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FLUDARAVIS 50 MG LYOPHILISATE FOR SOLUTION FOR INJECTION OR INFUSION

Active substance(s): FLUDARABINE PHOSPHATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Fludaravis 50mg Lyophilisate For Solution For Injection Or Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 50 mg fludarabine phosphate.
1ml of reconstituted solution contains 25 mg fludarabine phosphate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Powder for solution for injection or infusion.
White or almost white lyophilisate.

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 Fludaravis 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
Fludaravis should be administered under the supervision of a qualified
physician experienced in the use of antineoplastic therapy.
It is strongly recommended that Fludaravis 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. Each vial
is to be made up in 2 ml water for injection. Each ml of the resulting
reconstituted solution will contain 25 mg fludarabine phosphate. The required
dose (calculated on the basis of the patient's body surface) of the reconstituted
solution is drawn up into a syringe. For intravenous bolus injection this dose is
further diluted in10 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 Fludaravis be administered up to the achievement of
response (usually 6 cycles) and then the drug should be discontinued.
Hepatic impairment
No data are available concerning the use of fludarabine phosphate in patients
with hepatic impairment. In this group of patients, Fludaravis should be used
with caution and administered if the perceived benefit outweighs any potential
risk.
Renal impairment
Doses should be adjusted for patients with reduced renal 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 section 4.4. Fludaravis treatment is
contraindicated, if creatinine clearance is < 30 ml/min (see section 4.3).
Paediatric population
Fludarabine is not recommended for use in children and adolescents below age
18, due to a lack of data on safety and efficacy.
Geriatric population
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 (see also section 4.4).
4.3

Contraindications
Fludaravis is contraindicated
- in those patients who are hypersensitive to the active substance or any of the
excipients
- in renally impaired patients with creatinine clearance < 30 ml/min
- in patients with decompensated haemolytic anaemia
- during lactation.

4.4

Special warnings and precautions for use
Neurotoxicity
When used at high doses in dose-ranging studies in patients with acute
leukaemia, fludarabine phosphate was associated with severe neurological
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 with doses approximately four times greater (96
mg/m²/day for 5-7 days) than the dose recommended for treatment of CLL. In
patients treated at doses in the range of the dose recommended for CLL, 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. The effect of chronic administration of
fludarabine phosphate on the central nervous system is unknown. However,

patients tolerated the recommended dose, in some studies for relatively long
term treatment times, whereby up to 26 courses of therapy were administered.
Patients should be closely observed for signs of neurological side effects.
Impaired state of health
In patients with impaired state of health, Fludaravis 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.
Myelosuppression
Severe bone marrow suppression, notably anaemia, thrombocytopenia and
neutropenia, has been reported in patients treated with fludarabine phosphate.
In a Phase I study in solid tumour patients, the median time to nadir counts
was 13 days (range, 3 25 days) for granulocytes and 16 days (range, 2 32)
for platelets. Most patients had haematological 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 haematological monitoring.
Fludaravis is a potent antineoplastic agent with potentially significant toxic
side effects. Patients undergoing therapy should be closely observed for signs
of haematological and non-haematological 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
pancyopenia, sometimes resulting in death, have been reported in adult
patients. The duration of clinically significan cytopenia in the reported cases
has ranged fronm 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 sampling is considered.
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 patients treated with fludarabine
phosphate. Fatal outcome as a consequence of this disease has been reported
with a high frequency. Therefore, to minimize the risk, patients who require
blood transfusion and who are undergoing, or who have received, treatment
with Fludaravis should receive irradiated blood only.
Skin cancer
Reversible worsening or flare up of pre-existing skin cancer lesions as well as
new onset of skin cancer have been reported in some patients to occur during
or after fludarabine phosphate therapy.
Tumour lysis syndrome
Tumour lysis syndrome associated with fludarabine phosphate treatment has
been reported in CLL patients with large tumour burdens. Since fludarabine
phosphate 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.

Autoimmune impairment
Irrespective of any previous history of autoimmune processes or Coombs test
status, life-threatening and sometimes fatal autoimmune phenomena (e.g.
autoimmune haemolytic anaemia, autoimmune thrombocytopenia,
thrombocytopenic purpura, pemphigus, Evans' syndrome) (see section 4.8)
have been reported to occur during or after treatment with fludarabine
phosphate. The majority of patients experiencing haemolytic anaemia
developed a recurrence in the haemolytic process after rechallenge with
fludarabine phosphate. Patients treated with Fludaravis should be closely
monitored for signs of haemolysis.
Discontinuation of therapy with Fludaravis is recommended in case of
haemolysis. Blood transfusion (irradiated, see above) and adrenocorticoid
preparations are the most common treatment measures for autoimmune
haemolytic anaemia.
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).
Geriatric population
Since there are limited data for the use of fludarabine phoshpate in elderly
persons > 75 years), caution should be exercised with the administration of
Fludaravis 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.
Paediatric population
No data are available concerning the use of fludarabine phosphate in the
paediatric population. Therefore, treatment with Fludaravis in children and
adolescents below age 18 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 avaoid becoming pregnant while on fludarabine therapy.
Women of childbearing potential must be apprised of the potential hazard to
the foetus.
Contraception

