FLUDARA

Israel - English - Ministry of Health

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Active ingredient:
FLUDARABINE PHOSPHATE 50 MG/VIAL
Available from:
SANOFI - AVENTIS ISRAEL LTD
ATC code:
L01BB05
Pharmaceutical form:
POWDER FOR SOLUTION FOR INJ/INF
Administration route:
I.V
Manufactured by:
GENZYME EUROPE B.V., NETHERLANDS
Therapeutic group:
FLUDARABINE
Therapeutic indications:
Palliative treatment of patients with CLL refractory to other therapy. Treatment of less malignant Non-Hodgkin lymphoma of stage 3 to 4 in patients who have not responded to standard therapy with at least one alkylating agent or in whom the disease progressed during or after standard therapy. Fludara is indicated for the initial treatment of patients with B- cell chronic lymphocytic leukaemia (CLL) or after first line therapy, in patients with sufficient bone marrow reserves.
Authorization number:
063272777400
Authorization date:
2009-02-01

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Fludara.

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. PHARMACEUTICALFORM

Powder for solution for injection or infusion.

White lyophilisate for reconstitution.

4. CLINICALPARTICULARS

4.1 Therapeuticindications

Palliative treatment of patients with CLL refractory to other therapy. Treatment of

less malignant Non-Hodgkin lymphoma of stage 3 to 4 in patients who have not

responded to standard therapy with at least one alkylating agent or in whom the

disease progressed during or after standard therapy. Fludara is indicated for the

initial treatment of patients with B- cell chronic lymphocytic leukaemia (CLL) or after

first line therapy, in patients with sufficient bone marrow reserves.

First line treatment with Fludara 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.

4.2Posology and method of administration

Posology

Adults

The recommended dose is 25 mg fludarabine phosphate/m² body surface area

given daily for 5 consecutive days every 28 days by intravenous route. Each vial

is to be made up in 2 ml water for injection. Each ml of the resulting solution will

contain 25 mg fludarabine phosphate (see also section 6.6).

The required dose (calculated on the basis of the patient‘s body surface area)

of the reconstituted solution is drawn up into a syringe. For intravenous bolus

injection this dose is further diluted in 10ml sodium chloride 9 mg/ml (0.9%).

Alternatively, for infusion, the required dose drawn up in a syringe may be diluted

in 100 ml sodium chloride 9 mg/ml (0.9%) and infused over approximately 30

minutes.

The duration of treatment depends on the treatment success and the tolerability

of the drug.

In CLL patients, Fludara should be administered up to the achievement of best

response (complete or partial remission, usually 6 cycles) and then the drug

should be discontinued.

Special populations

Patients with renal impairment

Doses should be adjusted for patients with reduced kidney function. If creatinine

clearance is between 30 and 70 ml/min, the dose should be reduced by up to

50% and close haematological monitoring should be used to assess toxicity (see

section 4.4).

Fludara treatment is contraindicated, if creatinine clearance is < 30 ml/min (see

section 4.3).

Patients with hepatic impairment

No data are available concerning the use of Fludara in patients with hepatic

impairment. In this group of patients, Fludara should be used with caution.

Paediatric population

The safety and efficacy of Fludara in children has not been established. Therefore,

Fludara is not recommended for use in children.

Elderly patients

Since there are limited data for the use of Fludara in elderly persons (> 75years),

caution should be exercised with the administration of Fludara in these patients.

In patients over the age of 65 years, creatinine clearance should be measured,

see ‘Patients with renal impairment’ and section 4.4.

Method of administration

Fludara should be administered under the supervision of a qualified physician

experienced in the use of antineoplastic therapy.

It is strongly recommended that Fludara should be only administered intravenously.

No cases have been reported in which paravenously administered Fludara led to

severe local adverse reactions. However, unintentional paravenous administration

must be avoided.

For instructions on reconstitution of the medicinal product before administration, see

section 6.6

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

- Lactation

4.4Special warnings and precautions for use

Myelosuppression

Severe bone marrow suppression, notably anaemia, thrombocytopenia and

neutropenia, has been reported in patients treated with Fludara. In a Phase I

intravenous study in adult solid tumour patients, the median time to nadir counts

was 13days (range 3 – 25 days) for granulocytes and 16days (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

Fludara. The majority of patients experiencing haemolytic anaemia developed

a recurrence in the haemolytic process after rechallenge with Fludara. Patients

treated with Fludara should be closely monitored for signs of haemolysis.

