Fludarabine Phosphate 25 Mg/Ml Concentrate For Solution For Injection Or Infusion
teva UK Ref: 231-30-86207-L LEA FLUDARABINE 25 MG/ML SOL TEVAH <PCH Version: 1 06 August 2014
93.130.929-C
r
PRESCRIPTION INFORMATION LEAFLET
FLUDARABINE PHOSPHATE 25 mg/ml CONCENTRATE FOR SOLUTION FOR INJECTION OR INFUSION
1. NAME OF THE MEDICINAL PRODUCT
Fludarabine Phosphate 25 mg/ml Concentrate for Solution for Injection or Infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION Fludarabine phosphate 25 mg/ml
Injection vial of 2 ml contains 50 mg fludarabine phosphate.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for injection or infusion.
Fludarabine phosphate 25 mg/ml is a clear, colourless or slightly brownish-yellow solution, essentially free from particles.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of B-cell chronic lymphocytic leukaemia (CLL) in patients with sufficient bone marrow reserves.
First line treatment with fludarabine should only be initiated in patients with advanced disease, Rai stages III/IV (Binet stage C), or Rai stages I/II (Binet stage A/B) where the patient has disease related symptoms or evidence of progressive disease.
4.2 Posology and method of administration
Fludarabine should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.
It is strongly recommended that fludarabine should be only administered intravenously. No cases have been reported in which paravenously administered fludarabine led to severe local adverse reactions. However, the unintentional paravenous administration must be avoided.
Adults
The recommended dose is 25 mg fludarabine phosphate/m2 body surface given daily for 5 consecutive days every 28 days by the intravenous route. 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 into 10 ml of 0.9 % sodium chloride. Alternatively, for infusion, the required dose may be diluted in 100 ml 0.9 % sodium chloride and infused over approximately 30 minutes (see also section 6.6).
The optimal duration of treatment has not been clearly established. The duration of treatment depends on the treatment success and the tolerability of the drug.
It is recommended that fludarabine be administered up to the achievement of response (usually 6 cycles) and then the drug should be discontinued.
Special populations
Patients with hepatic impairment
No data are available concerning the use of fludarabine in patients with hepatic impairment. In this group of patients, fludarabine should be used with caution and administered if the perceived benefit outweighs any potential risk. Such patients should be monitored closely for excessive toxicity and dosage should be modified or the drug discontinued accordingly. See also 4.4.
Patients with renal impairment
The total body clearance of the principle plasma metabolite 2-F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced kidney function demonstrated an increased total body exposure (AUC of 2F-ara-A). Limited clinical data are available in patients with impairment of renal function (creatinine clearance below 70 ml/min). Therefore, if renal impairment is clinically suspected, or in patients over the age of 70 years, creatinine clearance should be measured. If creatinine clearance is between 30 and 70 ml/min, the dose should be reduced by up to 50 % and close haematological monitoring should be used to assess toxicity. Fludarabine treatment is contraindicated, if creatinine clearance is < 30 ml/min.
Children
Fludarabine is not recommended for use in children due to a lack of data on safety and/or efficacy.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients.
• Renal impairment with creatinine clearance < 30 ml/min.
• Decompensated haemolytic anaemia.
• Pregnancy and lactation
4.4 Special warnings and precautions for use
• Myelosuppression
Severe bone marrow suppression, notably anaemia, thrombocytopenia and neutropenia, has been reported in patients treated with Fludarabine. In a Phase I intravenous study in adult solid tumour patients, the median time to nadir counts was 13 days (range 3 - 25 days) for granulocytes and 16 days (range 2 - 32 days) for platelets. Most patients had haematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy.
Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of fludarabine phosphate requires careful haematologic monitoring.
Fludarabine phosphate is a potent antineoplastic agent with potentially significant toxic side effects. Patients undergoing therapy should be closely observed for signs of haematologic and non-haematologic toxicity. Periodic assessment of peripheral blood counts is recommended to detect the development of anaemia, neutropenia and thrombocytopenia.
Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients.
The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.
As with other cytotoxics, caution should be exercised with fludarabine phosphate, when further haematopoietic stem cell sampling is considered.