Females 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 Fludaravis vaccination with live vaccines
should be avoided.
Retreatment options after initial fludarabine treatment
A crossover from initial treatment with fludarbine phoshpate to chlorambucil
for non responders to fludarabine phosphate should be avoided because most
patients who have been resistant to fludarabine phoshpate have shown
resistance to chlorambucil.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per ml after
reconstitution, i.e. essentially sodium free.
4.5

Interaction with other medicinal products and other forms of interaction
In a clinical investigation using fludarabine phosphate 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 Fludaravis in combination with
pentostatin is not recommended.
The therapeutic efficacy of fludarabine phosphate may be reduced by
dipyridamole and other inhibitors of adenosine uptake.
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 leukemic 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 embryo
toxicity studies in rats and rabbits indicated an embryo lethal 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 foetal 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 breastfed infants, fludarabine is contraindicated in nursing mothers.
4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.
Fludaravis may influence the ability to drive and use machines since fatigue,
weakness, agitation, seizures and visual disturbances has been observed.

4.8

Undesirable effects
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 fatigue, weakness, stomatitis, mucositis, malaise, anorexia,
oedema, chills, peripheral neuropathy, visual disturbances and skin rashes.
Serious opportunistic infections have occurred in patients treated with
fludarabine phosphate. 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 Very Common Common
≥ 1/100 to <1/10
Class
≥1/10
MedDRA

Uncommon
≥ 1/1000 to
<1/100

Rare
≥1/10,000 to
<1/1000

Not known

System Organ Very Common Common
≥ 1/100 to <1/10
Class
≥1/10
MedDRA

Uncommon
≥ 1/1000 to
<1/100

Infections and Infections /
Opportunistic
infestations
infections (like
latent viral
reactivation,e.g.
progressive
multifocal
leucoencephalo
pathy, Herpes
zoster virus,
Epstein-Barrvirus),
Pneumonia
Neoplasms
benign,
malignant
and
unspecified
(incl cysts and
polyps)

Blood and
lymphatic
system
disorders
Immune
system
disorders

Neutropenia,
anaemia,
thrombocytopenia

Rare
≥1/10,000 to
<1/1000
Lymphoproliferative
disorder (EBVassociated)

Myelodysplastic
syndrome and
acute myeloid
leukaemia
(mainly
associated with
prior, concomitant or subsequent treatment
with alkylating
agents, topoisomerase
inhibitors or
irradiation)
Myelosuppression

Autoimmune
disorder
(including
autoimmune
haemolytic
anaemia,
Evans
syndrome,
thrombocytopenic purpura,
acquired
haemophilia,
pemphigus)

Not known

System Organ Very Common Common
≥ 1/100 to <1/10
Class
≥1/10
MedDRA

Uncommon
≥ 1/1000 to
<1/100

Metabolism
and nutrition
disorders

Anorexia

Tumour lysis
syndrome
(including
renal failure,
metabolic
acidosis,
hyperkalaemia
hypocalcemia,
hyperuricemia,
haematuria,
urate
crystalluria,
hyperphosphatemia)

Nervous
system
disorders

Neuropathy
peripheral

Confusion

Eye disorders

Visual
disturbance

Not known

Coma,
seizures,
agitation

Cerebral
haemorrhage

Blindness,
optic neuritis,
optic neuropathy
Heart failure,
arrhythmia

Cardiac
disorders
Respiratory,
thoracic and
mediastinal
disorders

Cough

Gastrointestinal
disorders

Vomiting,
diarrhoea,
nausea

Hepatobiliary
disorders

Rare
≥1/10,000 to
<1/1000

Pulmonary
toxicity
(including
pulmonary
fibrosis,
pneumonitis,
dyspnoea)
Stomatitis

Gastrointestinal
haemorrhage,
pancreatic
enzymes
abnormal
Hepatic
enzyme
abnormal

Pulmonary
haemorrhage

System Organ Very Common Common
≥ 1/100 to <1/10
Class
≥1/10
MedDRA
Skin and
subcutaneous
tissue
disorders

Renal and
urinary
disorder
Fever, fatigue,
General
disorders and weakness
administration
site conditions

Uncommon
≥ 1/1000 to
<1/100

Rash

Rare
≥1/10,000 to
<1/1000

Not known

Skin cancer,
necrolysis
epidermal toxic
(Lyell type) ,
StevensJohnson
syndrome
Haemorrhagic
cystitis

Oedema,
mucositis, chills,
malaise

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.
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
4.9