Discontinuation of therapy with Fludara is recommended in case of haemolysis.

Blood transfusion (irradiated, see below) and adrenocorticoid preparations are

the most common treatment measures for autoimmune haemolytic anaemia.

Neurotoxicity

The effect of chronic administration of Fludara 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 Fludara was associated with severe neurological effects,

including blindness, coma and death. Symptoms appeared from 21to 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 CLL, severe central nervous

system toxicity occurred rarely (coma, seizures and agitation) or uncommonly

(confusion) (see section 4.8).

In post-marketing experience neurotoxicity has been reported to occur earlier or

later than in clinical trials.

Tumour lysis syndrome

Tumour lysis syndrome has been reported in CLL patients with large tumour

burdens. Since Fludara 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

of non-irradiated blood in Fludara-treated patients. Fatal outcome as a

consequence of this disease has been reported with a high frequency. Therefore,

to minimise the risk of transfusion-associated graft-versus-host disease, patients

who require blood transfusion and who are undergoing, or who have received

treatment with Fludara 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 Fludara therapy.

Impaired state of health

In patients with impaired state of health, Fludara 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).

Fludara 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). Fludara treatment is

contraindicated if creatinine clearance is < 30ml/min (see section 4.3).

The elderly

Since there are limited data for the use of Fludara in elderly persons (> 75years),

caution should be exercised with the administration of Fludara in these patients

(see also section 4.2).

In patients aged 65 years or older, creatinine clearance should be measured

before start of treatment, see “Renal impairment” and section 4.2.

Pregnancy

Fludara 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 foetal harm (see sections 4.6 and 5.3). Prescribers may only

consider the use of Fludara, if the potential benefits justify the potential risks to the

foetus.

Women should avoid becoming pregnant while on Fludara 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 Fludara vaccination with live vaccines should be

avoided.

Retreatment options after initial Fludara treatment

A crossover from initial treatment with Fludara to chlorambucil for non responders

to Fludara should be avoided because most patients who have been resistant to

Fludara have shown resistance to chlorambucil.

Excipients

Each vial Fludara 50 mg powder for solution for injection/infusion contains less

than 1 mmol sodium (23 mg), i.e. essentially ‘sodium-free’.

4.5Interaction with other medicinal products and other forms of interaction

In a clinical investigation using intravenous Fludara 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 Fludara in combination with pentostatin is not recommended.

Dipyridamole and other inhibitors of adenosine uptake may reduce the therapeutic

efficacy of Fludara.

Clinical studies and in vitro experiments showed that during use of Fludara 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.

4.6Pregnancy and lactation

Fertility

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).

Pregnancy

Pre-clinical data in rats demonstrated a transfer of Fludara and/or metabolites

through the placenta. The results from intravenous embryotoxicity studies in rats

and rabbits indicated an embryolethal and teratogenic potential at the therapeutic

doses (see section 5.3).

There are very limited data of Fludara use in pregnant women in the first trimester:

Fludara 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). Fludara

has the potential to cause foetal harm. Prescribers may only consider the use of

Fludara 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.

However, there is evidence from preclinical data that fludarabine phosphate and

its metabolites transfer from maternal blood to milk.

Because of the potential for serious adverse reactions to Fludara in breast-fed

infants, Fludara is contraindicated in nursing mothers (see section 4.3).

4.7Effects on ability to drive and use machines

Fludara 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 Undesirableeffects

Based on the experience with the use of Fludara, 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 Fludara.

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 Fludara. The rare adverse reactions were mainly identified from the

post-marketing experience.

