Fludarabine Phosphate For Injection 50MG Anticancer Medicine
Each vial contains 50 mg fludarabine phosphate as a lyophilised
solid cake (equivalent to 39,05 mg fludarabine per vial).
Fludarabine phosphate, a fluorinated nucleotide analogue of the
antiviral agent vidarabine, 9-beta-D-arabinofuranosyladenine
(ara-A) that is relatively resistant to deamination by adenosine
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A
which is taken up by cells and then phosphorylated intracellularly
by deoxycytidine kinase to the active triphosphate,
2-fluoro-ara-ATP. This metabolite has been shown to inhibit
ribonucleotide reductase, DNA polymerase alpha/delta and epsilon,
DNA primase and DNA ligase thereby inhibiting DNA synthesis.
Furthermore, partial inhibition of RNA polymerase II and consequent
reduction in protein synthesis occurs.
While some aspects of the mechanism of action of 2-fluoro-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 chronic
lymphocytic leukaemia lymphocytes to 2F-ara-A triggers extensive
DNA fragmentation and cell death characteristic of apoptosis.
Plasma and urinary pharmacokinetics of fludarabine (2F-ara-A)
The pharmacokinetics of fludarabine (2F-ara-A) has been studied
after intravenous administration by rapid bolus injection,
short-term infusion and following continuous infusion of
fludarabine phosphate (Fludarabine, 2F-ara-AMP). 2F-ara-A demonstrated a similar pharmacokinetic
profile in chronic lymphocytic leukaemia.
No clear correlation was found between 2F-ara-A pharmacokinetics
and treatment efficacy in cancer patients. However, occurrence of
neutropenia and hematocrit changes indicated that the cytotoxicity
of fludarabine phosphate depresses hematopoiesis in a
Distribution and metabolism
After single dose infusion of 25 mg 2F-ara-AMP per m² to chronic
lymphocytic leukaemia patients for 30 minutes, 2F-ara-A reached
mean maximum concentrations in the plasma of 3,5 to 3,7 microM 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 to 4,8 microM 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 approximately
5 minutes, an intermediate half-life of 1 to 2 hours and a terminal
half-life of approximately 20 hours.
An interstudy comparison of 2F-ara-A pharmacokinetics resulted in a
mean total plasma clearance (CL) of 79 mL/min/m² (2,2 mL/min/kg)
and a mean volume of distribution (Vss) of 83 L/m² (2,4 L/kg). Data
showed a high interindividual variability. After intravenous
administration of fludarabine phosphate 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.
2F-ara-A elimination is largely by renal excretion, 40 to 60% of
the administered intravenous dose was excreted in the urine.
Characteristics in patients
Individuals with impaired renal function exhibited 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 chronic lymphocytic leukaemia patients were observed
at a median of 4 hours and exhibited a considerable variation with
a median peak concentration of approximately 20 microM, 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.
Fludarabine is indicated for the treatment of patients with B-cell chronic
lymphocytic leukaemia who have not responded to or have not
progressed during treatment with at least one standard
alkylating-agent containing regimen.
Fludarabine is contra-indicated in those patients who are hypersensitive to
fludarabine or its components and in renally impaired patients with
creatinine clearance <30 mL/minute and in patients with
The safety and effectiveness of Fludarabine in children has not been established.
Fludarabine should not be used during pregnancy.
Embryotoxicity studies in animals demonstrated an embryotoxic
and/or teratogenic potential posing a relevant risk to humans at
the envisaged therapeutic dose. Preclinical data in rats
demonstrated a transfer of fludarabine phosphate and/or metabolites
through the feto-placental barrier.
One case of fludarabine phosphate use during early pregnancy
leading to skeletal and cardiac malformation in the newborn has
Women of childbearing potential should be advised to avoid becoming
pregnant and to inform the treating physician immediately should
It is not known whether this drug is excreted in human milk.
However, there is evidence from preclinical data that fludarabine
phosphate and/or metabolites transfer from maternal blood to milk.
Therefore, breastfeeding should be discontinued for the duration of Fludarabine therapy.
DOSAGE AND DIRECTIONS FOR USE
Reduced kidney function
Doses should be adjusted for patients with reduced kidney function.
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. For further information see
“Special precautions”. Fludarabine treatment is contra-indicated if creatinine clearance is <30
Fludarabine should be prepared for parenteral use by aseptically adding sterile
water for injection.
When reconstituted with 2 mL of sterile water for injection, the
solid cake 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 to 8,2.
Discard within 8 hours of reconstitution.
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, unintentional
paravenous administration must be avoided.
The recommended dose is 25 mg/m² body surface given daily for 5
consecutive days every 28 days by the intravenous route. Each vial
is to be made up in 2 mL water for injection. Each mL of the
resulting solution will contain 25 mg fludarabine phosphate. The
dose should not be exceeded as severe neurotoxicity may occur.
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 physiological
saline. Alternatively, the required dose drawn up in a syringe may
be diluted into 100 mL physiological saline and infused over
approximately 30 minutes.
Depending on the treatment success and the tolerability of the
drug, Fludarabine should be administered in chronic lymphocytic leukaemia patients up
to the achievement of best response (complete or partial remission,
usually 6 cycles) and then the drug should be discontinued.
Handling and disposal
Fludarabine should not be handled by pregnant staff.
Procedures for proper handling and disposal should be observed.
Consideration should be given to handling and disposal according to
guidelines used for cytotoxic medicine. Any spillage or waste
material may be disposed of by incineration.
