FLUDARABIN EBEWE 50 MG2 ML

FULL PRESCRIBING INFORMATION

WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA,

AND PULMONARY TOXICITY

Fludarabine Phosphate Injection should be

administered under the supervision of a

qualified physician experienced in the use of

antineoplastic therapy. Fludarabine phosphate

can severely suppress bone marrow function.

When used at high doses in dose-ranging

studies in patients with acute leukemia,

fludarabine phosphate was associated with

severe neurologic effects, including blindness,

coma, and death. This severe central nervous

system toxicity occurred in 36% of patients

treated with doses approximately four times

greater (96 mg/m

2

/day for 5 to 7 days) than

the recommended dose. Similar severe central

nervous system toxicity has been rarely (<0.2%)

reported in patients treated at doses in the

range of the dose recommended for chronic

lymphocytic leukemia. [See Warnings and

Precautions (5.1)]

Instances of life-threatening and sometimes

fatal autoimmune hemolytic anemia have been

reported to occur after one or more cycles of

treatment with fludarabine phosphate. Patients

undergoing treatment with Fludarabine

Phosphate Injection should be evaluated and

closely monitored for hemolysis. [See Warnings

and Precautions (5.2)]

In a clinical investigation using fludarabine

phosphate in combination with pentostatin

(deoxycoformycin) for the treatment of

refractory chronic lymphocytic leukemia (CLL),

there was an unacceptably high incidence of

fatal pulmonary toxicity. Therefore, the use of

Fludarabine Phosphate Injection in combination

with pentostatin is not recommended. [See

Warnings and Precautions (5.6)]

1

INDICATIONS AND USAGE

Indication

Fludarabine Phosphate Injection is indicated

for 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. Fludarabine 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.

2

DOSAGE AND ADMINISTRATION

Chronic Lymphocytic Leukemia (CLL)

The recommended adult dose of Fludarabine

Phosphate Injection is 25 mg/m

diluted in

100 to 125 cc of 5% dextrose injection USP

or 0.9% sodium chloride USP administered

intravenously over a period of approximately

30 minutes daily for five consecutive days.

Each 5-day course of treatment should

commence every 28 days. Dosage may be

decreased or delayed based on evidence of

hematologic or nonhematologic toxicity.

Physicians should consider delaying or

discontinuing the drug if neurotoxicity

occurs.

A number of clinical settings may predispose to

increased toxicity from Fludarabine Phosphate

Injection. These include advanced age, renal

insufficiency, and bone marrow impairment.

Such patients should be monitored closely

for excessive toxicity and the dose modified

accordingly.

The optimal duration of treatment has not

been clearly established. It is recommended

that three additional cycles of Fludarabine

Phosphate Injection be administered following

the achievement of a maximal response and

then the drug should be discontinued.

Renal Impairment

Adult patients with moderate impairment

of renal function (creatinine clearance 30

to 70 mL/min/1.73 m

) should have a 20%

dose reduction of Fludarabine Phosphate

Injection. [See Warnings and Precautions

(5.7)]

Use of Infusion Solutions

Fludarabine Phosphate Injection contains

no antimicrobial preservative and should

be used within 8 hours of opening. Care

must be taken to assure sterility of infusion

solutions. Parenteral drug products should

be inspected visually for particulate matter

and discoloration prior to administration,

whenever solution and container permit.

3

DOSAGE FORMS AND STRENGTHS

50 mg/2 mL (25 mg/mL)

A clear, colorless or almost colorless, sterile solution

intended for intravenous administration

4

CONTRAINDICATIONS

None

5

WARNINGS AND PRECAUTIONS

Neurotoxicity

There are clear dose-dependent toxic effects

seen with fludarabine phosphate. Dose levels

approximately 4 times greater (96 mg/m

/day

for 5 to 7 days) than that recommended for

CLL (25 mg/m

/day for 5 days) were associated

with a syndrome characterized by delayed

blindness, coma and death. Symptoms

appeared from 21 to 60 days following the

last dose. Thirteen of 36 patients (36%) who

received fludarabine phosphate at high doses

(96 mg/m

/day for 5 to 7 days) developed this

severe neurotoxicity. This syndrome has been

reported rarely in patients treated with doses

in the range of the recommended CLL dose of

25 mg/m

/day for 5 days every 28 days. The

effect of chronic administration of fludarabine

phosphate on the central nervous system is

unknown; however, patients have received

the recommended dose for up to 15 courses

of therapy.