System Organ

Class VeryCommon

>1/10 Common

>1/100

to<1/10 Uncommon

>1/1000

to<1/100 Rare

>1/10,000

to<1/1000 Not Known

Infections and

infestations Infections /

Opportunistic

infections (like

latent viral

reactivation,

e.g. Progressive

multifocal leuko-

encephalopathy,

Herpes zoster virus

Esptein-Barr-virus),

pneumonia Lymphoproliferative

disorder

(EBV associated)

Neoplasms

benign,

malignant and

unspecified

(incl cysts and

polyps) Myelodysplastic

syndrome and

Acute Myeloid

Leukaemia (mainly

associated with

prior, concomitant

or subsequent

treatment with

alkylating agents,

topoisomerase

inhibitors or

irradiation)

Blood and

lymphatic

system

disorders Neutropenia,

anaemia,

thrombocytopenia Myelosuppression

Immune system

disorders Autoimmune

disorder (including

Autoimmune

haemolytic

anaemia, Evan’s

syndrome,

Thrombocytopenic

purpura, Acquired

haemophilia

Pemphigus)

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System Organ

Class VeryCommon

>1/10 Common

>1/100

to<1/10 Uncommon

>1/1000

to<1/100 Rare

>1/10,000

to<1/1000 Not Known

Metabolism

and nutrition

disorders Anorexia Tumour lysis

syndrome

(including

renal failure,

metabolic acidosis,

hyperkalaemia,

hypocalcaemia,

hyperuricaemia,

haematuria, urate

crystalluria, hyper-

phosphataemia)

Nervous system

disorders Peripheral

neurophathy Confusion Coma, seizures,

agitation Cerebral

haemorrhage

Eye disorders Visual disturbances Blindness, optic

neuritis, optic

neuropathy

Cardiac

disorders Heart failure,

arryhthmia

Respiratory,

thoracic and

mediastinal

disorders Cough Pulmonary

toxicity (including

pulmonary fibrosis,

pneumonitis,

dyspnoea) Pulmonary

haemorrhage

Gastrointestinal

disorders Vomiting, diarrhoea,

nausea Stomatitis Gastrointestinal

haemorrhage,

pancreatic enzymes

abnormal

Hepatobiliary

disorders Hepatic enzymes

abnormal

Skin and

subcutaneous

tissue disorders Rash Skin cancer,

necrolysis

epidermal toxic

(Lyell type)

Stevens-Johnson

syndrome

Renal and

urinary disorder Haemorrhagic

cystitis

General

disorders and

administration

site conditions 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 Fludara have been associated with 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 Fludara overdosage. Treatment consists of

drug discontinuation and supportive therapy.

5. PHARMACOLOGICALPROPERTIES

5.1 Pharmacodynamicproperties

Pharmacotherapeutic group: Antineoplastic agents, purine analogues

ATC-code L01B B05

Fludara contains fludarabine phosphate, a water-soluble fluorinated nucleotide

analogue of the antiviral agent vidarabine, 9-ß-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 polymeraseα/δandε, 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 Fludara 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 1 st line treatment with Fludara 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 Fludara group. The median survival of the two patient groups

was 56.1 months for Fludara 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 Fludara 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 Fludara 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 Fludara 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 Fludara group than

in the chlorambucil group.

Patients who initially respond to Fludara have a chance of responding again to

Fludara monotherapy.

A randomised trial of Fludara 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 Fludara compared to CAP (45% vs.

26% and 13% vs. 6%, respectively); response duration and overall survival were

similar with Fludara and CAP. Within the stipulated treatment period of 6 months

the number of deaths was 9 (Fludara) 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 Fludara and CAP in favour of

CAP in the subgroup of pretreated Binet stage C patients.

5.2 Pharmacokineticproperties

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 and after peroral dosing of fludarabine phosphate (Fludara,

2F-ara-AMP).

No clear correlation was found between 2F-ara-A pharmacokinetics and treatment

efficacy in cancer patients.

However, occurrence of neutropenia and haematocrit changes indicated that the

cytotoxicity of fludarabine phosphate depresses the haematopoiesis in a dose-

dependent manner.

Distribution and metabolism

2F-ara-AMP is a water-soluble prodrug of fludarabine (2F-ara-A), which is rapidly

and quantitatively dephosphorylated in the human organism to the nucleoside

fludarabine (2F-ara-A).

Another metabolite, 2F-ara-hypoxanthine, which represents the major metabolite

in the dog, was observed in humans only to a minor extent.

After single dose infusion of 25 mg 2F-ara-AMP per m² to CLL 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 approximately 5 minutes, an

intermediate half-life of 1 - 2 hours and a terminal half-life of approximately 20

hours.

