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FLUDARABINE PHOSPHATE 25 MG/ML CONCENTRATE FOR SOLUTION FOR INJECTION OR INFUSION

Active substance(s): FLUDARABINE PHOSPHATE

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TEVA UK Ref:

Version:

231-30-86207-L LEA FLUDARABINE 25 MG/ML SOL TEVAH
1

06 August 2014

93.130.929-C

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
Infections
and
infestations

Neoplasms
benign,
malignant
and
unspecified
(incl cysts
and polyps)

Blood and
lymphatic
system
disorders

Very
Common
>1/10

Common
>1/100 to
<1/10

Infections /
Opportunistic
infections
(like latent
viral
reactivation,
e.g.
Progressive
multifocal
leucoencephalopathy,
Herpes zoster
virus
Epstein-Barrvirus),
Pneumonia

Uncommon
>1/1000 to
<1/100

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)
Neutropenia, MyelosupAnaemia,
pression
Thrombocytopenia

Not
Known

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
PACKAGE LEAFLET:
patients on doses four times greater than
INFORMATION FOR THE USER recommended blindness, coma and death
have been reported. Some of these
FLUDARABINE PHOSPHATE
symptoms appeared delayed around 60 days
25 mg/ml CONCENTRATE FOR or more after treatment has been stopped.
SOLUTION FOR INJECTION • If you notice any pain in your side,
blood in your urine or reduced amount
OR INFUSION
of urine: tell your doctor immediately.
Read all of this leaflet carefully before you
When your disease is very severe, your
start using this medicine.
body may not be able to clear all the
• Keep this leaflet. You may need to read it
waste products from the cells destroyed
again.
by Fludarabine. This is called tumour
• If you have any further questions, ask
lysis syndrome and can cause kidney
your doctor or pharmacist.
failure and heart problems from the first
• This medicine has been prescribed for
week of treatment. Your doctor will be
you. Do not pass it on to others. It may
aware of this and may give you other
harm them, even if their symptoms are
medicines to help prevent it.
the same as yours.
• If you need to have stem cells collected
• If you get any side effects, talk to your
and you are being treated with Fludarabine
doctor or pharmacist. This includes any
(or have been): tell your doctor.
possible side effects not listed in this
• If you need a blood transfusion and you
leaflet. See section 4.
are being treated with Fludarabine (or
have been): tell your doctor.
IN THIS LEAFLET:
In case you need a blood transfusion
1. What Fludarabine Phosphate 25 mg/ml
your doctor will ensure that you only
is and what it is used for
receive blood that has been treated by
2. Before Fludarabine Phosphate 25 mg/ml
irradiation. There have been severe
is administered to you
complications and even death, from
3. How Fludarabine Phosphate 25 mg/ml
transfusions of non-irradiated blood.
is administered
• If you notice any changes to your skin
4. Possible side effects
either while you are receiving this
5. How to store Fludarabine Phosphate
medicine or after you have finished the
25 mg/ml
therapy: tell your doctor.
6. Contents of the pack and other
• If you have or have had skin cancer it
information
may worsen or flare up again whilst
receiving Fludarabine therapy or
FLUDARABINE PHOSPHATE
1 WHAT
afterwards. You may develop skin cancer
25 mg/ml IS AND WHAT IT IS
during or after Fludarabine therapy.
USED FOR
Other things to consider, while you are
Fludarabine is a cytotoxic (anti-cancer
treated with Fludarabine:
medicine): medicines that inhibit the
• Men and women, who are fertile must
growth of cancer cells.
use effective contraception during
Fludarabine Phosphate 25 mg/ml is used to
treatment and for at least 6 months
treat chronic B-cell lymphocytic leukaemia
afterwards. It cannot be ruled out that
(B-CLL), in patients with sufficient healthy
Fludarabine may harm an unborn baby.
blood cells production. First treatment for
Your doctor will carefully weigh the
chronic lymphocytic leukaemia with
benefit of your treatment against a
Fludarabine phosphate should only be
possible risk for an unborn child and, if
started in patients with advanced disease
