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RX The recommended dose is 25 mg fludarabine

phosphate/m2 body surface area given daily for 5
FLUDARABINE consecutive days every 28 days by intravenous
route (See also section 6.6).
PHOSPHATE 25 mg/ml
The required dose (calculated on the basis of the
CONCENTRATE FOR patient's body surface area) of the reconstituted
SOLUTION FOR INJECTION solution is drawn up into a syringe. For
intravenous bolus injection this dose is further
1.NAME OF THE MEDICINAL diluted in 10 ml sodium chloride 9 mg/ml
PRODUCT (0.9%). Alternatively, for infusion, the required
Fludarabine phosphate 25 mg/ml Concentrate dose drawn up in a syringe may be diluted in
for Solution for Injection or Infusion. 100 ml sodium chloride 9 mg/ml (0.9%) and
infused over approximately 30 minutes.
2. QUALITATIVE AND
The duration of treatment depends on the
QUANTITATIVE COMPOSITION
treatment success and the tolerability of the
Each ml contains 25 mg fludarabine phosphate. drug.
2 ml of solution contains 50 mg fludarabine In CLL patients, Fludarabine should be
phosphate. administered up to the achievement of best
response (complete or partial remission, usually
Excipient with known effect: 6 cycles) and then the drug should be
Each mL contains <1 mmol sodium. discontinued.

For the full list of excipients, see section 6.1. Special populations

3. PHARMACEUTICAL FORM Patients with renal impairment

Concentrate for solution for injection or Doses should be adjusted for patients with
infusion. reduced kidney function. If creatinine clearance
is between 30 and 70 ml/min, the dose should be
Clear, colourless or slightly brownish-yellow reduced by up to 50% and close haematological
solution, essentially free from particles. monitoring should be used to assess toxicity (see
pH: 6.0 – 7.1 section 4.4).
Fludarabine treatment is contraindicated, if
4. CLINICAL PARTICULARS
creatinine clearance is < 30 ml/min (see section
4.1 Therapeutic indications 4.3).
Treatment of B-cell chronic lymphocytic Patients with hepatic impairment
leukaemia (CLL) in adult patients with sufficient
bone marrow reserves. No data are available concerning the use of
Fludarabine in patients with hepatic impairment.
First line treatment with Fludarabine should only In this group of patients, Fludarabine should be
be initiated in adult patients with advanced used with caution(see also section 4.4).
disease, Rai stages III/IV (Binet stage C), or Rai
stages I/II (Binet stage A/B) where the patient Paediatric population
has disease related symptoms or evidence of
The safety and efficacy of Fludarabine in
progressive disease.
children below the age of 18 years have not been
4.2 Posology and method of established. Therefore, Fludarabine is not
administration recommended for use in children.