• Autoimmune disorders
Irrespective of any previous history of autoimmune processes or Coombs test status, life-threatening and sometimes fatal autoimmune phenomena (see section 4.8) have been reported to occur during or after treatment with Fludarabine. The majority of patients experiencing haemolytic anaemia developed a recurrence in the haemolytic process after rechallenge with Fludarabine. Patients treated with Fludarabine should be closely monitored for signs of haemolysis.
Discontinuation of therapy with Fludarabine is recommended in case of haemolysis. Blood transfusion (irradiated, see above) and adrenocorticoid preparations are the most common treatment measures for autoimmune haemolytic anaemia.
• Neurotoxicity
The effect of chronic administration of Fludarabine on the central nervous system is unknown. However, patients tolerated the recommended dose in some studies for relatively long treatment times (for up to 26 courses of therapy). Patients should be closely observed for signs of neurologic effects.
When used at high doses in dose-ranging studies in patients with acute leukaemia, intravenous Fludarabine was associated with severe neurologic effects, including blindness, coma and death. Symptoms appeared from 21 to 60 days from last dose. This severe central nervous system toxicity occurred in 36 % of patients treated intravenously with doses approximately four times greater (96 mg/m2/day for 5-7 days) than the recommended dose. In patients treated at doses in the range of the dose recommended for chronic lymphocytic leukaemia, severe central nervous system toxicity occurred rarely (coma, seizures and agitation) or uncommonly (confusion)
(see section 4.8).
In postmarketing experience neurotoxicity has been reported to occur earlier or later than in clinical trials.
• Tumour lysis syndrome
Tumour lysis syndrome has been reported in patients with large tumour burdens.
Since Fludarabine can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.
• Transfusion associated graft-versus-host disease Transfusion-associated graft-versus-host disease (reaction by the transfused immunocompetent lymphocytes to the host) has been observed after transfusion of non-irradiated blood in Fludarabine treated patients. Fatal outcome as a consequence of this disease has been reported with a high frequency. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received treatment with Fludarabine should receive irradiated blood only.
• Skin cancer
The worsening or flare-up of pre-existing skin cancer lesions as well as new onset of skin cancer has been reported in some patients during or after Fludarabine therapy.
• Impaired state of health
In patients with impaired state of health, Fludarabine should be given with caution and after careful risk/benefit consideration. This applies especially for patients with severe impairment of bone marrow function (thrombocytopenia, anaemia, and/or granulocytopenia), immunodeficiency or with a history of opportunistic infection.
• Renal impairment
The total body clearance of the principle plasma metabolite 2-F-ara-A shows a correlation with creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the compound. Patients with reduced renal function demonstrated an increased total body exposure (AUC of 2F-ara-A). There are limited clinical data available in patients with impairment of renal function (creatinine clearance <70 ml/min).
Fludarabine must be administered cautiously in patients with renal insufficiency. In patients with moderate impairment of renal function (creatinine clearance between 30 and 70 ml/min), the dose should be reduced by up to 50 % and the patient should be monitored closely (see section 4.2). Fludarabine treatment is contraindicated if creatinine clearance is < 30 ml/min (see section 4.3).
• Hepatic impairment
In patients with hepatic impairment fludarabine should be used with caution because it can cause hepatic toxicity. Fludarabine should only be administered if the perceived benefit outweighs any potential risk. Such patients should be monitored closely for
excessive toxicity and dosage modified or the drug discontinued accordingly. See also 4.2.
• The elderly
Since there are limited data for the use of Fludarabine in elderly persons (> 75 years), caution should be exercised with the administration of Fludarabine in these patients.
In patients aged 65 years or older, creatinine clearance should be measured before start of treatment, see “Renal impairment" and section “4.2".
• Children
No data are available concerning the use of Fludarabine in children. Therefore, treatment with fludarabine in children is not recommended.
• Pregnancy
Fludarabine should not be used during pregnancy unless clearly necessary (e.g. life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). It has the potential to cause fetal harm (see sections 4.6 and 5.3). Prescribers may only consider the use of Fludarabine, if the potential benefits justify the potential risks to the foetus.
Women should avoid becoming pregnant while on Fludarabine therapy.
Women of childbearing potential must be apprised of the potential hazard to the foetus.
