Included as part of the PRECAUTIONS section.
Myelosuppression, Immunosuppression, Bone Marrow Failure
Cytoxan (cyclophosphamide) can cause myelosuppression (leukopenia,
neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe
immunosuppression which may lead to serious and sometimes fatal infections,
including sepsis and septic shock. Latent infections can be reactivated [see ADVERSE
Antimicrobial prophylaxis may be indicated in certain
cases of neutropenia at the discretion of the managing physician. In case of
neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or
antivirals may also be indicated.
Monitoring of complete blood counts is essential during
cyclophosphamide treatment so that the dose can be adjusted, if needed.
Cyclophosphamide should not be administered to patients with neutrophils
≤ 1,500/mm³ and
platelets < 50,000/mm³.
Cyclophosphamide treatment may not be indicated, or should be interrupted, or
the dose reduced, in patients who have or who develop a serious infection.
G-CSF may be administered to reduce the risks of neutropenia complications
associated with cyclophosphamide use. Primary and secondary prophylaxis with
G-CSF should be considered in all patients considered to be at increased risk
for neutropenia complications. The nadirs of the reduction in leukocyte count
and thrombocyte count are usually reached in weeks 1 and 2 of treatment.
Peripheral blood cell counts are expected to normalize after approximately 20
days. Bone marrow failure has been reported. Severe myelosuppression may be
expected particularly in patients pretreated with and/or receiving concomitant
chemotherapy and/or radiation therapy.
Urinary Tract and Renal Toxicity
Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria
have been reported with cyclophosphamide. Medical and/or surgical supportive
treatment may be required to treat protracted cases of severe hemorrhagic
cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic
cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and
secondary cancer) may require interruption of cyclophosphamide treatment or
cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or
long-term use of cyclophosphamide.
Before starting treatment, exclude or correct any urinary
tract obstructions [see CONTRAINDICATIONS]. Urinary sediment should be
checked regularly for the presence of erythrocytes and other signs of
urotoxicity and/or nephrotoxicity. Cyclophosphamide should be used with
caution, if at all, in patients with active urinary tract infections.
Aggressive hydration with forced diuresis and frequent bladder emptying can
reduce the frequency and severity of bladder toxicity. Mesna has been used to
prevent severe bladder toxicity.
Myocarditis, myopericarditis, pericardial effusion
including cardiac tamponade, and congestive heart failure, which may be fatal,
have been reported with cyclophosphamide therapy
Supraventricular arrhythmias (including atrial
fibrillation and flutter) and ventricular arrhythmias (including severe QT
prolongation associated with ventricular tachyarrhythmia) have been reported
after treatment with regimens that included cyclophosphamide.
The risk of cardiotoxicity may be increased with high
doses of cyclophosphamide, in patients with advanced age, and in patients with
previous radiation treatment to the cardiac region and/or previous or
concomitant treatment with other cardiotoxic agents.
Particular caution is necessary in patients with risk
factors for cardiotoxicity and in patients with preexisting cardiac disease.
Monitor patients with risk factors for cardiotoxicity and
with pre-existing cardiac disease.
Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive
disease and other forms of pulmonary toxicity leading to respiratory failure
have been reported during and following treatment with cyclophosphamide. Late
onset pneumonitis (greater than 6 months after start of cyclophosphamide)
appears to be associated with increased mortality. Pneumonitis may develop
years after treatment with cyclophosphamide.
Monitor patients for signs and symptoms of pulmonary
Cyclophosphamide is genotoxic [see Nonclinical
Toxicology]. Secondary malignancies (urinary tract cancer, myelodysplasia,
acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in
patients treated with cyclophosphamide-containing regimens. The risk of bladder
cancer may be reduced by prevention of hemorrhagic cystitis.
Veno-occlusive Liver Disease
Veno-occlusive liver disease (VOD) including fatal
outcome has been reported in patients receiving cyclophosphamide-containing
regimens. A cytoreductive regimen in preparation for bone marrow
transplantation that consists of cyclophosphamide in combination with
whole-body irradiation, busulfan, or other agents has been identified as a
major risk factor. VOD has also been reported to develop gradually in patients
receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other
risk factors predisposing to the development of VOD include preexisting
disturbances of hepatic function, previous radiation therapy of the abdomen,
and a low performance status.
Cyclophosphamide can cause fetal harm when administered
to a pregnant woman [see Use In Specific Populations]. Exposure to
cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal
growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is
teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.
Advise female patients of reproductive potential to avoid
becoming pregnant and to use highly effective contraception during treatment
and for up to 1 year after completion of therapy [see Use in Specific
Male and female reproductive function and fertility may
be impaired in patients being treated with cyclophosphamide. Cyclophosphamide
interferes with oogenesis and spermatogenesis. It may cause sterility in both
sexes. Development of sterility appears to depend on the dose of
cyclophosphamide, duration of therapy, and the state of gonadal function at the
time of treatment. Cyclophosphamide-induced sterility may be irreversible in
some patients. Advise patients on the potential risks for infertility [see Use
in Specific Populations].
Impairment of Wound Healing
Cyclophosphamide may interfere with normal wound healing.