Posology Elderly
Fludarabine phosphate 25 mg/ ml Concentrate for Solution for Injection or Infusion SMPC, Taj Pharmaceuticals
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Since there are limited data for the use of Cumulative myelosuppression may be seen.
Fludarabine in older people (>75 years), caution While chemotherapy-induced myelosuppression
should be exercised with the administration of is often reversible, administration of fludarabine
Fludarabine in these patients. phosphate requires careful haematologic
monitoring.
In patients over the age of 65 years, creatinine
clearance should be measured, (see “Patients Fludarabine phosphate is a potent antineoplastic
with renal impairment” and section 4.4). agent with potentially significant toxic side
effects. Patients undergoing therapy should be
Method of administration
closely observed for signs of haematologic and
Fludarabine should be administered under the non-haematologic toxicity. Periodic assessment
supervision of a qualified physician experienced of peripheral blood counts is recommended to
in the use of antineoplastic therapy. detect the development of anaemia, neutropenia
and thrombocytopenia.
Fludarabine should only be administered
intravenously. No cases have been reported in Several instances of trilineage bone marrow
which paravenously administered Fludarabine hypoplasia or aplasia resulting in pancytopenia,
led to severe local adverse reactions. However, sometimes resulting in death, have been reported
unintentional paravenous administration must be in adult patients. The duration of clinically
avoided. significant cytopenia in the reported cases has
ranged from approximately 2 months to
Precautions to be taken before handling the approximately 1 year. These episodes have
medicinal product occurred both in previously treated or untreated
For instructions on handling and reconstitution patients.
of the medicinal product before administration, As with other cytotoxics, caution should be
see section 6.6. exercised with fludarabine phosphate, when
4.3 Contraindications further haematopoietic stem cell sampling is
- Hypersensitivity to the active substance or to considered.
any of the excipients listed in section 6.1 Autoimmune disorders
- Renal impairment with creatinine clearance < Irrespective of any previous history of
30 ml/min. autoimmune processes or Coombs test status,
- Decompensated haemolytic anaemia. life-threatening and sometimes fatal
autoimmune phenomena (see section 4.8) have
- Lactation. been reported to occur during or after treatment
with fludarabine. The majority of patients
4.4 Special Warnings and precautions for experiencing haemolytic anaemia developed a
use recurrence in the haemolytic process after
Myelosuppression rechallenge with fludarabine. Patients
treated with fludarabine should be closely
Severe bone marrow suppression, notably
anaemia, thrombocytopenia and neutropenia, has
monitored for signs of haemolysis.
been reported in patients treated with Discontinuation of therapy with fludarabine
Fludarabine. In a Phase I intravenous study in is recommended in case of haemolysis.
adult solid tumour patients, the median time to Blood transfusion (irradiated, see below)
nadir counts was 13 days (range 3 – 25 days) for
and adrenocorticoid preparations are the
granulocytes and 16 days (range 2 - 32 days) for
platelets. Most patients had haematologic most common treatment measures for
impairment at baseline either as a result of autoimmune haemolytic anaemia.
disease or as a result of prior myelosuppressive • Hepatic impairment
therapy.
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Fludarabine phosphate should be used with • or when Fludarabine is given in patients with
caution in patients with hepatic impairment due other risk factors such as cranical or total body
to the risk of liver toxicity. Fludarabine irradiation, Hematopoietic Cell Transplantation,
phosphate should be administered only if the Graft versus Host Disease, renal impairment, or
perceived benefit outweighs any potential risk. hepatic encephalopathy.
These patients should be closely observed for
signs of increased toxicity and the dosing should • at doses higher than the recommended dose
be modified or the treatment discontinued if LE, ATL or RPLS symptoms may include
indicated (see section 4.2). headache, nausea and vomiting, seizures, visual
Neurotoxicity disturbances such as vision loss, altered
sensorium, and focal neurological deficits.
The effect of chronic administration of Additional effects may include optic neuritis,
fludarabine on the central nervous system is and papillitis, confusion, somnolence, agitation,
unknown. However, patients tolerated the paraparesis/ quadriparesis, muscle spasticity and
recommended dose, in some studies for incontinence.
relatively long treatment times (for up to 26
courses of therapy). LE/ ATL/ RPLS may be irreversible, life-
threatening, or fatal.
Patients should be closely observed for signs of
neurologic effects. Whenever LE, ATL or RPLS is suspected,
Fludarabine treatment should be stopped.
When used at high doses in dose-ranging studies Patients should be monitored and should
in patients with acute leukaemia, intravenous undergo brain imaging, preferably utilizing
fludarabine was associated with severe MRI. If the diagnosis is confirmed, Fludarabine
neurological effects, including blindness, coma therapy should be permanently discontinued.
and death. Symptoms appeared from 21 to 60
Tumour lysis syndrome
days from last dose. This severe central nervous
system toxicity occurred in 36 % of patients Tumour lysis syndrome has been reported in
treated intravenously with doses approximately CLL patients with large tumour burdens. Since
four times greater (96 mg/m2/day for 5 - 7 days) fludarabine can induce a response as early as the
than the recommended dose. In patients treated first week of treatment, precautions should be