Hematological Adverse Reactions

Severe bone marrow suppression, notably

anemia, thrombocytopenia and neutropenia,

has been reported in patients treated with

fludarabine phosphate. In a Phase I study in

adult solid tumor patients, the median time

to nadir counts was 13 days (range, 3 to

25 days) for granulocytes and 16 days (range,

2 to 32 days) for platelets. Most patients

had hematologic 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 Injection requires

careful hematologic monitoring.

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.

Instances of life-threatening and sometimes

fatal autoimmune hemolytic anemia have

been reported to occur after one or more

cycles of treatment with fludarabine

phosphate in patients with or without a

previous history of autoimmune hemolytic

anemia or a positive Coombs’ test and who

may or may not be in remission from their

disease. Steroids may or may not be effective

in controlling these hemolytic episodes.

The majority of patients rechallenged

with fludarabine phosphate developed a

recurrence in the hemolytic process. The

mechanism(s) which predispose patients to

the development of this complication has

not been identified. Patients undergoing

treatment with Fludarabine Phosphate

Injection should be evaluated and closely

monitored for hemolysis.

Infections

Of the 133 adult CLL patients in the two

trials, there were 29 fatalities during study.

Approximately 50% of the fatalities were

due to infection and 25% due to progressive

disease.

Tumor Lysis Syndrome

Tumor lysis syndrome associated with

fludarabine phosphate treatment has been

reported in CLL patients with large tumor

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.

Use of Transfusions

Transfusion-associated graft-versus-host

disease has been observed rarely after

transfusion of non-irradiated blood in

fludarabine phosphate-treated patients.

Consideration should therefore be given

to the use of irradiated blood products in

those patients requiring transfusions while

undergoing treatment with Fludarabine

Phosphate Injection.

Pulmonary Toxicity

In a clinical investigation using fludarabine

phosphate in combination with pentostatin

(deoxycoformycin) for the treatment of

refractory chronic lymphocytic leukemia

(CLL) in adults, there was an unacceptably

high incidence of fatal pulmonary toxicity.

Therefore, the use of Fludarabine Phosphate

Injection in combination with pentostatin is

not recommended.

Renal Impairment

There are inadequate data on dosing of

patients with renal insufficiency. Fludarabine

Phosphate Injection must be administered

cautiously in patients with renal insufficiency.

The total body clearance of 2-fluoro-ara-A

has been shown to be directly correlated

with creatinine clearance. Patients with

moderate impairment of renal function

(creatinine clearance 30 to 70 mL/

min/1.73 m

) should have their fludarabine

phosphate dose reduced by 20% and be

monitored closely. Fludarabine phosphate is

not recommended for patients with severely

impaired renal function (creatinine clearance

less than 30 mL/min/1.73 m

). [See Dosage

and Administration (2.2)]

Monitoring

Hematologic and Nonhematologic

Toxicity

Fludarabine Phosphate Injection is an

antineoplastic agent with potentially

significant toxic side effects. Patients

undergoing therapy should be closely

observed for signs of hematologic and

nonhematologic toxicity. Periodic assessment

of peripheral blood counts is recommended

to detect the development of anemia,

neutropenia and thrombocytopenia.

Hematopoietic Suppression

During treatment, the patient’s hematologic

profile (particularly neutrophils and platelets)

should be monitored regularly to determine

the degree of hematopoietic suppression.

