Included as part of the PRECAUTIONS section.
There are clear dose dependent toxic effects seen with
fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m²/day
for 5 to 7 days) than that recommended for CLL (25 mg/m²/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/m²/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/m²/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
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.
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
Use Of Transfusions
Transfusion-associated graft-versus-host disease has been
observed rarely after transfusion of nonirradiated 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.
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
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 m²) 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 m²). [See DOSAGE AND ADMINISTRATION]
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.
During treatment, the patient's hematologic profile
(particularly neutrophils and platelets) should be monitored regularly to determine
the degree of hematopoietic suppression.
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal carcinogenicity studies with fludarabine have
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.
Use In Specific Populations
Pregnancy Category D. [See WARNINGS AND PRECAUTIONS]
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.
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]
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/m²) receiving 20% reduced
fludarabine phosphate dose had a similar exposure (AUC; 21 versus 20 nM·h/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.