Cardiac Toxicity: Although a few instances of cardiac dysfunction have been reported following the use of recommended doses of cyclophosphamide, no causal relationship has been established.
Cardiotoxicity has been observed in some patients receiving high doses of cyclophosphamide (120-270 mg/kg) administered over a period of a few days, usually as a portion of an intensive antineoplastic multidrug 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 within a few days after the first cyclophosphamide dose.
Histopathologic examination has primarily shown hemorrhagic myocarditis. 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.
Secondary Malignancies: Secondary 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 malignancies or lymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically.
Second urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis.
Renal pelvic and urethral tumor has also been reported in patients receiving long-term cyclophosphamide therapy.
In intraperitoneal or intravenous administration to rats, and intraperitoneal or hypodermic administration to mouse studies, there have been reports of tumors in several internal organs.
Although the clear relationship between the drug and malignancy in a patient has not been established, the possibility of cyclophosphamide-induced malignancy has been known on the basis of reliable data, therefore the possibility of cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.
Hematopoietic: Leukopenia is used as a guide for the expected effect and treatment. Thrombocytopenia or anemia may occur in a few patients and those symptoms reversibly occur. Acute leukemia has been reported in patients receiving long-term cyclophosphamide therapy.
Gastrointestinal Tract: Anorexia, nausea, vomiting are generally related to individual susceptibility to the drug as well as the dose of cyclophosphamide.
Oral mucosa ulcer, jaundice, hemorrhagic colitis during the therapy has been reported.
Urinary System: Hemorrhagic cystitis may develop in patients treated with cyclophosphamide, and it is considered to be due to urinary metabolite.
Non-hemorrhagic cystitis, fibrosis of the urinary bladder related to cyclophosphamide administration have been reported, and atypical urinary bladder epithelial cell have appeared in urinary sediment.
Sufficient water intake and frequent acceleration of urination prevent cystitis, and generally, although they occur, the administration doesn't have to be discontinued.
Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist for several months, and in severe case, supplementation of lost blood may be needed. Protracted cases are successfully treated with application of electrocautery to telangiectatic areas of urinary bladder, diversion of urine flow, or cryosurgery.
Renal toxicity such as bleeding, conglobation in renal pelvis has been reported.
In the patients treated with the drug, gonadal suppression related to the dose and therapy duration has been reported. It may result in amenorrhea or aspermatism and maybe reversible, therefore, these adverse reactions should be considered.
Ovarian fibrosis after the cyclophosphamide administration has been reported.
Integumentary: Alopecia may occur in patients treated with frequent cyclophosphamide therapy. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Pigmentation of the skin and changes in nails can occur. General dermatitis may occur.
Respiratory System: Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period.