Cyclophosphamide Information
Cyclophosphamide ()
Cyclophosphamide () Description
Cyclophosphamide () is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide () is a white crystalline powder with the molecular formula CHClNOP · HO and a molecular weight of 279.10. The chemical name for Cyclophosphamide () is 2-[Bis(2-chloroethyl)amino]tetrahydro-2-1,3,2-oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide () is soluble in water, saline, or ethanol and has the following structural formula:
Each tablet for oral administration contains Cyclophosphamide () USP (calculated as anhydrous) 25 or 50 mg. In addition, each tablet contains the following inactive ingredients: acacia, FD&C Blue No. 1, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.
Cyclophosphamide () Clinical Pharmacology
Cyclophosphamide () is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.
Cyclophosphamide () is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible for either the therapeutic or toxic effects of Cyclophosphamide () . Although elevated levels of metabolites of Cyclophosphamide () have been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated.
Cyclophosphamide () Contraindications
Continued use of Cyclophosphamide () is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide () is contraindicated in patients who have demonstrated a previous hypersensitivity to it. See and sections.
Cyclophosphamide () Warnings
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.
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/m to as high as 26 g/m, 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 after the first Cyclophosphamide () dose. Histopathologic examination 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.
Cyclophosphamide () Precautions
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.
Cyclophosphamide () Adverse Reactions
Information on adverse reactions associated with the use of Cyclophosphamide () is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the WARNINGS section.
Leukopenia occurs in patients treated with Cyclophosphamide () , is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm develops commonly in patients treated with an initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever has also been reported in patients with neutropenia.
Thrombocytopenia or anemia develop occasionally in patients treated with Cyclophosphamide () . These hematologic effects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.
See section for information on cystitis and urinary bladder fibrosis.
Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with Cyclophosphamide () . Such lesions usually resolve following cessation of therapy.
Cyclophosphamide () Overdosage
No specific antidote for Cyclophosphamide () is known. Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.
Cyclophosphamide () How Supplied
Cyclophosphamide () is available as:
NDC 0054-8089-25: Unit dose, 10 tablets per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
NDC 0054-4129-25: Bottles of 100 tablets.
NDC 0054-8130-25: Unit dose, 10 tablets per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
NDC 0054-4130-25: Bottles of 100 tablets.
Storage at or below 77°F (25°C) is recommended; this product will withstand brief exposure to temperatures up to 86°F (30°C) but should be protected from temperatures above 86°F (30°C).