at doses in the range of the dose recommended taken in those patients at risk of developing this
for CLL, severe central nervous system toxicity complication, and hospitalisation may be
occurred rarely (coma, seizures and agitation) or recommended for these patients during the first
uncommonly (confusion) (see section 4.8). course of treatment.
In post-marketing experience neurotoxicity has Transfusion-associated graft-versus-host disease
been reported to occur earlier or later than in
clinical trials. Transfusion-associated graft-versus-host disease
(reaction by the transfused immunocompetent
Administration of Fludarabine can be associated lymphocytes to the host) has been observed after
with leukoencephalopathy (LE), acute toxic transfusion of non-irradiated blood in
leukoencephalopathy (ATL) or reversible fludarabine - treated patients. Fatal outcome as a
posterior leukoencephalopathy syndrome consequence of this disease has been reported
(RPLS). with a high frequency. Therefore, to minimise
These may occur: the risk of transfusion-associated graft-versus-
host disease, patients who require blood
• at the recommended dose transfusion and who are undergoing, or who
have received treatment with fludarabine should
• when Fludarabine is given following, or in receive irradiated blood only.
combination with, medications known to be
associated with LE, ATL or RPLS, Skin cancer
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The worsening or flare up of pre-existing skin Fludarabine should not be used during
cancer lesions as well as new onset of skin pregnancy unless clearly necessary (e.g. life-
cancer has been reported in some patients during threatening situation, no alternative safer
or after fludarabine therapy. treatment available without compromising the
therapeutic benefit, treatment cannot be
Impaired state of health
avoided). It has the potential to cause foetal
In patients with impaired state of health, harm (see sections 4.6 and 5.3). Prescribers may
fludarabine should be given with caution and only consider the use of Fludarabine, if the
after careful risk/benefit consideration. This potential benefits justify the potential risks to the
applies especially for patients with severe foetus.
impairment of bone marrow function Women should avoid becoming pregnant while
(thrombocytopenia, anaemia, and/or on Fludarabine therapy.
granulocytopenia), immunodeficiency or with a
history of opportunistic infection. Women of childbearing potential must be
apprised of the potential hazard to the foetus.
Renal impairment
Contraception
The total body clearance of the principle plasma
metabolite 2-F-ara-A shows a correlation with Women of child-bearing potential or fertile
creatinine clearance, indicating the importance males must take effective contraceptive
of the renal excretion pathway for the measures during and at least for 6 months after
elimination of the compound. Patients with cessation of therapy (see section 4.6).
reduced renal function demonstrated an
increased total body exposure (AUC of 2F-ara- Vaccination
A). There are limited clinical data available in During and after treatment with Fludarabine
patients with impairment of renal function vaccination with live vaccines should be
(creatinine clearance < 70 ml/min). avoided.
Fludarabine must be administered cautiously in Retreatment options after initial Fludarabine
patients with renal insufficiency. In patients with treatment
moderate impairment of renal function
(creatinine clearance between 30 and 70 A crossover from initial treatment with
ml/min), the dose should be reduced by up to Fludarabine to chlorambucil for non responders
50% and the patient should be monitored closely to Fludarabine should be avoided because most
(see section 4.2). Fludarabine treatment is patients who have been resistant to Fludarabine
contraindicated if creatinine clearance is < 30 have shown resistance to chlorambucil.
ml/min (see section 4.3). Excipients
Elderly Each vial of Fludarabine phosphate 25 mg/ml
Since there are limited data for the use of concentrate for solution for injection/infusion
Fludarabine in elderly persons (> 75 years), contains less than 1 mmol sodium (23 mg), i.e.
caution should be exercised with the essentially 'sodium-free'.
administration of Fludarabine in these patients 4.5 Interaction with other medicinal
(see also section 4.2).
products and other forms of interaction
In patients aged 65 years or older, creatinine In a clinical investigation using intravenous
clearance should be measured before start of
Fludarabine in combination with pentostatin
treatment, see “Renal impairment” and section
(deoxycoformycin) for the treatment of
4.2.
refractory chronic lymphocytic leukaemia
Pregnancy (CLL), there was an unacceptably high
incidence of fatal pulmonary toxicity. Therefore,
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the use of Fludarabine in combination with However, there is evidence from preclinical data
pentostatin is not recommended. that fludarabine phosphate and its metabolites
transfer from maternal blood to milk.
Dipyridamole and other inhibitors of adenosine
uptake may reduce the therapeutic efficacy of Because of the potential for serious adverse
Fludarabine. reactions to Fludarabine in breast-fed infants.
Fludarabine is contraindicated in nursing
Clinical studies and in vitro experiments showed mothers (see section 4.3).
that during use of Fludarabine in combination
with cytarabine the intracellular peak 4.7 Effects on ability to drive and use
concentration and intracellular exposure of Ara- machines
CTP (active metabolite of cytarabine) increased
in leukaemic cells. Plasma concentrations of Fludarabine may reduce the ability to drive and
Ara-C and the elimination rate of Ara-CTP were use machines, since e.g. fatigue, weakness,
not affected. visual disturbances, confusion, agitation and
seizures have been observed.
4.6 Fertility, pregnancy and lactation
Fertility 4.8 Undesirable Effects