Pregnancy

Pregnancy Category D: Fludarabine phosphate

may cause fetal harm when administered to a

pregnant woman. Fludarabine phosphate was

teratogenic in rats and in rabbits. Fludarabine

phosphate was administered intravenously at

doses of 0, 1, 10 or 30 mg/kg/day to pregnant

rats on days 6 to 15 of gestation. At 10 and

30 mg/kg/day in rats, there was an increased

incidence of various skeletal malformations.

Fludarabine phosphate was administered

intravenously at doses of 0, 1, 5 or 8 mg/kg/

day to pregnant rabbits on days 6 to 15 of

gestation. Dose-related teratogenic effects

manifested by external deformities and

skeletal malformations were observed in the

rabbits at 5 and 8 mg/kg/day. Drug-related

deaths or toxic effects on maternal and

fetal weights were not observed. There are

no adequate and well-controlled studies in

pregnant women.

If Fludarabine Phosphate Injection is used

during pregnancy, or if the patient becomes

pregnant while taking this drug, the patient

should be apprised of the potential hazard to

the fetus. Women of childbearing potential

should be advised to avoid becoming

pregnant.

6

ADVERSE REACTIONS

Because clinical trials are conducted under widely

varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly

compared to rates in the clinical trials of another

drug and may not reflect the rates observed in

practice.

The most common adverse reactions include

myelosuppression (neutropenia, thrombocytopenia

and anemia), fever and chills, infection, and nausea

and vomiting. Other commonly reported events

include malaise, fatigue, anorexia, and weakness.

Serious opportunistic infections have occurred in

CLL patients treated with fludarabine phosphate.

The most frequently reported adverse reactions

and those reactions which are more clearly related

to the drug are arranged below according to body

system.

Hematopoietic Systems

Hematologic

events

(neutropenia,

thrombocytopenia, and/or anemia) were

reported in the majority of CLL patients

treated with fludarabine phosphate.

During fludarabine phosphate treatment

of 133 patients with CLL, the absolute

neutrophil count decreased to less than

500/mm

in 59% of patients, hemoglobin

decreased from pretreatment values by at

least 2 grams percent in 60%, and platelet

count decreased from pretreatment values

by at least 50% in 55%. Myelosuppression

may be severe, cumulative, and may affect

multiple cell lines. Bone marrow fibrosis

occurred in one CLL patient treated with

fludarabine phosphate.

Several instances of trilineage bone marrow

hypoplasia or aplasia resulting in pancytopenia,

sometimes resulting in death, have been

reported in post-marketing surveillance. 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.

Life-threatening and sometimes fatal

autoimmune hemolytic anemias have been

reported to occur in patients receiving

fludarabine phosphate. [See Warnings and

Precautions (5.2)] The majority of patients

rechallenged with fludarabine phosphate

developed a recurrence in the hemolytic

process.

Metabolic

Tumor lysis syndrome has been reported in CLL

patients treated with fludarabine phosphate.

This complication may include hyperuricemia,

hyperphosphatemia, hypocalcemia, metabolic

acidosis, hyperkalemia, hematuria, urate

crystalluria, and renal failure. The onset of

this syndrome may be heralded by flank pain

and hematuria.

Nervous System

Objective weakness, agitation, confusion,

visual disturbances, and coma have occurred

in CLL patients treated with fludarabine

phosphate at the recommended dose.

Peripheral neuropathy has been observed in

patients treated with fludarabine phosphate

and one case of wrist-drop was reported.

[See Warnings and Precautions (5.1)]

In post-marketing experience, cases of

progressive multifocal leukoencephalopathy

have been reported. Most cases had a

fatal outcome. Many of these cases were

confounded by prior and/or concurrent

chemotherapy. The median time to onset

was approximately one year.

Pulmonary System

Pneumonia, a frequent manifestation

of infection in CLL patients, occurred

in 16%, and 22% of those treated with

fludarabine phosphate in the MDAH and

SWOG studies, respectively. Pulmonary

hypersensitivity reactions to fludarabine

phosphate characterized by dyspnea, cough

and interstitial pulmonary infiltrate have been

observed.

