5.1 Neurologic
Toxicities
Additions and/or
revisions underlined:
Severe central nervous system
(CNS) adverse reactions, including coma, seizures, agitation and confusion, can
occur in patients treated with Fludarabine Phosphate
Injection. CNS adverse
reactions may occur either early or
late after the initiation of Fludarabine Phosphate Injection (range 7 to 225
days).
CNS adverse reactions are dose dependent
and occur at greater incidence
and severity in patients treated
at doses higher than the recommended dose of Fludarabine Phosphate
Injection [see Overdosage (10)].
Monitor patients for signs and symptoms
of neurologic toxicity
during and after treatment with Fludarabine
Phosphate Injection. Consider delaying or discontinuing Fludarabine Phosphate
Injection if neurotoxicity occurs. Do not administer Fludarabine Phosphate
Injection at doses higher than the recommended dose.
Advise patients that Fludarabine Phosphate Injection may reduce the ability to drive or use mechanical equipment, since fatigue,
weakness, visual disturbances, confusion, agitation, or seizures may
occur.
5.2
Myelosuppression
Subsection title revised
Additions and/or
revisions underlined:
Fludarabine phosphate can
cause severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia, or anemia. Cases
of trilineage bone marrow hypoplasia or aplasia resulting
in pancytopenia, sometimes
resulting in death, have been reported.
The
median time to nadir of counts was approximately 13 days (range,
3 to 25 days) for granulocytes and 16 days (range, 2
to 32 days) for platelets. The duration of the cytopenia in reported
cases has ranged from approximately 2 months to approximately 1 year.
Monitor complete blood counts at
baseline, prior to and during each treatment cycle, and as clinically needed.
Consider dosage delays,
dose reductions, or permanent discontinuation if recovery has not occurred
by the first day of the next scheduled cycle.
5.3 Autoimmune
Cytopenias
Subsection title revised
Additions and/or
revisions underlined:
Life-threatening and fatal
autoimmune hemolytic anemia, autoimmune thrombocytopenia/idiopathic thrombocytopenic purpura
(ITP), Evans syndrome, and acquired hemophilia can occur in patients treated
with fludarabine phosphate with or without a previous history of
autoimmune hemolytic anemia or a positive Coombs' test.
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.
Closely monitor
patients during treatment with Fludarabine Phosphate
Injection for autoimmune cytopenias and manage
as clinically indicated.
5.4 Transfusion
Associated Graft-Versus-Host Disease
Additions and/or
revisions underlined:
Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in
patients treated with fludarabine phosphate. Fatal outcome as a
consequence of this disease has been reported. 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 Phosphate Injection should receive irradiated blood only.
5.5
Tumor Lysis Syndrome
Subsection title revised
Additions and/or
revisions underlined:
Tumor lysis syndrome (TLS) can occur in patients
treated with Fludarabine Phosphate Injection. TLS has been reported in
patients with CLL who have large tumor burdens and can occur as early as the
first week of treatment. Closely monitor patients at risk for TLS, consider
appropriate prophylaxis including hydration, and manage as clinically
indicated.
5.6
Pulmonary Toxicity in Patients with CLL When Fludarabine Phosphate is Used with
Pentostatin
Subsection title revised
Additions and/or
revisions underlined:
In
clinical trials, patients experienced fatal pulmonary toxicity when treated
with fludarabine phosphate and pentostatin for refractory CLL. Avoid concomitant use of Fludarabine Phosphate Injection with pentostatin [see
Drug Interactions (7.1)].