• Contraception
Women of child-bearing potential or fertile males must take effective contraceptive measures during and at least for 6 months after cessation of therapy (see section 4.6).
• Vaccination
During and after treatment with Fludarabine vaccination with live vaccines should be avoided.
• Retreatment options after initial Fludarabine treatment
A crossover from initial treatment with Fludarabine to chlorambucil for non-responders to Fludarabine should be avoided because most patients who have been resistant to Fludarabine have shown resistance to chlorambucil.
• Excipients
Each vial Fludarabine 50 mg powder for solution for injection/infusion contains less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium-free'.
4.5 Interaction with other medicinal products and other forms of interaction
In a clinical investigation using fludarabine in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukaemia (CLL), there was an unacceptably high incidence of fatal pulmonary toxicity. Therefore, the use of fludarabine in combination with pentostatin is not recommended. Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic efficacy of Fludarabine.
Clinical studies and in vitro experiments showed that during use of Fludarabine in combination with cytarabine the intracellular peak concentration and intracellular exposure of Ara-CTP (active metabolite of cytarabine) increased in leukaemic cells. Plasma concentrations of Ara-C and the elimination rate of Ara-CTP were not affected.
4.6 Pregnancy and lactation Pregnancy
Preclinical data in rats demonstrated a transfer of Fludarabine and/or metabolites through the placenta. The results from intravenous embryotoxicity studies in rats and rabbits indicated an embyrolethal and teratogenic potential at the therapeutic doses (see section 5.3).
There are very limited data of Fludarabine use in pregnant women in the first trimester. Fludarabine should not be used during pregnancy unless clearly necessary (e.g. life-threatening situation, no alternative safer treatment available without compromising the therapeutic benefit, treatment cannot be avoided). Fludarabine has the potential to cause fetal harm. Prescribers may only consider the use of Fludarabine, if the potential benefits justify the potential risks to the foetus.
Women of childbearing potential must be apprised of the potential hazard to the foetus. Both sexually active men and women of childbearing potential must take effective contraceptive measures during and at least for 6 months after cessation of therapy (see section 4.4).
Lactation
It is not known whether this drug or its metabolites are excreted in human milk. However, there is evidence from preclinical data that fludarabine phosphate and/or metabolites transfer from maternal blood to milk.
Because of the potential for serious adverse reactions to Fludarabine in breast-fed infants, Fludarabine is contraindicated in nursing mothers (see section 4.3).
Fertility
There are no human data on the effect of fludarabine on fertility. In animals, fludarabine has been shown to adversely affect the male reproductive system (see section 5.3)."
4.7 Effects on ability to drive and use machines
Fludarabine may reduce the ability to drive and use machines, since e.g. fatigue, weakness, visual disturbances, confusion, agitation and seizures have been observed.
4.8 Undesirable effects
Based on the experience with the use of Fludarabine, the most common adverse events include myelosuppression (neutropenia, thrombocytopenia and anaemia), infection including pneumonia, cough, fever, fatigue, weakness, nausea, vomiting and diarrhoea. Other commonly reported events include chills, oedema, malaise, peripheral neuropathy, visual disturbance, anorexia, mucositis, stomatitis and skin rash. Serious opportunistic infections have occurred in patients treated with Fludarabine. Fatalities as a consequence of serious adverse events have been reported.
The table below reports adverse events by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data regardless of the causal relationship with Fludarabine. The rare adverse reactions were mainly identified from the post-marketing experience.
