Fludarabine Phosphate
Fludarabine Phosphate 50 mg Powder for Solution for Injection or Infusion
Fludarabine phosphate
1. WHAT FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECCTION OR INFUSION IS AND WHAT IT IS USED FOR
Fludarabine phosphate is an anti-cancer medicine. Fludarabine phosphate is used in the treatment of B-cell chronic lymphocytic leukaemia (B-CLL) in patients who have a sufficient amount of healthy blood cells in their bone marrow.
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.
Fludarabine phosphate works by stopping the growth of new cancer cells. 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 phosphate is taken up by the cancer cells and works by hindering the production of new DNA.
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. If there are too many abnormal white blood cells, they push aside healthy blood cells – which can result in infections, decrease in number of red blood cells (anaemia), bruising, unusually severe bleeding or even organ failure.
2. BEFORE YOU USE FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECTION OR INFUSION
Do not use Fludarabine Phosphate Powder for Solution for Injection or Infusion if you are allergic (hypersensitive) to fludarabine phosphate or any of the other ingredients of Fludarabine Phosphate Powder for Solution for Injection or Infusion
- if your kidney function is severely reduced
- if you have a low number of red blood cells because of a cetain type of anaemia (decompensated haemolytic anaemia)
Your doctor will have told you if you have this condition.
if you are pregnant or breast-feeding (see section Pregnancy and Breast-feeding)
It is important that you tell your doctor if you have problems even if those are on the above list or not.
Take special care with Fludarabine Phosphate Powder for Solution for Injection or Infusion
- because the active substance of Fludarabine Phosphate Powder for Solution for Injection or Infusion, 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. Therefore, it is very important that you report to your doctor all side effects which occur during the use of fludarabine phosphate. 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 skin cancer. Your doctor may decide not to give you fludarabine phosphate, 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 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). 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 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, 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, tell your doctor that you have received fludarabine phosphate.
- when you need a vaccination, consult your doctor, because live virus vaccines should be avoided during and after treatment with fludarabine phosphate.
- 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. 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.
- 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. No data are available concerning the use of fludarabine phosphate in children.
- with men and women who may still be fertile, see Section “Pregnancy and breast-feeding”.
- if your liver does not work properly; your doctor may decide not to give you this medicine, or may give you this medicine with caution.
- if you have any form of kidney disease or if you are over 70 years old, your kidney function should be checked regularly. If your kidneys are found not to work properly you may be given fludarabine phosphate 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 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 or Using other medicines
Attention: the following remarks can also apply to the use of medicines in the past or in the near future.
The medicines mentioned in this section may be known to you under a different name, often the brand name. In this section only the name of the active ingredient or group of active ingredients of the medicine is mentioned and not the brand name! Therefore, check on the package or insert what the active ingredient is of the medicine you are using.
An interaction means that medicines, when used at the same time, can influence each other’s action and/or side effects. An interaction can occur with this medicine when used together with:
pentostatin (=deoxycoformycin) (another medicine that inhibits the growth of cancer); you may not be treated with fludarabine phosphate some blood thinning medicines, such as dipyridamole; they reduce the effectiveness of fludarabine phosphate
Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
- Pregnancy and Breast-feeding
You should not be given fludarabine phosphate if you are pregnant, because animal studies and limited experience in humans have shown a possible risk of abnormalities in the developing foetus. If you are a woman who may still be fertile, you must avoid becoming pregnant. However, if you do become pregnant inform your doctor immediately, (see also Section “Do not use Fludarabine Phosphate Powder for Solution for Injection or Infusion”).
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.
It is not known if fludarabine appears in the breast milk of women treated with this medicine. However, in animal studies fludarabine has been found in breast milk. Therefore you should not breast feed during your treatment with this medicine. Ask your doctor for advice before taking any medicine.
- Driving and using machines
The effects of treatment with this medicine on the patient’s ability to drive or to operate machinery has not been evaluated. Consult your doctor if you doubt whether fludarabine phosphate negatively effects your ability to drive or react.
3. HOW TO USE FLUDARABINE PHOSPHATE POWDER FOR SOLUTION FOR INJECTION OR INFUSION
Carefully follow the advice of your doctor when using fludarabine phosphate. Your doctor will decide when and how long fludarabine phosphate will be given to you. Consult your doctor if you have the feeling that fludarabine phosphate is acting too strongly or not strongly enough.
The administered amount of fludarabine phosphate (the dose) depends on the size of your body. Technically this is measured in square metres (m2), but actually is calculated from your height and weight.
Fludarabine phosphate should be used under the supervision of a qualified doctor experienced in the use of anticancer therapy.
General guidance
The usual dose is 25 mg/m2 body surface per day. This will be given either as an injection or as an infusion for 5 consecutive days. This five day course of treatment will be repeated every 28 days until your doctor has decided that the best possible effect has been achieved. In general this is after 6 cycles, in other words after approximately 6 months. 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.
If you take more Fludarabine Phosphate Powder for Solution for Injection or Infusion than you should
As this medicine is given in a hospital, it is unlikely that you will be given too little or too much, however tell your doctor if you have any concerns.
There is no specific antidote for fludarabine phosphate overdosage. If you received too much fludarabine phosphate the doctor will stop the therapy and treat the symptoms.
High doses of fludarabine phosphate 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 Phosphate Powder for Solution for Injection or Infusion 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 phosphate can cause side effects, although not everybody gets them.
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
One or more of the following side effects can occur:
Immune system
Serious infections have occurred in patients treated with fludarabine phosphate. In some cases this has resulted in death.