you are pregnant, will only treat you
having disease related symptoms or
with Fludarabine if clearly necessary.
evidence of disease progression.
• If you consider or are breast-feeding you
CLL is a cancer of the white blood cells
should not start it or continue while on
(called lymphocytes).
treatment with Fludarabine.
If you are diagnosed with CLL, too many
• If you need a vaccination, check with
lymphocytes are produced. They either
your doctor, because live vaccinations
don’t work properly or are too young
should be avoided during and after
(immature) to carry out the normal disease
treatment with Fludarabine.
fighting functions of white blood cells. If
• If you have kidney problems or if you
there are too many of these abnormal cells
are over 70, you will have regular blood
they push aside (displace) healthy blood
and/or laboratory tests to check your
cells in the bone marrow (where most new
kidney function. If your kidney problems
blood cells are formed). They also displace
are severe, you will not be given this
the healthy blood cells in the blood and
medicine at all (see also section 2, ‘Do not
organs. Without enough healthy blood cells,
use Fludarabine phosphate 25 mg/ml’ and
infections, anaemia, bruising, excessive
section 3 ‘How Fludarabine is
bleeding (haemorrhaging) or even organ
administered’).
failure can result.
• If you are over 75 years old, Fludarabine
phosphate 25 mg/ml will be given with
FLUDARABINE
2 BEFORE
caution.
PHOSPHATE 25 mg/ml IS
This medicine contains less than 1 mmol
ADMINISTERED TO YOU
sodium (23 mg) per ml, i.e. essentially
Do not use Fludarabine Phosphate
‘sodium-free’.
25 mg/ml:
Using other medicines
• If you are allergic (hypersensitive) to
Attention: the following remarks can also
fludarabine phosphate or any of the
apply to the use of medicines in the past or
other ingredients of the injection.
in the near future.
• If your kidney function is severely
The medicines mentioned in this section
reduced. Your doctor will decide, based
may be known to you under a different
on your kidney function whether
Fludarabine phosphate 25 mg/ml may or name, often the brand name. In this section
only the name of the active ingredient or
may not be used.
group of active ingredients of the medicine
• If you have a specific type of anaemia
is mentioned and not the brand name.
(decompensated haemolytic anaemia;
Therefore, check on the package or insert
this is a shortage of red blood cells). Your
what the active ingredient is of the
doctor will have told you if you have this
medicine you are using.
condition.
• If you are breast-feeding (see also Section Please tell your doctor if you are taking or
have recently taken any, including
“Pregnancy and breast-feeding”).
medicines obtained without a prescription.
Take special care with Fludarabine
Ask your doctor or pharmacist for advice
Phosphate 25 mg/ml:
before taking any medicine.
• If your bone marrow is not working
It is especially important to tell your doctor
properly or if you have a poorly
about:
functioning or depressed immune
system or a history of serious infections: • pentostatin (deoxycoformycin), also used
to treat B-CLL. Taking these two drugs
your doctor may decide to not give you
together can lead to severe lung problems.
this medicine, or may take precautions.
• dipyridamole, used to prevent excessive
• If you feel very unwell, notice any
blood clotting or other similar
unusual bruising, more bleeding than
substances. They may reduce the
usual after injury, or if you seem to be
effectiveness of Fludarabine
catching a lot of infections: tell your
• cytarabine (Ara-C) used to treat chronic
doctor if any of these apply before your
lymphatic leukaemia. If Fludarabine is
treatment.
combined with cytarabine, levels of the
• If during treatment you have a red to
active form of Fludarabine in leukaemic
brownish urine, or have a rash or any
cells may rise. However, the overall levels
blisters on your skin: tell your doctor
in the blood and its elimination from the
immediately. These may be signs of a
blood were not shown to have changed.
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.