|
System Organ Class MedDRA |
Very Common >1/10 |
Common >1/100 to <1/10 |
Uncommon >1/1000 to <1/100 |
Rare >1/10,000 to <1/1000 |
Not Known |
|
Infections and infestations |
Infections / Opportunistic infections (like latent viral reactivation, e.g. Progressive multifocal leucoen- cephalopathy, Herpes zoster virus Epstein-Barr- virus), Pneumonia |
Lymphoprolif- erative disorder (EBV-associated) | |||
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
Myelodys- plastic syndrome and Acute myeloid leukaemia (mainly associated with prior, concomitant or subsequent treatment with alkylating agents, topoisomer- ase inhibitors or irradiation) | ||||
|
Blood and lymphatic system disorders |
Neutropenia, Anaemia, Thrombocy topenia |
Myelosup- pression |
FLUDARABINE PHOSPHATE 25 mg/ml CONCENTRATE FOR SOLUTION FOR INJECTION OR INFUSION
Read all of this leaflet carefully before you
start using 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 you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
1. What Fludarabine Phosphate 25 mg/ml is and what it is used for
2. Before Fludarabine Phosphate 25 mg/ml is administered to you
3. How Fludarabine Phosphate 25 mg/ml is administered
4. Possible side effects
5. How to store Fludarabine Phosphate 25 mg/ml
6. Contents of the pack and other information
OWHAT FLUDARABINE PHOSPHATE 25 mg/ml IS AND WHAT IT IS USED FOR
Fludarabine is a cytotoxic (anti-cancer medicine): medicines that inhibit the growth of cancer cells.
Fludarabine Phosphate 25 mg/ml 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 white blood cells (called lymphocytes).
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.
©BEFORE FLUDARABINE PHOSPHATE 25 mg/ml IS ADMINISTERED TO YOU
Do not use Fludarabine Phosphate
25 mg/ml:
• If you are allergic (hypersensitive) to fludarabine phosphate or any of the other ingredients of the injection.
• If your kidney function is severely reduced. Your doctor will decide, based on your kidney function whether Fludarabine phosphate 25 mg/ml 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.
• If you are breast-feeding (see also Section “Pregnancy and breast-feeding").
Take special care with Fludarabine
Phosphate 25 mg/ml:
• 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 before. During treatment with Fludarabine 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.
• If you notice any unusual symptoms of your nervous system such as disturbed vision: tell your doctor.
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. 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. 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): tell your doctor.
• If you need a blood transfusion and you are being treated with Fludarabine (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 whilst receiving Fludarabine therapy or afterwards. You may develop skin cancer during or after Fludarabine therapy.
Other things to consider, while you are treated with Fludarabine:
• 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 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 breast-feeding 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 70, 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 25 mg/ml' and section 3 ‘How Fludarabine is administered').
• If you are over 75 years old, Fludarabine phosphate 25 mg/ml will be given with caution.
This medicine contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium-free'.
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.
Please tell your doctor if you are taking or have recently taken any, 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
• cytarabine (Ara-C) used to treat chronic lymphatic 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 and breast-feeding
You should not be given Fludarabine Phosphate 25 mg/ml 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 25 mg/ml").
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
93.130.929-C
r
during your treatment with this medicine. Ask your doctor for advice before taking any medicine.
Driving and using machines
Fludarabine may reduce the ability to drive and use machines, since e.g. tiredness, weakness, visual disturbances, confusion, agitation and seizures have been observed.
©HOW FLUDARABINE PHOSPHATE 25 mg/ml IS ADMINISTERED
Carefully follow the advice of your doctor when using Fludarabine Phosphate 25 mg/ml. Your doctor will have decided when and how long Fludarabine Phosphate 25 mg/ml will be given to you. Consult your doctor if you feel that Fludarabine Phosphate 25 mg/ml is acting too strongly or not strongly enough.
The administered amount of Fludarabine Phosphate 25 mg/ml (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 25 mg/ml 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 five consecutive days. This 5 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 six 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.
The safety of this medicine in children has not been established.
If you received too much Fludarabine Phosphate 25 mg/ml
There is no specific antidote for Fludarabine Phosphate 25 mg/ml overdosage. If you have received too much Fludarabine Phosphate 25 mg/ml, the doctor will stop the therapy and treat the symptoms.
High doses of Fludarabine Phosphate 25 mg/ml 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 25 mg/ml 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.
^ POSSIBLE SIDE EFFECTS
Like all medicines, Fludarabine 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 with Fludarabine phosphate 25 mg/ml').
• 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, diarrhoea, 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 with Fludarabine phosphate 25 mg/ml')
• tumour lysis syndrome (see section 2, ‘Take special care with Fludarabine phosphate 25 mg/ml')
• 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 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)
• inflammation of the bladder, which can cause pain when passing urine, and can lead to blood in the urine (haemorrhagic cystitis).
• Not known
• Bleeding of the lungs (pulmonary haemorrhage)
• Bleeding into brain tissue (cerebral haemorrhage).