Blood
A common side effect is the reduced production of blood cells by the bone marrow, which can lead to anaemia, abnormal bleeding or bruising.
A reduction in the number of blood cells has been reported in most patients treated with fludarabine phosphate. In rare cases, the production of blood cells was severely reduced (myelodysplastic syndrome), but most of these patients received other cancer treatments during or prior to treatment with fludarabine phosphate. Because of the way in which this medicine works, you are more susceptible to infections. Sometimes, during or after use of fludarabine phosphate, your body’s own immune system might attack different parts of your body. This can cause a number of conditions all related to the function or production of red blood cells. These are:
- anaemia as a consequence of a severe breakdown of the blood (autoimmune haemolytic anaemia)
- blood disorders (low platelet count) accompanied with easy bruising and bleeding(autoimmune thrombocytopenia)
- bruising, nosebleeds and bleeding gums caused by blood disorders (thrombocytopenic purpura)
- skin disease characterised by blistering, affecting the entire body (pemphigus)
- “Evan’s syndrome”, a disease characterised by fatigue, pale skin, shortness of breath, anaemia, bleeding tendencies and bruising.
Although these conditions are rare, they can sometimes be fatal.
Tell your doctor immediately:
- if you feel unusually tired or breathless
- if you notice any unusual bruising or excessive bleeding after injury
- if you seem to be catching a lot of infections
- if you have a rash or any blisters on your skin. (See section ‘Take special care with Fludarabine Phosphate Powder for Solution for Injection or Infusion’).
Nervous system
Numb or weak limbs (peripheral neuropathy) are commonly observed. Confusion occasionally occurs. Coma, excitement and restlessness (agitation) and seizures (fits, epileptic attacks) are rarely observed.
Eyes
Problems with sight are commonly reported. In rare cases, inflammation of the optic nerve, damage of the optic nerve and blindness have occurred.
Heart
In rare cases, heart failure and an abnormal heart rate have been reported. If you experience any difficulty in breathing, have chest pains or suddenly become aware of your heart beat (palpitations), tell your doctor immediately.
Respiratory system
Infection of the lung (pneumonia) commonly occurs in association with fludarabine phosphate treatment. Other allergic type reactions (pulmonary hypersensitivity) have been uncommonly observed. If you experience any difficulty in breathing, have a cough or have chest pains tell your doctor immediately.
Gastrointestinal tract
Gastrointestinal side effects such as nausea (feeling sick), vomiting (being sick), diarrhoea, inflammation of the lining of the mouth (stomatitis) and loss of appetite are common. Gastrointestinal bleeding occurs occasionally. There may also be changes in the proteins (enzymes) found in the pancreas.
Liver or bile
Changes in the proteins (enzymes) found in the liver are uncommon.
Skin
Skin rash has been commonly reported. In rare cases the skin may redden, peel (blister forming) or get inflamed (Stevens-Johnson syndrome or toxic epidermal necrolysis).
Kidneys and urinary tract
In rare cases inflammation of the bladder with blood in the urine (haemorrhagic cystitis) has been reported.
Other
A condition called tumour lysis syndrome may occur where the body is unable to cope with all the waste products of the cells killed by fludarabine phosphate. Although uncommon, it may lead to abnormal levels of waste products in your blood and possibly to kidney failure. If you notice a pain in your side or blood in your urine, tell your doctor immediately.
Inflammations (infections), fever, feeling of tiredness, weakness, general feeling of illness, oedema and chills have been commonly reported.
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 POWDER FOR SOLUTION FOR INJECTION OR INFUSION
Keep out of the reach and sight of children. As packaged for sale: Store below 25°C.
For storage conditions after reconstitution and dilution: please refer to section ‘Information for medical and healthcare professionals’
Do not use Fludarabine Phosphate Powder for Solution for Injection or Infusion 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.
Any vials which are damaged in anyway should be discarded.
The reconstituted solution is clear and colourless, only clear, colourless and particle free solutions should be used.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
- What Fludarabine Phosphate Powder for Solution for Injection or Infusion contains
The active substance is fludarabine phosphate. Each vial contains 50 mg fludarabine phosphate
The other ingredients are mannitol and sodium hydroxide used as a pH adjuster 1 ml of reconstituted solution contains 25 mg of fludarabine phosphate.
- What Fludarabine Phosphate Powder for Solution for Injection or Infusion looks like and contents of the pack
Fludarabine Phosphate Powder for Solution for Injection or Infusion is a sterile white to off-white powder for solution for injection or infusion in a 10 ml clear, colourless vial sealed with a rubber closure and a flip-off cap. The powder is reconstituted with Water for Injection and further diluted.
The reconstituted solution is clear and colourless.
Fludarabine Phosphate Powder for Solution for Injection or Infusion is available in packs containing 5 vials.
The following information is intended for medical or healthcare professionals only:
Fludarabine Phosphate Powder for Solution for Injection or Infusion as other potiential 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
For intravenous use only
Incompatibilities
Must not be mixed with other drugs.
Instructions for use and handling Reconstitution
Fludarabine Phosphate Powder for Solution for Injection or Infusion 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 15 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
Shelf-life after reconstitution: After reconstitution with sterile Water for Injections to concentration of 25 mg/ml, should the product be stored in 2°C-8°C protected against light or in 25°C in normal light up to 8 hours. Reconstituted solution with sodium chloride 0.9 % or glucose 5 % is chemically stable stored in infusion bag in 2°C-8°C protected against light or in 25°C in normal light up to 8 hours.
From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. In-use storage times and conditions prior to use and would normally not be longer than 8 hours at 2-8°C or 8 hours at room temperature.
- 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.
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