5.8
Embryo-Fetal Toxicity
Subsection title revised
Additions and/or
revisions underlined:
Based on findings in animals and
its mechanism of action, Fludarabine Phosphate
Injection can cause fetal harm when administered to a pregnant
woman. In animal reproduction studies, administration of fludarabine
phosphate to pregnant animals during organogenesis resulted in adverse
developmental outcomes, including embryo-fetal mortality and structural
abnormalities at maternal doses below (rabbits) and above (rats) those in
patients at the recommended human dose. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive
potential to use effective contraception during treatment with Fludarabine
Phosphate Injection and for 6 months after the last dose. Advise males with
female partners of reproductive potential to
use effective contraception during treatment with Fludarabine Phosphate
Injection and for 3 months after the last
dose [see Use in Specific Populations
(8.1)]
6.1 Clinical
Trials Experience
Extensive changes;
please refer to label for complete information
6.2 Postmarketing
Experience
Additions and/or
revisions underlined:
The following adverse reactions
have been identified during postapproval use of fludarabine phosphate. Because these
reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Blood and Lymphatic: Bone marrow hypoplasia or aplasia resulting in pancytopenia (range: 2 months to 12 months
after treatment initiation; some fatal); myelodysplastic syndrome and acute myeloid leukemia
Infection: Progressive multifocal leukoencephalopathy (range:
3 weeks to one year after treatment initiation; some fatal)
Pulmonary:
Acute Respiratory Distress
Syndrome (ARDS), respiratory distress, pulmonary hemorrhage, pulmonary fibrosis,
pneumonitis, respiratory failure
8.1 Pregnancy
Additions and/or
revisions underlined:
Risk Summary
Based on findings in animals and
its mechanism of action [see Clinical
Pharmacology (12.1)], Fludarabine Phosphate Injection can cause
fetal harm when administered to a pregnant woman. There are no available
data on Fludarabine Phosphate Injection use in pregnant women to evaluate for a
drug-associated risk. In animal reproduction
studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental
outcomes, including embryo-fetal mortality and structural abnormalities at
maternal doses below (rabbits) and above (rats) those in patients at the
recommended human dose (see Data). Advise pregnant women of the potential risk
to a fetus.
In the U.S. general
population, the estimated
background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%
to 4% and 15% to 20%, respectively.
Data
Animal Data
In
rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times
the recommended human intravenous dose (25 mg/m2)
administered during organogenesis caused an increase in resorptions, skeletal
and visceral malformations (cleft palate, exencephaly, and fetal vertebrae
deformities) and decreased fetal body weights.
Maternal toxicity was not apparent at 2.4 times the human intravenous
dose, and was limited to slight body weight decreases at 7.2 times the human intravenous
dose. In rabbits, repeated
intravenous doses of fludarabine phosphate at 3.8 times the human intravenous
dose administered during organogenesis increased embryo and fetal lethality as
indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations
including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the
digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib
anomalies were seen in all dose levels (greater than or equal to 0.5 times
the human intravenous dose).
8.2 Lactation
Additions and/or
revisions underlined:
Risk Summary
There are no data on the presence of
fludarabine phosphate or
its metabolites in human milk, the effects
on the breastfed child, or the
effects on milk production. Because of the potential for serious
adverse reactions in the breastfed child, advise patients that breastfeeding
is not recommended during treatment with Fludarabine Phosphate Injection,
and for 1 week after the last dose.
8.3 Females and
Males of Reproductive Potential
Newly added
subsection:
Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant
woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify
pregnancy status in females of reproductive potential
prior to initiation of Fludarabine Phosphate Injection [see Use in Specific Populations (8.1)].
Contraception
Females
Advise female patients of reproductive potential
to use effective contraception during
treatment with Fludarabine
Phosphate Injection and for 6 months after the last dose.
Males
Based on genotoxicity findings,
advise males with female partners of reproductive potential to use effective
contraception during treatment with Fludarabine Phosphate
Injection and for 3 months
after the last dose [see
Nonclinical Toxicology (13.1)].
Infertility
Males
Based on findings in animals and
humans, Fludarabine Phosphate Injection may impair male fertility. Fludarabine
phosphate may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The reversibility of this effect
is unknown [see Nonclinical Toxicology (13.1)].
8.4
Pediatric Use
Additions and/or
revisions underlined:
The safety and effectiveness of Fludarabine Phosphate Injection have not been established in
pediatric patients.
Safety and effectiveness were assessed, but not established for Fludarabine Phosphate Injection in pediatric patients 1 year to < 17 years
with refractory acute leukemia or solid tumors. No new safety signals were
observed in pediatric patients across these studies.