In post-marketing experience, cases of

severe pulmonary toxicity have been

observed with fludarabine phosphate use

which resulted in ARDS, respiratory distress,

pulmonary hemorrhage, pulmonary fibrosis,

and respiratory failure. After an infectious

origin has been excluded, some patients

experienced symptom improvement with

corticosteroids.

Gastrointestinal System

Gastrointestinal disturbances such as nausea

and vomiting, anorexia, diarrhea, stomatitis

and gastrointestinal bleeding have been

reported in patients treated with fludarabine

phosphate.

Cardiovascular

Edema has been frequently reported.

One patient developed a pericardial

effusion possibly related to treatment with

fludarabine phosphate. No other severe

cardiovascular events were considered to

be drug-related.

Fludarabin “Ebewe“ 50 mg/2 ml

Solution for Injection/

Concentrate for Solution for Infusion

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information

needed to use Fludarabine Phosphate Injection

safely and effectively. See full prescribing

information for Fludarabine Phosphate

Injection.

WARNING: CNS TOXICITY, HEMOLYTIC

ANEMIA, AND PULMONARY TOXICITY

See full prescribing information for

complete boxed warning.

Severe central nervous system toxicity

occurred in 36% of patients treated with

doses approximately four times greater

(96 mg/m

2

/day for 5 to 7 days) than the

recommended dose. This toxicity was

seen in <0.2% of patients treated at the

recommended dose levels (25 mg/m

2

).

(5.1)

Instances of life-threatening and sometimes

fatal autoimmune hemolytic anemia have

been reported after one or more cycles of

treatment. (5.2)

In a clinical investigation of the combination

of fludarabine phosphate with pentostatin

(deoxycoformycin) for the treatment of

refractory chronic lymphocytic leukemia

(CLL), there was an unacceptably high

incidence of fatal pulmonary toxicity.

(5.6)

INDICATIONS AND USAGE

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. Fludarabine 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.

DOSAGE AND ADMINISTRATION

Chronic Lymphocytic Leukemia (CLL) (2.1):

The recommended adult dose is 25 mg/m

administered intravenously over a period of

approximately 30 minutes daily for five consecutive

days.

Each 5-day course of treatment should commence

every 28 days.

Renal Insufficiency (2.2):

Adult patients with moderate impairment

of renal function (creatinine clearance 30 to

70 mL/min/1.73 m

) should have 20% dose

reduction.

Not indicated in patients with severe renal

impairment.

Use of Infusion Solutions (2.3):

Fludarabine Phosphate Injection contains no

antimicrobial preservative and should be used

within 8 hours of opening. Care must be taken to

assure sterility of infusion solutions. Parenteral drug

products should be inspected visually for particulate

matter and discoloration prior to administration.

DOSAGE FORMS AND STRENGTHS

A 50 mg/2 mL (25 mg/mL), clear, colorless to almost

colorless, sterile solution intended for intravenous

administration.

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

Severe bone marrow suppression, notably anemia,

thrombocytopenia and neutropenia. Monitor blood

counts before and during treatment. (5.2)

Transfusion-associated graft-versus-host disease.

Use only irradiated blood products for transfusions.

(5.5)

Infections. Monitor for infection. (5.3)

Renal Insufficiency. Reduce dose for moderate renal

impairment and monitor closely. Do not administer

to patients with severe renal impairment. (5.7)

Tumor lysis syndrome (TLS). Take precautions for

patients at high risk for TLS. (5.4)

May cause fetal harm when administered to a

pregnant woman. Women should be advised to

avoid becoming pregnant. (5.9)

ADVERSE REACTIONS

Most common adverse reactions (incidence

>30%) include myelosuppression (neutropenia,

thrombocytopenia and anemia), fever, infection,

nausea and vomiting, fatigue, anorexia, cough and

weakness. (6)

DRUG INTERACTIONS

Fludarabine Phosphate Injection in combination

with pentostatin is not recommended due to the

risk of severe pulmonary toxicity. (5.6 and 7.1)

USE IN SPECIFIC POPULATIONS

Renal clearance represents approximately 40% of

the total body clearance. Patients with moderate

renal impairment (17 to 41 mL/min/m

) receiving

20% reduced fludarabine phosphate dose had a

similar exposure (AUC; 21 versus 20 nMh/mL)

compared to patients with normal renal function

receiving the recommended dose. (2.2, 5.7 and

8.6)

S e e

1 7

f o r

PAT I E N T

C O U N S E L I N G

INFORMATION.

