Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Myelosuppression
Additions
and/or revisions underlined:
IFEX
can
cause myelosuppression that results in severe or fatal infections
including sepsis or septic shock. Ifosfamide-induced myelosuppression includes leukopenia,
neutropenia, thrombocytopenia (with bleeding events), and anemia. The nadir of the
leukocyte count usually occurs during the second week after
administration of IFEX. The risk of myelosuppression is dose-dependent
and increased in patients with reduced renal function
bone
marrow metastases, prior radiation, and concomitant or prior therapy
with other cytotoxic agents.
Monitor
complete blood counts, including leukocytes, neutrophils, platelets, and
hemoglobin prior to each administration of IFEX, at appropriate intervals
during treatment, and as clinically indicated.
Myelosuppression
may require dosage delays. Avoid administration of IFEX to patients with a WBC
count below 2000/µL, a platelet count below 50,000/µL, or when signs or
symptoms of active infection or severe immunosuppression are present.
5.2 Encephalopathy
Additions
and/or revisions underlined:
IFEX
can cause encephalopathy which may be fatal. Signs and symptoms may include
confusion, somnolence, coma, hallucination, blurred vision, psychotic behavior,
extrapyramidal symptoms, urinary incontinence, and seizures.
Risk
factors include high ifosfamide dosage, hypoalbuminemia, impaired renal
function, poor performance status, bulky abdominal-pelvic disease, nephrotoxic
treatments including cisplatin, CNS active drugs, or alcohol use.
Signs
and symptoms may occur or recur within hours to days after administration of
IFEX. Continue supportive care until complete resolution of CNS signs and
symptoms.
Monitor
for signs and symptoms of encephalopathy during and after IFEX treatment. Dose
interruption or permanent discontinuation may be required based on individual
safety and tolerability. Consider methylene blue for treatment of
encephalopathy.
5.3 Nephrotoxicity and Urotoxicity
Additions
and/or revisions underlined:
IFEX
can cause severe or fatal nephrotoxicity and urotoxicity including
glomerular or tubular dysfunction, tubular necrosis, renal parenchymal
necrosis, acute renal failure, chronic renal failure, and hemorrhagic
cystitis (requiring blood transfusion).
Tubular damage may occur up to years after cessation
of IFEX treatment. The risk of nephrotoxicity is increased in patients with
renal impairment or reduced nephron reserve. Hemorrhagic cystitis is dose-dependent
and the risk is increased with past or concomitant radiation of the bladder or
busulfan treatment.
Evaluate glomerular and
tubular kidney function before treatment with IFEX, during IFEX treatment,
and as clinically indicated. Monitor serum and urine chemistries (including
phosphorus and potassium) and urinary sediment for the presence of erythrocytes
or other signs of nephrotoxicity. Signs and symptoms may include a decrease
in glomerular filtration rate, increased serum creatinine, proteinuria,
enzymuria, cylindruria, aminoaciduria, phosphaturia, glycosuria, osteomalacia,
tubular acidosis, Fanconi syndrome, and syndrome of inappropriate antidiuretic
hormone secretion (SIADH).
Before starting treatment, exclude or correct any
urinary tract obstructions [see
Contraindications (4)].During or immediately after administration, provide
oral or intravenous fluid to force dieresis to reduce the risk of urinary
tract toxicity. Administer mesna with IFEX to reduce the incidence and
severity of urotoxicity [see Dosage and
Administration (2.1)].
Obtain a urinalysis prior to each dose of IFEX. Avoid
administration of IFEX in patients with active urinary tract infections. If
microscopic hematuria (greater than 10 RBCs per high power field) is present,
then withhold administration of IFEX until complete resolution.
Further administration of IFEX should be givenwith vigorous oral or parenteral hydration.
Dosage interruption or permanent discontinuation may be required based on
individual safety and tolerability.
5.4 Cardiotoxicity
Additions and/or revisions underlined:
IFEX can cause severe or fatal cardiotoxicity including
any of the following:
…
Cardiotoxic effects are
dose-dependent and the risk is increased in patients with cardiac
disease, prior or concomitant treatment
with other cardiotoxic agents, radiation of the cardiac region, and renal
impairment.
5.5 Pulmonary Toxicity
Additions and/or revisions underlined:
IFEX can cause severe or fatal pulmonary toxicities
including interstitial pneumonitis, pulmonary
fibrosis, and respiratory failure. Monitor for signs and symptoms of pulmonary
toxicity and treat as clinically indicated.
5.6 Secondary Malignancies
Additions and/or revisions underlined:
The incidence of secondary malignancies
is increased in patients treated with IFEX-containing regimens. Cases of myelodysplastic
syndrome, acute leukemias, lymphomas, thyroid cancers, and
sarcomas have occurred
and may develop several years after chemotherapy has
been discontinued.
5.8 Embryo-Fetal Toxicity
Additions and/or revisions underlined:
Based on mechanism of action and human and animal
data, IFEX can cause fetal harm when administered to a
pregnant woman [see Use in Specific
Populations (8.1), Clinical Pharmacology (12.1) and Nonclinical Toxicology
(13.1)]. Fetal growth retardation and neonatal anemia have been
reported following exposure to ifosfamide-containing chemotherapy regimens
during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ
cells. Embryotoxic and teratogenic effects have been observed in mice, rats and
rabbits at doses 0.05 to 0.075 times the human dose.
Advise pregnant women
and females of reproductive potential of the potential risk to the
fetus [see Use in Specific Populations
(8.1)]. Verify the pregnancy status of females of reproductive
potential prior to initiation of IFEX. Advise females of reproductive potential
to use effective contraception during treatment with IFEX and for up to 12
months after completion of therapy.
