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.