FULL PRESCRIBING INFORMATION: CONTENTS*

INDICATIONS AND USAGE

Indication

DOSAGE AND ADMINISTRATION

Chronic Lymphocytic Leukemia (CLL)

Renal Impairment

Use of Infusion Solutions

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Neurotoxicity

Hematological Adverse Reactions

Infections

Tumor Lysis Syndrome

Use of Transfusions

Pulmonary Toxicity

Renal Impairment

Monitoring

Pregnancy

ADVERSE REACTIONS

Hematopoietic Systems

Metabolic

Nervous System

Pulmonary System

Gastrointestinal System

Cardiovascular

Genitourinary System

Skin

Adverse Reactions from Clinical Trials

DRUG INTERACTIONS

Pentostatin

USE IN SPECIFIC POPULATIONS

Pregnancy

Nursing Mothers

Pediatric Use

Patients with Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

12.2

Pharmacodynamics

12.3

Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment

of Fertility

14 CLINICAL STUDIES

14.1

Adults

14.2

Pediatrics

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1

How Supplied

16.2

Storage

16.3

Handling and Disposal

17 PATIENT COUNSELING INFORMATION

17.1

Monitoring

17.2

Laboratory Tests

17.3

Pregnancy

Sections or subsections omitted from the full

prescribing information are not listed.

782648–02

Genitourinary System

Hemorrhagic cystitis has been reported

in patients treated with fludarabine

phosphate.

Skin

Skin toxicity, consisting primarily of skin

rashes, has been reported in patients treated

with fludarabine phosphate.

Adverse Reactions from Clinical Trials

Data in Table 1 are derived from the

133 patients with CLL who received

fludarabine phosphate in the MDAH and

SWOG studies.

TABLE 1: PERCENT OF CLL PATIENTS

REPORTING NON-HEMATOLOGIC ADVERSE

REACTIONS

ADVERSE REACTIONS

MDAH

(N=101)

SWOG

(N=32)

ANY ADVERSE REACTION

Body as a whole

Fever

Chills

Fatigue

Infection

Pain

Malaise

Diaphoresis

Alopecia

Anaphylaxis

Hemorrhage

Hyperglycemia

Dehydration

72

84

Neurological

Weakness

Paresthesia

Headache

Visual disturbance

Hearing loss

Sleep disorders

Depression

Cerebellar syndrome

Impaired mentation

21

69

Pulmonary

Cough

Pneumonia

Dyspnea

Sinusitis

Pharyngitis

Upper respiratory

infection

Allergic pneumonitis

Epistaxis

Hemoptysis

Bronchitis

Hypoxia

35

69

Gastrointestinal

Nausea/vomiting

Diarrhea

Anorexia

Stomatitis

Gi bleeding

Esophagitis

Mucositis

Liver failure

Abnormal liver function

test

Cholelithiasis

Constipation

Dysphagia

46

63

Cutaneous

Rash

Pruritus

Seborrhea

17

18

Genitourinary

Dysuria

Urinary infection

Hematuria

Renal failure

Abnormal renal

Function test

Proteinuria

Hesitancy

12

22

Cardiovascular

Edema

Angina

Congestive heart failure

Arrhythmia

Supraventricular

tachycardia

Myocardial infarction

Deep venous thrombosis

Phlebitis

Transient ischemic attack

Aneurysm

Cerebrovascular accident

12

38

Musculosketal

Myalgia

Osteoporosis

Arthralgia

7

16

Tumor lysis syndrome

1

0

More than 3000 adult patients received

fludarabine phosphate in studies of other

leukemias, lymphomas, and other solid

tumors. The spectrum of adverse effects

reported in these studies was consistent with

the data presented above.