Advise male
patients with female partners of reproductive potential to use effective
contraception during treatment with IFEX and for 6 months after completion of
therapy [see Use in Specific Populations
(8.1, 8.3)].
5.9 Infertility
Additions and/or revisions underlined:
Male and female
reproductive function and fertility may be impaired in patients treated with
IFEX. Ifosfamide interferes
with oogenesis and spermatogenesis. Amenorrhea, azoospermia; and sterility in
both sexes have been reported. Development of sterility appears to depend on
the dose of ifosfamide, duration of therapy, and state of gonadal function at
the time of treatment. Sterility may be irreversible in some patients.
Advise patients on the potential risks for infertility [see Use in Specific
Populations (8.3 and 8.4)].
6
Adverse Reactions
6.1 Clinical
Trials Experience
Extensive
additions and/or revisions, please refer to label for complete information.
6.2 Postmarketing
Experience
Extensive
additions and/or revisions, please refer to label for complete information.
8
Use in Specific Populations
8.4 Pediatric Use
Additions
and/or revisions underlined:
Safety
and effectiveness have not been established in pediatric patients.
Renal
rickets and growth retardation in pediatric patients treated with ifosfamide
have been reported.
IFEX
may cause temporary or permanent infertility in prepubertal girls or in females
of child-bearing potential and may have an increased risk of developing
premature menopause.
IFEX
may cause abnormal secondary sexual characteristic development in prepubertal
males. Sterility, azoospermia, and testicular atrophy have been reported in
male patients. Azoospermia may be reversible in some
patients, but may not occur for several years after cessation of IFEX therapy.
8.5 Geriatric Use
Additions
and/or revisions underlined:
Clinical
studies of IFEX did not include sufficient numbers of patients aged 65 and over
to determine whether they respond differently from younger subjects.
…
…
Because
elderly patients are more likely to have decreased renal function, closely
monitor for adverse reactions and monitor renal function as
clinically indicated.
8.6 Use in Patients with Renal Impairment
Additions
and/or revisions underlined:
Ifosfamide
and its metabolites are known to be excreted by the kidneys and may accumulate in
plasma with decreased renal function. Closely monitor patients with renal
impairment for adverse reactions and consider dosage modifications.
Ifosfamide and its metabolites are dialyzable.
8.7 Use in Patients with Hepatic Impairment
Additions and/or
revisions underlined:
Ifosfamide is extensively metabolized in the liver
and forms both efficacious and toxic metabolites. Closely monitor patients with impaired hepatic function for
adverse reactions during treatment with IFEX.
8.1 Pregnancy
Revisions
to better align with the FDA Guidance for PLLR information in labeling, Additions
and/or revisions underlined:
Risk
Summary
Based
on mechanism of action [see Clinical
Pharmacology (12.1)], and human and animal data (see Data), IFEX can cause fetal harm when administered to a
pregnant woman. Fetal growth retardation and neonatal anemia have been reported
following exposure to ifosfamide-containing chemotherapy regimens during
pregnancy.
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
…
8.2 Lactation
Revisions
to better align with the FDA Guidance for PLLR information in labeling, Additions
and/or revisions underlined:
Risk
Summary
Ifosfamide
is excreted in breast milk. Because of the potential for serious adverse
events, and the tumorigenicity shown for ifosfamide in animal studies, advise
women not to breastfeed during treatment with IFEX and for one week
after the last dose.
8.3 Females and
Males of Reproductive Potential
PLLR
conversion:
IFEX
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 initiating IFEX [see Use in Specific Populations (8.1)].
Contraception
Females
Advise
female patients of reproductive potential to use effective contraception during
treatment with IFEX and for 12 months after the last dose.
Males
Advise
males with female sexual partners of reproductive potential to use effective
contraception during treatment with IFEX and for 6 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Females
Amenorrhea
has been reported in patients treated with ifosfamide. The risk of permanent
chemotherapy induced amenorrhea increases with age.
Males
Men
treated with
ifosfamide may develop oligospermia or azoospermia. Azoospermia may be reversible
in some patients, though the reversibility may not occur for several years
after cessation of therapy. Sexual function and libido are generally unimpaired
in these patients. Some degree of testicular atrophy may occur. Patients
treated with ifosfamide have subsequently fathered children.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
…
Encephalopathy
Advise
patients on the risk of encephalopathy and other neurotoxic effects with
fatal outcome [see Boxed Warning,
Warnings and Precautions (5.2)].
Inform patients that IFEX may impair the ability to
operate an automobile or other heavy machinery
[see Boxed Warning, Warnings and Precautions (5.2)].
Nephrotoxicity
and Urotoxicity
Advise
patients on the risk of bladder and kidney toxicity.
Advise
patients of the need to increase fluid intake and frequent voiding to prevent
accumulation in the bladder [see Warnings
and Precautions (5.3)].
…
Embryo-Fetal
Toxicity
Advise
pregnant women and females of reproductive potential of the potential risk
to a fetus. Advise females to inform their healthcare provider of a known or
suspected pregnancy [see Warnings and
Precautions (5.8) and Use in Specific Populations (8.1)].
Advise
females of reproductive potential to use effective contraception during
treatment with IFEX and for 12 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 IFEX and for 6 months after the last dose [see Use
in Specific Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with
IFEX and for 1 week after the last dose [see
Use in Specific Populations (8.2)].
Infertility
Advise
females and males of reproductive potential that IFEX may cause
temporary or permanent infertility [see
Use in Specific Populations (8.3)].
…
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