WARNINGS
Carcinogenesis, Mutagenesis, Impairment of Fertility
Second malignancies have developed in some patients treated
with cyclophosphamide used alone or in association with
other antineoplastic drugs and/or modalities. Most frequently,
they have been urinary bladder, myeloproliferative, or
lymphoproliferative malignancies. Second malignancies
most frequently were detected in patients treated for
primary myeloproliferative or lymphoproliferative malignancies
or nonmalignant disease in which immune processes are
believed to be involved pathologically.
In some cases, the second malignancy developed several
years after cyclophosphamide treatment had been discontinued.
In a single breast cancer trial utilizing two to four
times the standard dose of cyclophosphamide in conjunction
with doxorubicin a small number of cases of secondary
acute myeloid leukemia occurred within two years of treatment
initiation. Urinary bladder malignancies generally have
occurred in patients who previously had hemorrhagic cystitis.
In patients treated with cyclophosphamide-containing regimens
for a variety of solid tumors, isolated case reports of
secondary malignancies have been published. One case of
carcinoma of the renal pelvis was reported in a patient
receiving long-term cyclophosphamide therapy for cerebral
vasculitis. The possibility of cyclophosphamide-induced
malignancy should be considered in any benefit-to-risk
assessment for use of the drug.
Cyclophosphamide can cause fetal harm when administered
to a pregnant woman and such abnormalities have been reported
following cyclophosphamide therapy in pregnant women.
Abnormalities were found in two infants and a six-month
old fetus born to women treated with cyclophosphamide.
Ectrodactylia was found in two of the three cases. Normal
infants have also been born to women treated with cyclophosphamide
during pregnancy, including the first trimester. If this
drug is used during pregnancy, or if the patient becomes
pregnant while taking (receiving) 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.
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.
Amenorrhea associated with decreased estrogen and increased
gonadotropin secretion develops in a significant proportion
of women treated with cyclophosphamide. Affected patients
generally resume regular menses within a few months after
cessation of therapy. Girls treated with cyclophosphamide
during prepubescence 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 prepubescence
has been reported. Girls treated with cyclophosphamide
during prepubescence subsequently have conceived.
Men treated with cyclophosphamide may develop oligospermia
or azoospermia associated with increased gonadotropin
but normal testosterone secretion. Sexual potency and
libido are unimpaired in these patients. Boys treated
with cyclophosphamide during prepubescence 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. Men temporarily rendered sterile by cyclophosphamide
have subsequently fathered normal children.
Urinary System
Hemorrhagic cyctitis may develop in patients treated
with cyclophosphamide. Rarely, this condition can be severe
and even fatal. Fibrosis of the urinary bladder, sometimes
extensive, also may develop with or without accompanying
cystitis. Atypical urinary bladder epithelial cells may
appear in the urine. These adverse effects appear to depend
on the dose of cyclophosphamide and the duration of therapy.
Such bladder injury is thought to be due to cyclophosphamide
metabolites excreted in the urine. Forced fluid intake
helps to assure an ample output of urine, necessitates
frequent voiding, and reduces the time the drug remains
in the bladder. This helps to prevent cystitis. Hematuria
usually resolves in a few days after cyclophosphamide
treatment is stopped, but it may persist. Medical and/or
surgical supportive treatment may be required, rarely,
to treat protracted cases of severe hemorrhagic cystitis.
It is usually necessary to discontinue cyclophosphamide
therapy in instances of severe hemorrhagic cystitis.
Cardiac Toxicity
Although a few instances of cardiac dysfunction have
been reported following use of recommended doses of cyclophosphamide,
no causal relationship has been established. Acute cardiac
toxicity has been reported with doses as low as 2.4 g/m2
to as high as 26 g/m2 , usually as a portion of an intensive
antineoplastic multi-drug regimen or in conjunction with
transplantation procedures. In a few instances with high
doses of cyclophosphamide, severe, and sometimes fatal,
congestive heart failure has occurred after the first
cyclophosphamide dose. Histopathologic enaminution has
primarily shown hemorrhagic myocarditis. Hemopericardium
has occurred secondary to hemorrhagic myocarditis and
myocardial necrosis. Pericarditis has been reported independent
of any hemopericardium.
No residual cardiac abnormalities, as evidenced by electrocardiogram
or echocardiogram appear to be present in patients surviving
episodes of apparent cardiac toxicity associated with
high doses of cyclophosphamide.
Cyclophosphamide has been reported to potentiate doxorubicin-induced
cardiotoxicity.
Infections
Treatment with cyclophosphamide may cause significant
suppression of immune responses. Serious, sometimes fatal,
infections may develop in severely immunosuppressed patients.
Cyclophosphamide treatment may not be indicated or should
be interrupted or the dose reduced in patients who have
or who develop viral, bacterial, fungal, protozoan, or
helminthic infections.
Other
Anaphylactic reactions have been reported; death has
also been reported in association with this event. Possible
cross-sensitivity with other alkylating agents has been
reported.
PRECAUTIONS
General
Special attention to the possible development of toxicity
should be exercised in patients being treated with cyclophosphamide
if any of the following conditions are present.
1. Leukopenia
2. Thrombocytopenia
3. Tumor cell infiltration of bone marrow
4. Previous X-ray therapy
5. Previous therapy with other cytotoxic agents
6. Impaired hepatic function
7. Impaired renal function
Laboratory Tests
During treatment, the patient’s hematologic profile
(particularly neutrophils and platelets) should be monitored
regularly to determine the degree of hematopoietic suppression.
Urine should also be examined regularly for red cells
which may precede hemorrhagic cystitis.
Drug Interactions
The rate of metabolism and the leukopenic activity of
cyclophosphamide reportedly are increased by chronic administration
of high doses of phenobarbital.
The physician should be alert for possible combined drug
actions, desirable or undesirable, involving cyclophosphamide
even though cyclophosphamide has been used successfully
concurrently with other drugs, including other cytotoxic
drugs.
Cyclophosphamide treatment, which causes a marked and
persistent inhibition of cholinesterase activity, potentiates
the effect of succinylcholine chloride.
If a patient has been treated with cyclophosphamide within
10 days of general anesthesia, the anesthesiologist should
be alerted.
Adrenalectomy
Since cyclophosphamide has been reported to be more toxic
in adrenalectomized drugs, adjustment of the doses of
both replacement steroids and cyclophosphamide may be
necessary for the adrenalectomized patient.
Wound Healing
Cyclophosphamide may interfere with normal wound healing.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See
WARNINGS
section for information on carcinogenesis, mutagenesis,
and impairment of fertility.
Pregnancy
Pregnancy Category D— See
WARNINGS
section.
Nursing Mothers
Cyclophosphamide is excreted in breast milk. Because
of the potential for serious adverse reactions and the
potential for tumorigenicity shown for cyclophosphamide
in humans, 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.
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