7

DRUG INTERACTIONS

Pentostatin

The use of Fludarabine Phosphate Injection

in combination with pentostatin is not

recommended due to the risk of severe

pulmonary toxicity. [See Warnings and

Precautions (5.6)]

8

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D. [See Warnings and

Precautions (5.9)]

Nursing Mothers

It is not known whether fludarabine

phosphate is excreted in human milk.

Because many drugs are excreted in human

milk and because of the potential for serious

adverse reactions including tumorigenicity in

nursing infants, a decision should be made

to discontinue nursing or discontinue the

drug, taking into account the importance

of the drug for the mother.

Pediatric Use

Data submitted to the FDA was insufficient

to establish efficacy in any childhood

malignancy.

Limited pharmacokinetic data for fludarabine

phosphate are available from a published

study of children (ages 1 to 21 years) with

refractory acute leukemias or solid tumors

(Children’s Cancer Group Study 097). When

fludarabine phosphate was administered as

a loading dose over 10 minutes immediately

followed by a 5-day continuous infusion,

steady-state conditions were reached early.

[See Clinical Studies (14.2)]

Patients with Renal Impairment

The total body clearance of the principal

metabolite 2-fluoro-ara-A correlated with

the creatinine clearance, indicating the

importance of the renal excretion pathway for

the elimination of the drug. Renal clearance

represents approximately 40% of the total

body clearance. Patients with moderate renal

impairment (17 to 41 mL/min/m

) receiving

20% reduced fludarabine phosphate dose had

a similar exposure (AUC; 21 versus 20 nMh/

mL) compared to patients with normal renal

function receiving the recommended dose.

The mean total body clearance was 172 mL/

min for normal and 124 mL/min for patients

with moderately impaired renal function.

10 OVERDOSAGE

High doses of fludarabine phosphate [See

Indications and Usage (1.1) and Warnings and

Precautions (5.1, 5.2)] have been associated with

an irreversible central nervous system toxicity

characterized 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.

11 DESCRIPTION

Fludarabine Phosphate Injection contains fludarabine

phosphate, a nucleotide metabolic inhibitor.

Fludarabine phosphate is a fluorinated nucleotide

analog of the antiviral agent vidarabine, 9-

arabinofuranosyladenine (ara-A), that is relatively

resistant to deamination by adenosine deaminase.

Each mL contains 25 mg of the active ingredient

fludarabine phosphate, 1.78 mg disodium phosphate

dihydrate, water for injection, qs; and sodium

hydroxide to adjust pH to 7.5. The pH range for the

final product is 7.3 to 7.7. Fludarabine Phosphate

Injection is a sterile solution intended for intravenous

administration.

The chemical name for fludarabine phosphate is

9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-

arabinofuranosyl)(2-fluoro-ara-AMP).

The molecular formula of fludarabine phosphate

is C

P (MW 365.2) and the structure is

provided in Figure 1

Figure 1: Chemical Structure of Fludarabine

Phosphate

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fludarabine

phosphate

rapidly

dephosphorylated to 2-fluoro-ara-A

and then phosphorylated intracellularly

by deoxycytidine kinase to the active

triphosphate, 2-fluoro-ara-ATP. This

metabolite appears to act by inhibiting DNA

polymerase alpha, ribonucleotide reductase

and DNA primase, thus inhibiting DNA

synthesis. The mechanism of action of this

antimetabolite is not completely characterized

and may be multi-faceted.

12.2 Pharmacodynamics

Phase I studies in humans have demonstrated

that fludarabine phosphate is rapidly

converted to the active metabolite, 2-fluoro-

ara-A, within minutes after intravenous

infusion.