Women of childbearing potential must be Summary of safety profile

apprised of the potential hazard to the foetus.
Based on the experience with the use of
Both sexually active men and women of Fludarabine, the most common adverse events
childbearing potential must take effective include myelosuppression (neutropenia,
contraceptive measures during and at least for 6 thrombocytopenia and anaemia), infection
months after cessation of therapy (see section including pneumonia, cough, fever, fatigue,
4.4). weakness, nausea, vomiting and diarrhoea.
Other commonly reported events include chills,
Pregnancy
oedema, malaise, peripheral neuropathy, visual
Pre-clinical data in rats demonstrated a transfer disturbance, anorexia, mucositis, stomatitis and
of Fludarabine and/or metabolites through the skin rash. Serious opportunistic infections have
placenta. The results from intravenous occurred in patients treated with Fludarabine.
embryotoxicity studies in rats and rabbits Fatalities as a consequence of serious adverse
indicated an embryolethal and teratogenic events have been reported.
potential at the therapeutic doses (see section
Tabulated list of adverse reactions
5.3).
The table below reports adverse events by
There are very limited data of Fludarabine use in
MedDRA system organ classes (MedDRA
pregnant women in the first trimester:
SOCs). The frequencies are based on clinical
Fludarabine should not be used during trial data regardless of the causal relationship
pregnancy unless clearly necessary (e.g. life- with Fludarabine. The rare adverse reactions
threatening situation, no alternative safer were mainly identified from the post-marketing
treatment available without compromising the experience.
therapeutic benefit, treatment cannot be
avoided). Fludarabine has the potential to cause
foetal harm. Prescribers may only consider the
use of Fludarabine if the potential benefits
justify the potential risks to the foetus.
Lactation
It is not known whether this drug or its
metabolites are excreted in human milk.
Fludarabine phosphate 25 mg/ ml Concentrate for Solution for Injection or Infusion SMPC, Taj Pharmaceuticals
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System Very Common Uncommon Rare Not Nervous Peripheral Confusion Coma, Cerebral
Organ Common ≥1/100 to ≥1/1000 to ≥1/10,000 known system neurophath seizures, haemorr
Class ≥1/10 <1/10 <1/100 to disorders y agitation hage,
<1/1000 leukoenc
Infections Infections / Lympho ephalopa
and Opportunis proliferativ thy (see
infestations tic e disorder section
infections (EBV- 4.4),
(like latent associated) acute
viral toxic
reactivatio
leukoenc
n, e.g.
Progressive ephalopa
multifocal thy (see
leukoencep section
halopathy, 4.4),
Herpes reversibl
zoster virus e
Esptein-
posterior
Barr-virus),
pneumonia leukoenc
ephalopa
Neoplasms Myelodysp
thy
benign, lastic
malignant syndrome syndrom
and and Acute e (RPLS)
unspecified Myeloid (see
(incl cysts Leukaemia section
and (mainly 4.4)
polyps) associated
with prior, Eye Visual Blindness,
concomitan disorders disturbance optic
t or s neuritis,
subsequent optic
treatment neuropathy
with Cardiac Heart
alkylating disorders failure,
agents, arryhthmia
topoisomer
ase Respirator Cough Pulmonary Pulmona
inhibitors y, thoracic toxicity ry
or and (including Haemorr
irradiation) mediastina pulmonary
l disorders fibrosis,
hage
Blood and Neutropeni Myelosupp pneumonitis,
lymphatic a, anaemia, ression dyspnoea)
system thrombocyt
disorders openia Gastrointe Vomiting, Stomatitis Gastrointestinal
stinal diarrhoea, haemorrhage,
Immune Autoimmune disorders nausea pancreatic
system disorder enzymes
disorders (including Auto abnormal
immune
haemolytic Hepatobili Hepatic enzymes
anaemia, Evan's ary abnormal
syndrome, disorders
Thrombo Skin and Rash Skin
cytopenic subcutaneo cancer,
purpura, us tissue necrolysis
Acquired disorders epidermal
haemophilia toxic (Lyell
Pemphigus) type)
Metabolis Anorexia Tumour lysis Stevens-
m and syndrome Johnson
nutrition (including renal syndrome
disorders failure, metabolic General Fever, Oedema,
acidosis, disorders fatigue, mucositis,
hyperkalaemia, and weakness chills,
hypocalcaemia, administra malaise
hyperuricaemia, tion site
haematuria, urate conditions
crystalluria,
hyperphosphatae The most appropriate MedDRA term to describe
mia) a certain adverse event is listed. Synonyms or
related conditions are not listed, but should be
taken into account as well. Adverse event term
Fludarabine phosphate 25 mg/ ml Concentrate for Solution for Injection or Infusion SMPC, Taj Pharmaceuticals
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representation is based on MedDRA version Fludarabine phosphate is rapidly