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

TEVA UK Ref:

Version:

231-30-86207-L LEA FLUDARABINE 25 MG/ML SOL TEVAH
1

06 August 2014

93.130.929-C
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.







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
HOW FLUDARABINE PHOSPHATE
myeloid leukaemia. Most patients with
3 25
mg/ml IS ADMINISTERED
these conditions were previously, or at
the same time or later treated with other
Carefully follow the advice of your doctor
cancer drugs (alkylating agents,
when using Fludarabine Phosphate
topoisomerase inhibitors) or radiation
25 mg/ml. Your doctor will have decided
therapy)
when and how long Fludarabine Phosphate
• bone marrow depression
25 mg/ml will be given to you. Consult
(myelosuppression)
your doctor if you feel that Fludarabine
Phosphate 25 mg/ml is acting too strongly • severe loss of appetite leading to weight
loss (anorexia)
or not strongly enough.
• numbness or weakness in limbs
The administered amount of Fludarabine
(peripheral neuropathy)
Phosphate 25 mg/ml (the dose) depends
• disturbed vision
on the size of your body. Technically this is
• inflammation of the inside of the mouth
measured in square metres (m2), but actually
(stomatitis)
is calculated from your height and weight.
• skin rash
Fludarabine phosphate 25 mg/ml should be • swelling due to excessive fluid retention
used under the supervision of a qualified
(oedema)
doctor experienced in the use of anticancer • inflammation of the mucous coat of the
therapy.
digestive system from the mouth to the
anus (mucositis)
General guidance:
• chills
The usual dose is 25 mg/m2 body surface
• generally feeling unwell.
per day. This will be given either as an
injection or as an infusion for five
• Uncommon means between 1 and 10 in
consecutive days. This 5 day course of
every 1,000 patients are likely to get these:
treatment will be repeated every 28 days
• autoimmune disorder (see section 2,
until your doctor has decided that the best
‘Take special care with Fludarabine
possible effect has been achieved. In general
phosphate 25 mg/ml’)
this is after six cycles, in other words after
• tumour lysis syndrome (see section 2,
approximately 6 months. The dosage may
‘Take special care with Fludarabine
be decreased or the repeat course delayed
phosphate 25 mg/ml’)
if side effects are a problem.
• confusion
If you have kidney problems you will
• lung toxicity; scarring throughout the
receive a reduced dose and you will have
lungs (pulmonary fibrosis), inflammation
regular blood tests.
of the lungs (pneumonitis), shortness of
breath (dyspnoea)
The safety of this medicine in children has
• bleeding in the stomach or intestines
not been established.
• abnormal levels of the liver or pancreas
If you received too much Fludarabine
enzymes.
Phosphate 25 mg/ml
There is no specific antidote for Fludarabine • Rare means less than 10 in every 10,000
patients are likely to get these:
Phosphate 25 mg/ml overdosage. If you
• disorders of the lymph system due to a
have received too much Fludarabine
viral infection (EBV-associated
Phosphate 25 mg/ml, the doctor will stop
lymphoproliferative disorder)
the therapy and treat the symptoms.
• coma
High doses of Fludarabine Phosphate
• seizures
25 mg/ml have been associated with
• agitation
irreversible central nervous system side
• blindness
effects characterised by delayed blindness,
• inflammation or damage of the nerve of
coma, and death.
the eyes (optic neuritis; optic neuropathy)
High doses are also associated with severe
reduction in the number of certain types of • heart failure
• irregular heart beat (arrhythmia)
blood cells (severe thrombocytopenia
• skin cancer
(decreased number of platelets attended
with bruises and bleeding) and neutropenia • skin and/or mucous coat reaction with
redness, inflammation, blistering and
(decreased number of white blood cells
tissue break down (Lyell's syndrome,
attended with increased infection risk)) due
Stevens-Johnson syndrome)
to decreased activity of the bone marrow
• inflammation of the bladder, which can
(bone marrow suppression).
cause pain when passing urine, and can
If administration of Fludarabine Phosphate
lead to blood in the urine (haemorrhagic
25 mg/ml is forgotten.
cystitis).
Your doctor will set the times at which you
• Not known
are to receive this medicine. If you think
you may have missed a dose, contact your • Bleeding of the lungs (pulmonary
haemorrhage)
doctor as soon as possible.
• Bleeding into brain tissue (cerebral
haemorrhage).
4 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)

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.

5

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.

6

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

Autoimmune
disorder
(including
Autoimmune
haemolytic
anaemia,
Evans
syndrome,
Thrombocytopenic
purpura,
Acquired
haemophilia,
Pemphigus)

Immune
system
disorders

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

Cerebral
haemorrhage

Blindness,
Optic neuritis,
Optic
neuropathy

Cardiac
disorders

Heart
failure,
Arrhythmia

Respiratory,
thoracic and
mediastinal
disorders

Cough

Gastrointestinal
disorders

Vomiting,
Diarrhoea,
Nausea

Pulmonary
toxicity
(including
Pulmonary
fibrosis,
Pneumonitis,
Dyspnoea)
Stomatitis

Hepatobiliary disorders
Skin and
subcutaneous tissue
disorders

Rash

Pulmonary
haemorrhage

Gastrointestinal
haemorrhage,
Pancreatic
enzymes
abnormal
Hepatic
enzyme
abnormal
Skin cancer,
Necrolysis
epidermal
toxic (Lyell
type),
StevensJohnson
syndrome
Haemorrhagic
cystitis

Renal and
urinary
disorder

General
disorders
and
administration site
conditions

Coma,
Seizures,
Agitation

Fever,
Fatigue,
Weakness

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. 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-β-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 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 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 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 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 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 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:
Concentration

Stability for

Storage in

Medium

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

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

Glass
Bottle

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
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

86207-L

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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