Caution should be exercised in the handling and preparation of the
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.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
The most common adverse events include myelosuppression
(neutropenia, thrombocytopenia and anaemia), fever, chills and
infection including pneumonia. Other commonly reported events
include oedema, malaise, fatigue, weakness, peripheral neuropathy,
visual disturbances, anorexia, nausea, vomiting, diarrhoea,
stomatitis and skin rashes. Serious opportunistic infections have
occurred in patients treated with Fludarabine. Fatalities as a consequence of serious adverse events have been
The most frequently reported adverse events and those reactions
which are more clearly related to the drug are arranged below
according to body system. Their frequencies (common >1%, uncommon >0,1% and <1%) are based on clinical trial data regardless of the
causal relationship with Fludarabin. The rare events (<0,1%) were mainly identified from
Body as a whole
Fever, chills, infection, malaise, weakness and fatigue have been
Haemic and lymphatic system
Haematologic events (neutropenia, thrombocytopenia, and anaemia)
have been reported in the majority of patients treated with Fludarabine. Myelosuppression may be severe and cumulative. Fludara’s
prolonged effect on the decrease in the number of T-lymphocytes may
lead to increased risk for opportunistic infections, including
those due to latent viral reactivation, eg progressive multifocal
Clinically significant autoimmune phenomena are uncommon in
patients receiving Fludarabine (see “Special precautions”).
Metabolic and nutritional disorders
Tumour lysis syndrome has been reported in patients treated with Fludarabine. This complication may include hyperuricaemia, hyperphosphataemia,
hypocalcaemia, metabolic acidosis, hyperkalaemia, haematuria, urate
crystalluria, and renal failure. The onset of this syndrome may be
heralded by flank pain and haematuria.
Oedema has been commonly reported.
Changes in hepatic and pancreatic enzyme levels are uncommon.
Coma, seizures and agitation occur rarely and confusion uncommonly.
Peripheral neuropathy has been commonly observed.
Visual disturbances are commonly reported events in patients
treated with Fludarabine. In rare cases, optic neuritis, optic neuropathy and blindness
Pneumonia commonly occurs in association with Fludarabine treatment. Pulmonary hypersensitivity reactions to Fludara
(pulmonary infiltrates/pneumonitis/fibrosis) associated with
dyspnoea and cough are uncommon.
Gastrointestinal disturbances such as nausea and vomiting,
anorexia, diarrhoea and stomatitis are common events.
Gastrointestinal bleeding, mainly related to thrombocytopenia, has
been reported in patients treated with Fludarabine.
In rare cases, heart failure and arrhythmia have been reported in
patients treated with Fludarabine.
Rare cases of haemorrhagic cystitis have been reported in patients
treated with Fludarabine.
Skin and appendages
Skin rashes have been commonly reported in patients treated with Fludarabine.
In rare cases a Stevens-Johnson syndrome or a toxic epidermal
necrolysis (Lyell's syndrome) may develop.
When used at high doses in dose-ranging studies in patients with
acute leukaemia, Fludarabine was associated with severe neurologic effects, including blindness,
coma and death. 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 to 7 days)
than the dose recommended for treatment of chronic lymphocytic
leukaemia. 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). Patients should be closely
observed for signs of neurologic side effects.
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, whereby up to 26 courses of therapy were
Impaired state of health
In patients with impaired state of health, Fludarabine should not be given. 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.
Severe bone marrow suppression, notably anaemia, thrombocytopenia
and neutropenia, has been reported in patients treated with Fludarabine. In a Phase I study in solid tumour patients, the median time to
nadir counts was 13 days (range, 3 to 25 days) for granulocytes and
16 days (range, 2 to 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 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
Transfusion of blood products
Transfusion-associated graft-versus-host disease (reaction by the
transfused immunocompetent lymphocytes to the host) has been
observed rarely 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 patients who
require blood transfusion and who are undergoing, or who have
received, treatment with Fludarabine should receive irradiated blood only.
Skin cancer lesions
Reversible worsening or flare up of pre-existing skin cancer
lesions has been reported in some patients during or afterFludarabine therapy.
Tumour lysis syndrome
Tumour lysis syndrome associated with Fludarabine treatment 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
Irrespective of any previous history of autoimmune processes or
Coombs test status, life-threatening and sometimes fatal autoimmune
phenomena (eg autoimmune haemolytic anaemia, autoimmune
thrombocytopenia, thrombocytopenic purpora, pemphigus, Evans’
syndrome) 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
Patients undergoing treatment with Fludarabine should be closely monitored for signs of autoimmune haemolytic
anaemia (decline in haemoglobin linked with haemolysis and positive
Coombs test). 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.
Reduced renal function
The total body clearance of the principal 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). Limited
clinical data are available in patients with impairment of renal
function (creatinine clearance below 70 mL/minute).
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 contra-indicated, if creatinine clearance is <30
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.
Females of child-bearing potential and males must take
contraceptive measures during and at least for 6 months after
cessation of therapy.
During and after treatment with Fludarabine, vaccination with live vaccines should be avoided.
Interaction with other medicines and other forms of interaction
In clinical investigation using Fludarabine in combination with pentostatin (deoxycoformycin) for the treatment
of refractory chronic lymphocytic leukaemia there was an
unacceptably high incidence of fatal pulmonary toxicity. Therefore,
the use of Fludarabine in combination with pentostatin is not recommended.
The therapeutic efficacy of Fludarabine may be reduced by dipyridamole and other inhibitors of adenosine
Shading, the cold preservation
KEEP OUT OF REACH OF CHILDREN.