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 at: www.mhra.gov.uk/yellowcard.
By reporting side effects you can help provide more information on the safety of this medicine.
©HOW TO STORE FLUDARABINE PHOSPHATE 25 mg/ml
Store in a refrigerator (2-8°C). Do not freeze. Keep out of the reach and sight of children.
Do not use Fludarabine Phosphate 25 mg/ml after the expiry date which is stated on the carton and vial after the words "Do not use after" or "exp.". The first 2 numbers indicate the month, the last numbers indicate the year.
Medicines should not be disposed in wastewater or household waste. Ask your pharmacist how to dispose of medicines when no longer required. These measures will help to protect the environment.
O CONTENTS OF THE PACK AND OTHER INFORMATION
What Fludarabine Phosphate 25 mg/ml contains
• The active substance is fludarabine phosphate.
• The other ingredients are mannitol (E421), sodium hydroxide (E524) and water for injections.
What Fludarabine Phosphate 25 mg/ml looks like and contents of the pack
Fludarabine Phosphate 25 mg/ml is a clear solution in a colourless glass vial with rubber stopper, aluminium seal and plastic snap-cap. Each pack contains one vial.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation holder:
TEVA UK Limited, Eastbourne, BN22 9AG. Company responsible for manufacture:
Pharmachemie B.V., 2003 RN Haarlem, the Netherlands.
This leaflet was last revised: August 2014
86207-L
|
Immune system disorders |
Autoimmune disorder (including Autoimmune haemolytic anaemia, Evans syndrome, Thrombocy topenic purpura, Acquired haemophilia, Pemphigus) | ||||
|
Metabolism and nutrition disorders |
Anorexia |
Tumour lysis syndrome (including Renal failure, Metabolic acidosis, Hyperkalae- mia, Hypocalce mia, Hyperurice mia, Haematuria, Urate crystalluria, Hyperphos phatemia) | |||
|
Nervous system disorders |
Neuropathy peripheral |
Confusion |
Coma, Seizures, Agitation |
Cerebral haemor rhage | |
|
Eye disorders |
Visual disturbance |
Blindness, Optic neuritis, Optic neuropathy | |||
|
Cardiac disorders |
Heart failure, Arrhythmia | ||||
|
Respiratory, thoracic and mediastinal disorders |
Cough |
Pulmonary toxicity (including Pulmonary fibrosis, Pneumonitis, Dyspnoea) |
Pulmonary haemor rhage | ||
|
Gastroin testinal disorders |
Vomiting, Diarrhoea, Nausea |
Stomatitis |
Gastrointesti nal haemorrhage, Pancreatic enzymes abnormal | ||
|
Hepatobiliary disorders |
Hepatic enzyme abnormal | ||||
|
Skin and subcutaneous tissue disorders |
Rash |
Skin cancer, Necrolysis epidermal toxic (Lyell type), Stevens- Johnson syndrome | |||
|
Renal and urinary disorder |
Haemor rhagic cystitis | ||||
|
General disorders and administration site conditions |
Fever, Fatigue, Weakness |
Oedema, Mucositis, Chills, Malaise |
Brampton Road,
Hampden Park, Eastbourne,
East Sussex, BN22 9AG.
8. MARKETING AUTHORISATION NUMBER(S)
PL 00289/0938
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 23 May 2007
10. DATE OF REVISION OF THE TEXT
December 2010
The most appropriate MedDRA term to describe a certain adverse event is listed. Synonyms or related conditions are not listed, but should be taken into account as well. Adverse event term representation is based on MedDRA version 12.0.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
4.9 Overdose
High doses of fludarabine have been associated with an irreversible central nervous system toxicity characterised by delayed blindness, coma, and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for fludarabine overdosage. Treatment consists of drug discontinuation and supportive therapy.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents.
ATC code: L01B B05
Fludarabine contains fludarabine phosphate, a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-|3-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase.
Fludarabine phosphate is rapidly dephosphorylated to 2F-ara-A which is taken up by cells and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2F-ara-ATP. This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase a/6 and e, DNA primase and DNA ligase thereby inhibiting DNA synthesis. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occur.