16.1 dephosphorylated to 2F-ara-A which is taken up
by cells and then phosphorylated intracellularly
Within each frequency grouping, undesirable by deoxycytidine kinase to the active
effects are presented in order of decreasing triphosphate, 2F-ara-ATP. This metabolite has
seriousness.
been shown to inhibit ribonucleotide reductase,
Reporting of suspected adverse reactions DNA polymerase α/δ and ε, DNA primase and
DNA ligase thereby inhibiting DNA synthesis.
Reporting suspected adverse reactions after Furthermore, partial inhibition of RNA
authorisation of the medicinal product is polymerase II and consequent reduction in
important. It allows continued monitoring of the protein synthesis occur.
benefit/risk balance of the medicinal product.
While some aspects of the mechanism of action
4.9 Overdose of 2F-ara-ATP are as yet unclear, it is assumed
High doses of Fludarabine have been associated that effects on DNA, RNA and protein synthesis
with leukoencephalopathy, acute toxic all contribute to inhibition of cell growth with
leukoencephalopathy, or reversible posterior inhibition of DNA synthesis being the dominant
leukoencephalopathy syndrome (RPLS). factor. In addition, in vitro studies have shown
Symptoms may include headache, nausea and that exposure of CLL lymphocytes to 2F-ara-A
vomiting, seizures, visual disturbances such as triggers extensive DNA fragmentation and cell
vision loss, altered sensorium, and focal death characteristic of apoptosis.
neurological deficits. Additional effects may
include optic neuritis, and papillitis, confusion, Clinical efficacy and safety
somnolence, agitation, paraparesis/ A phase III trial in patients with previously
quadriparesis, muscle spasticity, incontinence, untreated B-chronic lymphocytic leukaemia
irreversible central nervous system toxicity comparing treatment with Fludarabine vs.
characterised by delayed blindness, coma, and chlorambucil (40mg / m² q4 weeks) in 195 and
death. High doses are also associated with 199 patients respectively showed the following
severe thrombocytopenia and neutropenia due to outcome: statistically significant higher overall
bone marrow suppression. response rates and complete response rates after
There is no known specific antidote for 1st line treatment with Fludarabine compared to
Fludarabine overdosage. Treatment consists of chlorambucil (61.1% vs. 37.6% and 14.9% vs.
drug discontinuation and supportive therapy. 3.4%, respectively); statistically significant
longer duration of response (19 vs. 12.2 months)
5. PHARMACOLOGICAL and time to progression (17 vs. 13.2 months) for
PROPERTIES the patients in the Fludarabine group. The
median survival of the two patient groups was
5.1 Pharmacodynamic properties 56.1 months for Fludarabine and 55.1 months
• Pharmacotherapeutic group: Antineoplastic for chlorambucil, a non-significant difference
agents, purine analogues was also shown with performance status. The
Mechanism of action proportion of patients reported to have toxicities
were comparable between Fludarabine patients
Fludarabine phosphate 25 mg/ml concentrate for (89.7%) and chlorambucil patients (89.9%).
solution for injection or infusion contains While the difference in the overall incidence of
fludarabine phosphate a water-soluble haematological toxicities was not significant
fluorinated nucleotide analogue of the antiviral between the two treatment groups, significantly
agent vidarabine, 9-ß-D- greater proportions of Fludarabine patients
arabinofuranosyladenine (ara-A) that is experienced white blood cell (p=0.0054) and
relatively resistant to deamination by adenosine lymphocyte (p=0.0240) toxicities than
deaminase.. chlorambucil patients. The proportions of
patients who experienced nausea, vomiting, and
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diarrhoea were significantly lower for Distribution and metabolism