12.3 Pharmacokinetics

Clinical pharmacology studies have focused

on 2-fluoro-ara-A pharmacokinetics. After

the five daily doses of 25 mg 2-fluoro-ara-

AMP/m

to cancer patients infused over

30 minutes, 2-fluoro-ara-A concentrations

show a moderate accumulation. During

a 5-day treatment schedule, 2-fluoro-

ara-A plasma trough levels increased by a

factor of about 2. The terminal half-life of

2-fluoro-ara-A was estimated as approximately

20 hours. In vitro, plasma protein binding of

fludarabine ranged between 19% and 29%.

A correlation was noted between the degree

of absolute granulocyte count nadir and

increased area under the concentration x

time curve (AUC).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment

of Fertility

No animal carcinogenicity studies with

fludarabine have been conducted.

Fludarabine phosphate was clastogenic

in vitro to Chinese hamster ovary cells

(chromosome aberrations in the presence

of metabolic activation) and induced sister

chromatid exchanges both with and without

metabolic activation. In addition, fludarabine

phosphate was clastogenic in vivo (mouse

micronucleus assay) but was not mutagenic to

germ cells (dominant lethal test in male mice).

Fludarabine phosphate was not mutagenic

to bacteria (Ames test) or mammalian cells

(HGRPT assay in Chinese hamster ovary cells)

either in the presence or absence of metabolic

activation.

Studies in mice, rats and dogs have

demonstrated dose-related adverse effects on

the male reproductive system. Observations

consisted of a decrease in mean testicular

weights in mice and rats with a trend toward

decreased testicular weights in dogs and

degeneration and necrosis of spermatogenic

epithelium of the testes in mice, rats and

dogs. The possible adverse effects on

fertility in humans have not been adequately

evaluated.

14 CLINICAL STUDIES

14.1 Adults

Two single-arm open-label studies of

fludarabine phosphate have been conducted

in adult patients with CLL refractory to at least

one prior standard alkylating agent-containing

regimen. In a study conducted by M.D.

Anderson Cancer Center (MDAH), 48 patients

were treated with a dose of 22 to 40 mg/m

daily for 5 days every 28 days. Another study

conducted by the Southwest Oncology Group

(SWOG) involved 31 patients treated with

a dose of 15 to 25 mg/m

daily for 5 days

every 28 days. The overall objective response

rates were 48% and 32% in the MDAH and

SWOG studies, respectively. The complete

response rate in both studies was 13%;

the partial response rate was 35% in the

MDAH study and 19% in the SWOG study.

These response rates were obtained using

standardized response criteria developed by

the National Cancer Institute CLL Working

Group and were achieved in heavily pre-

treated patients. The ability of fludarabine

phosphate to induce a significant rate of

response in refractory patients suggests

minimal cross-resistance with commonly

used anti-CLL agents.

The median time to response in the MDAH

and SWOG studies was 7 weeks (range of

1 to 68 weeks) and 21 weeks (range of 1 to

53 weeks), respectively. The median duration

of disease control was 91 weeks (MDAH)

and 65 weeks (SWOG). The median survival

of all refractory CLL patients treated with

fludarabine phosphate was 43 weeks and

52 weeks in the MDAH and SWOG studies,

respectively.

Rai stage improved to Stage II or better in

7 of 12 MDAH responders (58%) and in 5 of

7 SWOG responders (71%) who were Stage

III or IV at baseline. In the combined studies,

mean hemoglobin concentration improved

from 9.0 g/dL at baseline to 11.8 g/dL at the

time of response in a subgroup of anemic

patients. Similarly, average platelet count

improved from 63,500/mm

to 103,300/mm

at the time of response in a subgroup of

patients who were thrombocytopenic at

baseline.

14.2 Pediatrics

Fludarabine phosphate was evaluated in

62 pediatric patients (median age 10, range

1 to 21) with refractory acute leukemia

(45 patients) or solid tumors (17 patients).

