation of fludarabine phosphate solution. The use of protective gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If the solution comes in contact with skin or mucous membranes, the affected area should be cleaned thoroughly with soap and water.

The medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

Incompatibilities:

It is not recommended to mix up fludarabine solutions with other drugs or other solutions except physiological saline under aseptic conditions.

Any unused product or waste material should be disposed of in accordance with local requirements. Administration:

It is strongly recommended that Fludarabine should be only administered intravenously. No cases have been reported in which relevant local irritation was observed after paravenous administration. However, pareavenous administration should be avoided.

Storage and shelf life:

As packaged for sale:

Store in a refrigerator (2°C - 8°C).

Shelf life after dilution:

Infusion solutions cited above are physically and chemically refrigerator (2-8°C) with protection from light and at room protection from light.

From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.