Fludarabine patients (p<0.0001, p<0.0001, and
p=0.0489, respectively) than chlorambucil 2F-ara-AMP is a water-soluble prodrug of
patients. Toxicities of the liver were also fludarabine (2F-ara-A), which is rapidly and
reported for significantly (p=0.0487) less quantitatively dephosphorylated in the human
proportions of patients in the Fludarabine group organism to the nucleoside fludarabine (2F-ara-
than in the chlorambucil group. A).

Patients who initially respond to Fludarabine Another metabolite, 2F-ara-hypoxanthine, which

represents the major metabolite in the dog, was
have a chance of responding again to
Fludarabine monotherapy. observed in humans only to a minor extent.
After single dose infusion of 25 mg 2F-ara-AMP
A randomised trial of Fludarabine vs.
cyclophosphamide, adriamycin and prednisone per m² to CLL patients for 30 minutes 2F-ara-A
(CAP) in 208 patients with CLL Binet stage B reached mean maximum concentrations in the
or C revealed the following results in the plasma of 3.5 - 3.7 μM at the end of the
subgroup of 103 previously treated patients: the infusion. Corresponding 2F-ara-A levels after
the fifth dose showed a moderate accumulation
overall response rate and the complete response
rate were higher with Fludarabine compared to with mean maximum levels of 4.4 - 4.8 µM at
CAP (45% vs. 26% and 13% vs. 6%, the end of infusion. During a 5-day treatment
respectively); response duration and overall schedule 2F-ara-A plasma trough levels
survival were similar with Fludarabine and CAP. increased by a factor of about 2. An
Within the stipulated treatment period of 6 accumulation of 2F-ara-A over several treatment
cycles can be excluded. Postmaximum levels
months the number of deaths was 9
(Fludarabine) vs. 4 (CAP). decayed in three disposition phases with an
initial half-life of approximately 5 minutes, an
Post-hoc analyses using only data of up to 6 intermediate half-life of 1 - 2 hours and a
months after start of treatment revealed a terminal half-life of approximately 20 hours.
difference between survival curves of
Fludarabine and CAP in favour of CAP in the An interstudy comparison of 2F-ara-A
subgroup of pretreated Binet stage C patients. 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
5.2 Pharmacokinetic properties distribution (Vss) of 83 ± 55 l/m² (2.4 ± 1.6
l/kg). Data showed a high interindividual
Plasma and urinary pharmacokinetics of variability. After intravenous and peroral
fludarabine (2F-ara-A) administration of fludarabine phosphate plasma
The pharmacokinetics of fludarabine (2F-ara-A) levels of 2F-ara-A and areas under the plasma
have been studied after intravenous level time curves increased linearly with the
administration by rapid bolus injection and dose, whereas half-lives, plasma clearance and
short-term infusion as well as following volumes of distribution remained constant
continuous infusion and after peroral dosing of independent of the dose indicating a dose linear
fludarabine phosphate (Fludarabine, 2F-ara- behaviour.
AMP). Elimination
No clear correlation was found between 2F-ara- 2F-ara-A elimination is largely by renal
A pharmacokinetics and treatment efficacy in excretion. 40 to 60 % of the administered
cancer patients. intravenous dose was excreted in the urine. Mass
However, occurrence of neutropenia and balance studies in laboratory animals with ³H-
haematocrit changes indicated that the 2F-ara-AMP showed a complete recovery of
cytotoxicity of fludarabine phosphate depresses radio-labelled substances in the urine.
the haematopoiesis in a dose-dependent manner. Characteristics in patients
Fludarabine phosphate 25 mg/ ml Concentrate for Solution for Injection or Infusion SMPC, Taj Pharmaceuticals
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Individuals with impaired renal function dose levels and duration of dosing and the
exhibited a reduced total body clearance, observed changes were generally considered to
indicating the need for a dose reduction. In vitro be reversible. In principle, the available
investigations with human plasma proteins experience from the therapeutic use of
revealed no pronounced tendency of 2F-ara-A Fludarabine points to a comparable toxicological
protein binding. profile in humans, although additional
undesirable effects such as neurotoxicity were
Cellular pharmacokinetics of fludarabine observed in patients (see section 4.8).
triphosphate
Embryotoxicity