The fludarabine phosphate regimen tested

for pediatric acute lymphocytic leukemia (ALL)

patients was a loading bolus of 10.5 mg/m

day followed by a continuous infusion of

30.5 mg/m

/day for 5 days. In 12 pediatric

patients with solid tumors, dose-limiting

myelosuppression was observed with a

loading dose of 8 mg/m

/day followed by a

continuous infusion of 23.5 mg/m

/day for

5 days. The maximum tolerated dose was

a loading dose of 7 mg/m

/day followed

by a continuous infusion of 20 mg/m

day for 5 days. Treatment toxicity included

bone marrow suppression. Platelet counts

appeared to be more sensitive to the effects

of fludarabine phosphate than hemoglobin

and white blood cell counts. Other adverse

reactions included fever, chills, asthenia, rash,

nausea, vomiting, diarrhea, and infection.

There were no reported occurrences of

peripheral neuropathy or pulmonary

hypersensitivity reaction.

15 REFERENCES

Preventing Occupational Exposures to

Antineoplastic and Other Hazardous Drugs

in Health Care Settings. NIOSH Alert 2004-

165.

OSHA Technical Manual, TED 1-0.15A, Section

VI: Chapter 2. Controlling Occupational

Exposure to Hazardous Drugs. OSHA, 1999.

http://www.osha.gov/dts/osta/otm/otm vi/

otm vi 2.html

American Society of Health-System

Pharmacists. ASHP guidelines on handling

hazardous drugs. Am J Health-Syst Pharm.

2006;63:1172-1193.

Polovich, M., White, J. M., & Kelleher, L.O.

(eds.) 2005. Chemotherapy and biotherapy

guidelines and recommendations for practice

(2nd. ed.) Pittsburgh, PA: Oncology Nursing

Society

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

50 mg/2 mL (25 mg/mL)

16.2 Storage

Store at 2° to 8°C.

16.3 3 years Shelf life

Shelf life after first opening: 28 days when

stored at 2-8°C and at 20-25°C without light

protection.

Shelf life after dilution: the dilution has

to take place in controlled and validated

aseptic conditions.

Only use clear and colorless solutions without

particles.

The maximum shelf life for the diluted drug

product at a concentration of 0.1 mg/ml up to

1.5 mg/ml can be stored at 2-8°C protected

from light as well as at 20-25°C with and

without light protection for 35 days.

The maximum shelf life for the drug product

diluted with saline solution at a concentration

of 0.1 mg/ml is 14 days.

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 2-8°C, unless dilution has

taken place in controlled and validated aseptic

conditions.

16.4 Handling and Disposal

Procedures for proper handling and disposal

should be considered. Consideration should

be given to handling and disposal according

to guidelines issued for cytotoxic drugs.

Several guidelines on this subject have been

published.

Caution should be exercised in

the handling and preparation of Fludarabine

Phosphate Injection 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

contacts the skin or mucous membranes,

wash thoroughly with soap and water; rinse

eyes thoroughly with plain water. Avoid

exposure by inhalation or by direct contact

of the skin or mucous membranes.

Manufactured by:

EBEWE Pharma Ges.m.b.H. Nfg.KG

A-4866 Unterach, AUSTRIA

Importer and License Holder:

Pharmalogic Ltd.,

P.O.B. 3838, Petah-Tikva 4951623

1-800-071-277

17 PATIENT COUNSELING INFORMATION

17.1 Monitoring

Patients should be informed of the importance

of periodic assessment of their blood count

to detect the development of anemia,

neutropenia and thrombocytopenia.

17.2 Laboratory Tests

During treatment, the patient’s hematologic

profile (particularly neutrophils, red blood

cells, and platelets) should be monitored

regularly to determine the degree of

hematopoietic suppression. [See Warnings

and Precautions (5.1)]

17.3 Pregnancy

Fludarabine phosphate may cause fetal harm

when administered to a pregnant woman.

Women should be advised to avoid becoming

pregnant. [See Warnings and Precautions

(5.9)]

The format of this leaflet was determined by the

Ministry of Health and its content was checked and

approved in February 2013.

FLUD SOL PHY SH 260614