Overdose
High doses of fludarabine phosphate 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 phosphate overdosage. Treatment consists of drug
discontinuation and supportive therapy.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents ATC-code L01B B05
Fludaravis contains fludarabine phosphate, a water-soluble fluorinated
nucleotide analogue of the antiviral agent vidarabine, 9 ß-Darabinofuranosyladenine (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 α/δ and ε, 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 phosphate vs. chlorambucil
(40mg / 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 phosphate
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 phosphate group. The median survival of the two patient groups
was 56.1 months for fludarabine phsophate 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 phosphate 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 phosphate 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 phosphate 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 phosphate group than in the chlorambucil group.
Patients who initially respond to fludarabine phosphate have a chance of
responding again to fludarabine phosphate monotherapy.
A randomised trial of fludarabine phosphate vs. cyclophosphamide,
adriamycin 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 phosphate compared to CAP (45% vs. 26% and 13% vs. 6%,
respectively); response duration and overall survival were similar with
fludarabine phosphate and CAP. Within the stipulated treatment period of 6
months the number of deaths was 9 (fludarabine phosphate) 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 phosphate 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
phosphate, 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 μM 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 µM 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 radiolabelled 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 µM. 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 2Fara-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
In acute toxicity studies, single doses of fludarabine phosphate produced
severe intoxication symptoms or death at dosages about two orders of
magnitude above the therapeutic dose. As expected for a cytotoxic compound,
the bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys and male
gonads were affected.
Systemic toxicity studies following repeated administration of fludarabine
phosphate showed also the expected effects on rapidly proliferating tissues
above a threshold dose. The severity of morphological manifestations
increased with dose levels and duration of dosing and the observed changes
were generally considered to be reversible. In principle, the available
experience from the therapeutic use of fludarabine phosphate points to a
comparable toxicological profile in humans, although additional undesirable
effects such as neurotoxicity were observed in patients (see section 4.8).
The results from animal embryotoxicity studies indicated a teratogenic
potential of fludarabine phosphate. In view of the small safety margin between
the teratogenic doses in animals and the human therapeutic dose as well as in
analogy to other antimetabolites which are assumed to interfere with the

process of differentiation, the therapeutic use of fludarabine phosphate is
associated with a relevant risk of teratogenic effects in humans (see section
4.6).
Fludarabine phosphate has been shown to induce chromosomal aberrations in
an in vitro cytogenetic assay, to cause DNA-damage in a sister chromatid
exchange test and to increase the rate of micronuclei in the mouse
micronucleus test in vivo, but was negative in gene mutation assays and in the
dominant lethal test in male mice. Thus, the mutagenic potential was
demonstrated in somatic cells but could not be shown in germ cells.
The known activity of fludarabine phosphate at the DNA-level and the
mutagenicity test results form the basis for the suspicion of a tumorigenic
potential. No animal studies which directly address the question of
tumorigenicity have been conducted, because the suspicion of an increased
risk of second tumours due to fludarabine phosphate therapy can exclusively
be verified by epidemiological data.
According to the results from animal experiments following intravenous
administration of fludarabine phosphate, no remarkable local irritation has to
be expected at the injection site. Even in case of misplaced injections, no
relevant local irritation was observed after paravenous, intraarterial, and
intramuscular administration of an aqueous solution containing 7.5 mg
fludarabine phosphate/ml.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Mannitol
Sodium hydroxide (for pH adjustment).

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products
except those mentioned in section 6.6.

6.3

Shelf life
Vial before opening:
4 years.
After reconstitution:
The physicochemical stability of the drug product after reconstitution in water
for injections has been demonstrated for 8 hours at 25°C ± 2°C/ 60% ± 5 %RH
and for 7 days at 5°C ± 3°C. 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.

6.4

Special precautions for storage
Store below 25°C.
For storage after reconstitution or dilution, see Section 6.3.

6.5.

Nature and contents of container
Colourless glass vial (type I) with bromobutylic rubber stopper and metallic
cap (aluminium) with polypropylene disk. Vial will be packed with or without
a protective plastic overwrap.
Pack sizes
1 x 50 mg vial
5 x 50 mg vial
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
Reconstitution
Fludaravis should be prepared for parenteral use by aseptically adding sterile
water for injection. When reconstituted with 2 ml of sterile water for injection,
the powder 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 - 8.2.
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 (see section 4.2).
Inspection prior to use
The reconstituted solution is clear and colourless. It should be visually
inspected before use.
Only clear and colourless solutions without particles should be used.
Fludaravis should not be used in case of a defective container.
Handling and disposal
Fludaravis 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
and preparation of the Fludaravis 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 for
cytotoxic agents.

7

MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf
Reykjavíkurvegur 76-78

IS-220 Hafnarfjörður
Iceland

8

MARKETING AUTHORISATION NUMBER(S)
PL 30306/0007

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/03/2008

10

DATE OF REVISION OF THE TEXT
18/11/2010

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Source: Medicines and Healthcare Products Regulatory Agency

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