2F-ara-A is actively transported into leukaemic
cells, whereupon it is rephosphorylated to the The results from intravenous animal
monophosphate and subsequently to the di- and embryotoxicity studies in rats and rabbits
triphosphate. The triphosphate 2F-ara-ATP is indicated an embryolethal and teratogenic
the major intracellular metabolite and the only potential of fludarabine phosphate as manifested
metabolite known to have cytotoxic activity. in skeletal malformations, foetal weight loss and
Maximum 2F-ara-ATP levels in leukaemic post implantation loss. In view of the small
lymphocytes of CLL patients were observed at a safety margin between the teratogenic doses in
median of 4 hours and exhibited a considerable animals and the human therapeutic dose as well
variation with a median peak concentration of as in analogy to other antimetabolites which are
approximately 20 µM. 2F-ara-ATP levels in assumed to interfere with the process of
leukaemic cells were always considerably higher differentiation, the therapeutic use of
than maximum 2F-ara-A levels in the plasma Fludarabine is associated with a relevant risk of
indicating an accumulation at the target sites. In- teratogenic effects in humans (see section 4.6).
vitro incubation of leukaemic lymphocytes
Genotoxic potential, tumorigenicity
showed a linear relationship between
extracellular 2F-ara-A exposure (product of 2F- Fludarabine phosphate has been shown, to cause
ara-A concentration and duration of incubation) DNA-damage in a sister chromatid exchange
and intracellular 2F-ara-ATP enrichment. 2F- test, to induce chromosomal aberrations in an in
ara-ATP elimination from target cells showed vitro cytogenetic assay and to increase the rate
median half-life values of 15 and 23 hours. of micronuclei in the mouse micronucleus test in
vivo, but was negative in gene mutation assays
5.3 Preclinical safety data and in the dominant lethal test in male mice.
Systemic toxicity Thus, the mutagenic potential was demonstrated
in somatic cells but could not be shown in germ
In acute toxicity studies, single doses of cells.
fludarabine phosphate produced severe
intoxication symptoms or death at dosages about The known activity of fludarabine phosphate at
two orders of magnitude above the therapeutic the DNA-level and the mutagenicity test results
dose. As expected for a cytotoxic compound, the form the basis for the suspicion of a tumorigenic
bone marrow, lymphoid organs, gastrointestinal potential. No animal studies which directly
mucosa, kidneys and male gonads were affected. address the question of tumorigenicity have been
In patients, severe side effects were observed conducted, because the suspicion of an increased
closer to the recommended therapeutic dose risk of second tumours due to Fludarabine
(factor 3 to 4) and included severe neurotoxicity therapy can exclusively be verified by
partly with lethal outcome (see section 4.9). epidemiological data.
Systemic toxicity studies following repeated Local tolerance
administration of fludarabine phosphate showed
According to the results from animal
also the expected effects on rapidly proliferating
experiments following intravenous
tissues above a threshold dose. The severity of
administration of fludarabine phosphate, no
morphological manifestations increased with
remarkable local irritation has to be expected at
Fludarabine phosphate 25 mg/ ml Concentrate for Solution for Injection or Infusion SMPC, Taj Pharmaceuticals
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the injection site. Even in case of misplaced For storage conditions of the diluted medicinal
injections, no relevant local irritation was product, see section 6.3.
observed after paravenous, intraarterial, and
intramuscular administration of an aqueous 6.5 Nature and contents of container
solution containing 7.5 mg fludarabine 2 ml Type I glass vials with fluorotec rubber
phosphate/ml. stopper and an aluminium flip-off cap.
The similarity in nature of the observed lesions 2 ml-vials contain 50 mg fludarabine phosphate
in the gastrointestinal tract after intravenous or and are supplied in packs of 1, 5 and 10 vials.
intragastric dosing in animal experiments
supports the assumption that the fludarabine Not all pack sizes may be marketed.
phosphate induced enteritis is a systemic effect.
6.6 Special precautions for disposal and
6. PHARMACEUTICAL other handling
PARTICULARS • Dilution