An inter-study 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 inter-individual variability. After intravenous and peroral administration of

fludarabine phosphate plasma levels of 2F-ara-A and areas under the plasma

level time curves increased linearly with the dose, whereas half-lives, plasma

clearance and volumes of distribution remained constant independent of the dose

indicating a dose linear behavior.

Elimination

2F-ara-A elimination is largely by renal excretion. 40 to 60 % of the administered

intravenous dose was excreted in the urine. Mass balance studies in laboratory

animals with ³H-2F-ara-AMP showed a complete recovery of radio-labelled

Characteristics in patients

Individuals with impaired renal function exhibited a reduced total body clearance,

indicating the need for a dose reduction. In vitro investigations with human plasma

proteins revealed no pronounced tendency of 2F-ara-A protein binding.

Cellular pharmacokinetics of fludarabine triphosphate

2F-ara-A is actively transported into leukaemic cells, whereupon it is

rephosphorylated to the monophosphate and subsequently to the di- and

triphosphate. The triphosphate 2F-ara-ATP is the major intracellular metabolite and

the only metabolite known to have cytotoxic activity. Maximum 2F-ara-ATP levels in

leukaemic lymphocytes of CLL patients were observed at a median of 4 hours and

exhibited a considerable variation with a median peak concentration of approximately

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 15and 23hours.

5.3Preclinical safety data

Systemictoxicity

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. In patients, severe side effects were observed closer to the

recommended therapeutic dose (factor 3 to 4) and included severe neurotoxicity

partly with lethal outcome (see section 4.9).

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 Fludara points to a comparable toxicological profile in humans,

although additional undesirable effects such as neurotoxicity were observed in

patients (see section 4.8).

Embryotoxicity

The results from intravenous animal embryotoxicity studies in rats and rabbits

indicated an embryolethal and teratogenic potential of fludarabine phosphate as

manifested in skeletal malformations, foetal weight loss and post implantation

loss. 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 Fludara is associated with a relevant risk of teratogenic effects in humans

(see section 4.6).

Genotoxic potential, tumorigenicity

Fludarabine phosphate has been shown, to cause DNA-damage in a sister

chromatid exchange test, to induce chromosomal aberrations in an in vitro

cytogenetic assay 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 Fludara therapy can exclusively be verified by epidemiological

data.

Local tolerance

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.

The similarity in nature of the observed lesions in the gastrointestinal tract

after intravenous or intragastric dosing in animal experiments supports the

assumption that the fludarabine phosphate induced enteritis is a systemic

effect.

6. PHARMACEUTICALPARTICULARS

6.1List of excipients

Mannitol

Sodium hydroxide (to adjust the pH to 7.7).

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed

with other medicinal products.

6.3Shelflife

As packaged for sale: 3 years.

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 should not be longer than 24hours at 2 to 8 °C or

8 hours at room temperature

6.4Special precautions for storage

Store at room temperature, below 30°C.

For storage conditions of the reconstituted or diluted medicinal product,

see section 6.3.

6.5Nature and contents of container

10ml colourless Type I glass vials containing 50 mg fludarabine phosphate.

Each package contains 5 vials.

6.6Special precautions for disposal

Reconstitution

Fludara 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 15seconds 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 10ml sodium chloride

9mg/ml (0.9%). Alternatively, for infusion, the required dose may be diluted in 100

ml sodium chloride 9mg/ml (0.9%) and infused over approximately 30 minutes.

In clinical studies, the product has been diluted in 100 ml or 125 ml of 5 %

dextrose injection or sodium chloride 9mg/ml (0.9%).

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. Fludara

should not be used in case of a defective container.

Handling and disposal

Fludara 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 Fludara

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, spillage or

waste material should be disposed of in accordance with local requirements.

7.MANUFACTURER

Genzyme Europe BV

The Netherlands

8.LICENSE NUMBER

063 -27-27774-00

9. REGISTRATIONHOLDER

Sanofi-Aventis Israel ltd. 10Beni Gaon, POB 8090, Netanya

The format of this leaflet has been determined by the Ministry of Health and the

content thereof has been checked and approved – June 2011.

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