Hyponatremia associated with increased total body water,
acute water intoxication, and a syndrome resembling SIADH (syndrome of
inappropriate secretion of antidiuretic hormone), which may be fatal, has been
Carcinogenesis, Mutagenesis, Impairment of Fertility
Cyclophosphamide administered by different routes,
including intravenous, subcutaneous or intraperitoneal injection, or in
drinking water, caused tumors in both mice and rats. In addition to leukemia
and lymphoma, benign and malignant tumors were found at various tissue sites,
including urinary bladder, mammary gland, lung, liver, and injection site [see WARNINGS
Cyclophosphamide was mutagenic and clastogenic in
multiple in vitro and in vivo genetic toxicology studies.
Cyclophosphamide is genotoxic in male and female germ
cells. Animal data indicate that exposure of oocytes to cyclophosphamide during
follicular development may result in a decreased rate of implantations and
viable pregnancies, and in an increased risk of malformations. Male mice and
rats treated with cyclophosphamide show alterations in male reproductive organs
(e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases
in reproductive potential (e.g., decreased implantations and increased
post-implantation loss) and increases in fetal malformations when mated with
untreated females [see Use In Specific Populations].
Use In Specific Populations
Pregnancy Category D - Risk Summary
Cyclophosphamide can cause fetal harm when administered
to a pregnant woman based on its mechanism of action and published reports of
effects in pregnant patients or animals. Exposure to cyclophosphamide during
pregnancy may cause fetal malformations, miscarriage, fetal growth retardation,
and toxic effects in the newborn. Cyclophosphamide is teratogenic and
embryo-fetal toxic in mice, rats, rabbits and monkeys. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug,
apprise the patient of the potential hazard to a fetus.
Malformations of the skeleton, palate, limbs and eyes as
well as miscarriage have been reported after exposure to cyclophosphamide in
the first trimester. Fetal growth retardation and toxic effects manifesting in
the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow
hypoplasia, and gastroenteritis have been reported after exposure to
Administration of cyclophosphamide to pregnant mice,
rats, rabbits and monkeys during the period of organogenesis at doses at or
below the dose in patients based on body surface area resulted in various
malformations, which included neural tube defects, limb and digit defects and
other skeletal anomalies, cleft lip and palate, and reduced skeletal
Cyclophosphamide is present in breast milk. Neutropenia,
thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants
breast fed by women treated with cyclophosphamide. Because of the potential for
serious adverse reactions in nursing infants from cyclophosphamide, a decision
should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.
Pre-pubescent girls treated with cyclophosphamide
generally develop secondary sexual characteristics normally and have regular
menses. Ovarian fibrosis with apparently complete loss of germ cells after
prolonged cyclophosphamide treatment in late pre-pubescence has been reported.
Girls treated with cyclophosphamide who have retained ovarian function after
completing treatment are at increased risk of developing premature menopause.
Pre-pubescent boys treated with cyclophosphamide develop
secondary sexual characteristics normally, but may have oligospermia or
azoospermia and increased gonadotropin secretion. Some degree of testicular
atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some
patients, though the reversibility may not occur for several years after
cessation of therapy.
There is insufficient data from clinical studies of cyclophosphamide
available for patients 65 years of age and older to determine whether they
respond differently than younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac functioning, and of concomitant disease or other drug therapy.
Females and Males of Reproductive Potential
Pregnancy should be avoided during treatment with
cyclophosphamide because of the risk of fetal harm [see Use in Specific
Female patients of reproductive potential should use
highly effective contraception during and for up to 1 year after completion of
Male patients who are sexually active with female
partners who are or may become pregnant should use a condom during and for at
least 4 months after treatment.
Amenorrhea, transient or permanent, associated with
decreased estrogen and increased gonadotropin secretion develops in a
proportion of women treated with cyclophosphamide. Affected patients generally
resume regular menses within a few months after cessation of therapy. The risk
of premature menopause with cyclophosphamide increases with age. Oligomenorrhea
has also been reported in association with cyclophosphamide treatment.
Animal data suggest an increased risk of failed pregnancy
and malformations may persist after discontinuation of cyclophosphamide as long
as oocytes/follicles exist that were exposed to cyclophosphamide during any of
their maturation phases. The exact duration of follicular development in humans
is not known, but may be longer than 12 months [see Nonclinical Toxicology].
Men treated with cyclophosphamide may develop
oligospermia or azoospermia which are normally associated with increased gonadotropin
but normal testosterone secretion.
Use in Patients with Renal Impairment
In patients with severe renal impairment, decreased renal
excretion may result in increased plasma levels of cyclophosphamide and its
metabolites. This may result in increased toxicity [see CLINICAL
PHARMACOLOGY]. Monitor patients with severe renal impairment (CrCl =10
mL/min to 24 mL/min) for signs and symptoms of toxicity.
Cyclophosphamide and its metabolites are dialyzable
although there are probably quantitative differences depending upon the
dialysis system being used. In patients requiring dialysis, use of a consistent
interval between cyclophosphamide administration and dialysis should be
Use in Patients with Hepatic Impairment
Patients with severe hepatic impairment have reduced
conversion of cyclophosphamide to the active 4hydroxyl metabolite, potentially
reducing efficacy [see CLINICAL PHARMACOLOGY].