6.1 List of excipients The required dose (calculated on the basis of the
patient's body surface) is drawn up into a
Mannitol syringe.

Disodium hydrogen phosphate dihydrate. For intravenous bolus injection this dose is
further diluted in 10 ml sodium chloride 9mg/ml
Water for Injection (0.9%). Alternatively, for infusion, the required
dose may be diluted in 100 ml sodium chloride
6.2 Incompatibilities
9mg/ml (0.9%) and infused over approximately
This medicinal product must not be mixed with 30 minutes.
other medicinal products except those mentioned
In clinical studies, the product has been diluted
in section 6.6
in 100 ml or 125 ml of 5 % dextrose injection or
6.3 Shelf life sodium chloride 9mg/ml (0.9%).
As packaged for sale: 2 years. • Inspection prior to use
Chemical and physical in-use stability has been The diluted solution is clear, colourless or
demonstrated at 0.2 mg/ml & 6.0 mg/ml after slightly brownish yellow. It should be visually
dilution with 0.9% Sodium chloride and 5% inspected before use.
Glucose Injection for 7 days at 2-8 °C and 5
Only clear, colourless or slightly brownish
days at 20 – 25 °C in non-PVC bags and Glass
bottles. yellow solutions without particles should be
used. Fludarabine phosphate Injection should
From a microbiological point of view, the not be used in case of a defective container.
product should be used immediately. If not used
• Handling and disposal
immediately, in-use storage times and conditions
prior to use are the responsibility of the user and Fludarabine should not be handled by pregnant
should not be longer than 24 hours at 2 to 8 °C staff.
unless dilution has taken place in controlled and
validated aseptic conditions. Procedures for proper handling should be
followed according to local requirements for
6.4 Special precautions for storage cytotoxic drugs.

Store in a refrigerator (2 - 8°C). Caution should be exercised in the handling and

preparation of the Fludarabine phosphate
Do not freeze. solution. The use of latex gloves and safety
glasses is recommended to avoid exposure in
Fludarabine phosphate 25 mg/ ml Concentrate for Solution for Injection or Infusion SMPC, Taj Pharmaceuticals
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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, spillage or waste material
should be disposed of in accordance with local
requirements.
7. MANUFACTURER:

Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)