8.5
Geriatric Use
Additions and/or
revisions underlined:
Among patients with CLL evaluated in two randomized
active-controlled trials treated with fludarabine, cyclophosphamide, and
rituximab, 36% were 65 years of age or older; of these, 15% were 70
years of age or older. The incidence
of Grade 3 and 4 adverse reactions was higher among patients receiving
fludarabine in combination with cyclophosphamide and rituximab who were 70 years or older compared
to younger patients for neutropenia, febrile
neutropenia, anemia, thrombocytopenia, pancytopenia, and infections.
Clinical studies of fludarabine as a single agent for
patients with B-cell CLL did not include a sufficient numbers of younger adults
to determine if patients with B-cell CLL who are 65 years of age and older respond
differently from younger adults.
8.6 Renal Impairment
Additions and/or
revisions underlined:
Reduce the dosage in patients with CLcr 30 to 79 mL/min. A dosage has not been established for patients with severe renal impairment (CLcr < 30
mL/min) [see Dosage and Administration
(2.2)].
The total body clearance of
2-fluoro-ara-A is correlated with the creatinine clearance [see Clinical Pharmacology (12.3)]; however, the effect of varying degrees
of renal impairment on the pharmacokinetics of this metabolite has not been fully characterized.
Additions and/or
revisions underlined:
Neurologic Toxicities
Inform patients
that Fludarabine Phosphate Injection can cause severe CNS adverse reactions, including coma,
seizures, agitation, and confusion. Advise patients of the risk of engaging in
any activity where sudden loss of consciousness could cause serious harm to
themselves or others. Inform patients to contact their healthcare provider
immediately if they experience signs or symptoms of CNS adverse reactions [see Warnings and Precautions (5.1)].
Myelosuppression
Inform patients
Fludarabine Phosphate Injection can cause a decrease in white blood cells,
platelets, and red blood cells, and the need for
frequent monitoring of blood counts.
Advise patients to report shortness of breath,
significant fatigue, bleeding, fever, or other signs of infection [see Warnings
and Precautions (5.2) and Adverse Reactions (6.1)].
Autoimmune
Cytopenias
Inform patients that Fludarabine Phosphate Injection
can cause autoimmune hemolytic anemia, autoimmune thrombocytopenia/ITP, Evans syndrome, and acquired hemophilia. Advise patients to seek immediate
medical attention if any signs or symptoms of autoimmune cytopenias
occur [see Warnings and Precautions (5.3)].
Tumor Lysis Syndrome
Inform patients about the risk of and the signs and symptoms of tumor lysis
syndrome. Advise patients
to notify their healthcare
provider if they experience these symptoms [see
Warnings and Precautions (5.5)].
Vaccination
Advise patients
they should avoid
vaccinations with live vaccines during
and after treatment
[see Warnings and
Precautions (5.7)].
Nausea and Vomiting
Advise patients
that Fludarabine Phosphate
Injection may cause nausea and/or vomiting. Inform
patients to report nausea and
vomiting so that symptomatic treatment may be provided when this occurs [see Adverse Reactions (6.1)].
Rash
Advise patients that a rash or itching
may occur during
treatment with Fludarabine Phosphate Injection. Advise patients to immediately report
severe or worsening rash or itching [see
Adverse Reactions (6.1)].
Embryo-Fetal Toxicity
Advise pregnant women and females of
reproductive potential of the potential risk to a fetus. Advise female patients to contact their healthcare provider
of a known or suspected
pregnancy [see Warnings and Precautions
(5.8), Use in Specific Populations (8.1)].
Advise females
of reproductive potential
to use effective contraception during
treatment with Fludarabine Phosphate Injection and for 6
months after the last dose [see Use in
Specific Populations (8.3)].
Advise male patients with female partners
of reproductive potential
to use effective contraception during treatment with Fludarabine
Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations (8.3)].
Lactation
Advise
women not to breastfeed during treatment
and for 1 week after the last dose of Fludarabine Phosphate Injection [see Use in Specific Populations (8.2)].
Infertility
Advise males of reproductive potential
that Fludarabine Phosphate
Injection may impair
fertility [see Use in Specific Populations (8.3)].