While some aspects of the mechanism of action of 2F-ara-ATP are as yet unclear, it is assumed that effects on DNA, RNA and protein synthesis all contribute to inhibition of cell growth with inhibition of DNA synthesis being the dominant factor. In addition, in vitro studies have shown that exposure of CLL lymphocytes to 2F-ara-A triggers extensive DNA fragmentation and cell death characteristic of apoptosis.
A phase III trial in patients with previously untreated B-chronic lymphocytic leukaemia comparing treatment with fludarabine vs. chlorambucil (40 mg/m2 q4 weeks) in 195 and 199 patients respectively showed the following outcome: statistically significant higher overall response rates and complete response rates after 1st line treatment with fludarabine compared to chlorambucil (61.1 % vs. 37.6 % and 14.9 % vs. 3.4 %, respectively); statistically significant longer duration of response (19 vs. 12.2 months) and time to progression (17 vs. 13.2 months) for the patients in the fludarabine group. The median survival of the two patient groups was 56.1 months for fludarabine and
55.1 months for chlorambucil, a non-significant difference was also shown with performance status. The proportion of patients reported to have toxicities were comparable between fludarabine patients (89.7 %) and chlorambucil patients (89.9 %). While the difference in the overall incidence of haematological toxicities was not significant between the two treatment groups, significantly greater proportions of fludarabine patients experienced white blood cell (p=0.0054) and lymphocyte (p=0.0240) toxicities than chlorambucil patients. The proportions of patients who experienced nausea, vomiting, and diarrhoea were significantly lower for fludarabine patients (p<0.0001, p<0.0001, and p=0.0489, respectively) than chlorambucil patients. Toxicities of the liver were also reported for significantly (p=0.0487) less proportions of patients in the fludarabine group than in the chlorambucil group. Patients who initially respond to fludarabine have a chance of responding again to fludarabine monotherapy.
A randomised trial of fludarabine vs. cyclophosphamide, adriamycin (doxorubicin) and prednisone (CAP) in 208 patients with CLL Binet stage B or C revealed the following results in the subgroup of 103 previously treated patients: the overall response rate and the complete response rate were higher with fludarabine compared to CAP (45 % vs. 26 % and 13 % vs. 6 %, respectively); response duration and overall survival were similar with fludarabine and CAP. Within the stipulated treatment period of 6 months the number of deaths was 9 (fludarabine) vs. 4 (CAP).
Post-hoc analyses using only data of up to 6 months after start of treatment revealed a difference between survival curves of fludarabine and CAP in favour of CAP in the subgroup of pretreated Binet stage C patients.
5.2 Pharmacokinetic properties
Plasma and urinary pharmacokinetics of fludarabine (2F-ara-A)
The pharmacokinetics of fludarabine (2F-ara-A) have been studied after intravenous administration by rapid bolus injection and short-term infusion as well as following continuous infusion of fludarabine phosphate (fludarabine, 2F-ara-AMP).
2F-ara-AMP is a water-soluble prodrug, which is rapidly and quantitatively dephosphorylated in the human organism to the nucleoside fludarabine (2F-ara-A). After single dose infusion of 25 mg 2F-ara-AMP per m2 to cancer patients for 30 minutes 2F-ara-A reached mean maximum concentrations in the plasma of 3.5 - 3.7 pM at the end of the infusion. Corresponding 2F-ara-A levels after the fifth dose showed a moderate accumulation with mean maximum levels of 4.4 - 4.8 pM at the end of infusion. During a 5-day treatment schedule 2F-ara-A plasma trough levels increased by a factor of about 2. An accumulation of 2F-ara-A over several treatment cycles can be excluded. Postmaximum levels decayed in three disposition phases with an initial half-life of approx. 5 minutes, an intermediate half-life of 1 - 2 hours and a terminal half-life of approx. 20 hours.
An interstudy comparison of 2F-ara-A pharmacokinetics resulted in a mean total plasma clearance (CL) of 79 ± 40 ml/min/m2 (2.2 ± 1.2 ml/min/kg) and a mean volume of distribution (Vss) of 83 ± 55 l/m2 (2.4 ± 1.6 l/kg). Data showed a high interindividual variability. Plasma levels of 2F-ara-A and areas under the plasma level time curves increased linearly with the dose, whereas half-lives, plasma clearance and volumes of distribution remained constant independent of the dose indicating a dose linear behaviour.
Occurrence of neutropenia and haematocrit changes indicated that the cytotoxicity of fludarabine phosphate depresses the haematopoiesis in a dose dependent manner. 2F-ara-A elimination is largely by renal excretion. 40 to 60 % of the administered i.v. dose was excreted in the urine. Mass balance studies in laboratory animals with 3H-2F-ara-AMP showed a complete recovery of radio-labelled substances in the urine. Another metabolite, 2F-ara-hypoxanthine, which represents the major metabolite in the dog, was observed in humans only to a minor extent. Individuals with impaired renal function exhibit a reduced total body clearance, indicating the need for a dose reduction. In vitro investigations with human plasma proteins revealed no pronounced tendency of 2F-ara-A protein binding.
Cellular pharmacokinetics of fludarabine triphosphate
2F-ara-A is actively transported into leukaemic cells, whereupon it is rephosphorylated to the monophosphate and subsequently to the di- and triphosphate. The triphosphate 2F-ara-ATP is the major intracellular metabolite and the only metabolite known to have cytotoxic activity. Maximum 2F-ara-ATP levels in leukaemic lymphocytes of CLL patients were observed at a median of 4 hours and exhibited a considerable variation with a median peak concentration of approx. 20 pM. 2F-ara-ATP levels in leukaemic cells were always considerably higher than maximum 2F-ara-A levels in the plasma indicating an accumulation at the target sites. In-vitro incubation of leukaemic lymphocytes showed a linear relationship between extracellular 2F-ara-A exposure (product of 2F-ara-A concentration and duration of incubation) and intracellular 2F-ara-ATP enrichment. 2F-ara-ATP elimination from target cells showed median half-life values of 15 and 23 hours.
No clear correlation was found between 2F-ara-A pharmacokinetics and treatment efficacy in cancer patients.
5.3 Preclinical safety data
Acute and repeat dose toxicology studies in animals showed that the bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys and the male reproductive organs were the primary target organs of toxicity. Neurotoxicity was seen at high dosages. Fludarabine phosphate was teratogenic in animals and caused skeletal malformations and external deformities at dosages similar or less than the therapeutic dose. Genotoxicity studies demonstrated that fludarabine phosphate was negative in gene mutation assays and in the dominant lethal test in male mice, but did induce clastogenic effects in the non-activated chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells and in the in vivo mouse micronucleus test.
No carcinogenicity studies have been performed.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients Mannitol (e421)
Sodium hydroxide (for pH adjustment)
Water for Injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products than those mentioned in section 6.6.
6.3 Shelf life
Vial before opening
36 months
After dilution
Chemical and physical in-use stability of the solution prepared for injection or infusion has been demonstrated as:
|
Storage in |
Medium |
Concentration |
Stability for |
|
Non-PVC bag |
0.9% sodium chloride |
0.3-6 mg/mL |
5 days in a refrigerator (2-8°C) or at ambient temperature/light |
|
5% glucose |
0.3-6 mg/mL |
5 days in a refrigerator (2-8°C) or at ambient temperature/light | |
|
Glass Bottle |
0.9% sodium chloride |
0.3-6 mg/mL |
5 days in a refrigerator (2-8°C) or at ambient temperature/light |
|
5% glucose |
0.3 mg/mL |
5 days in a refrigerator (2-8°C) or at ambient temperature/light | |
|
6 mg/mL |
5 days in a refrigerator (2-8°C) or 3 days at ambient temperature/light |
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 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions
6.4 Special precautions for storage Store in a refrigerator (2 - 8°C).
Do not freeze.
6.5 Nature and contents of container
One Type I glass vial with bromobutyl rubber stopper, aluminium seal and polypropylene snap-cap containing 2 ml of solution.
6.6 Special precautions for 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 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.
In clinical studies, Fludarabine has been diluted in 100 ml or 125 ml of 5 % dextrose injection or 0.9 % sodium chloride.
Inspection prior to use
Only clear and colourless solutions without particles should be used. The product 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 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.
The medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER TEVA UK Limited
POM
86207-L