Cyclomide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to Cyclomide treatment: Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. ... Read more Cyclomide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to Cyclomide treatment: Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. Multiple myeloma. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (Cyclomide given during remission is effective in prolonging its duration). Mycosis fungoides (advanced disease). Neuroblastoma (disseminated disease). Adenocarcinoma of the ovary. Retinoblastoma. Carcinoma of the breast. Nonmalignant Disease : Biopsy Proven "Minimal Change" Nephrotic Syndrome in Children: Cyclomide is useful in carefully selected cases of biopsy-proven "minimal change" nephrotic syndrome in children but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adreno corticosteroid therapy or in whom the adreno-corticosteroid therapy produces or threatens to produce intolerable side effects, Cyclomide may induce a remission. Cyclomide is not indicated for the nephrotic syndrome in adults or for any other renal disease.
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. Concen- trations 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.
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Treatment of Malignant Diseases : Adults and Children When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly. Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing. Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm 3 (following short courses) or more persistent reduction to 3000 cells/mm 3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia. When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs. Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of cyclophosphamide metabolism, but there is no consistent evidence indicating a need for cyclophosphamide dosage modification in patients with renal function impairment. Treatment of Nonmalignant Diseases Biopsy Proven "Minimal Change" Nephrotic Syndrome in Children : An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and azoospermia increases if the duration of cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of cyclophosphamide therapy.
Information on adverse reactions associated with the use of Cyclomide is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. Digestive System : Nausea and vomiting commonly occur with Cyclomide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when Cyclomide treatment is stopped. Skin and Its Structures : Alopecia occurs commonly in patients treated with Cyclomide. 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. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during post-marketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to cyclophospha- mide has not been established. Hematopoietic System : Leukopenia occurs in patients treated with Cyclomide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm 3 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 without documented infection has been reported in neutropenic patients. Thrombocytopenia or anemia develops occasionally in patients treated with Cyclomide. 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. Urinary System : Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with Cyclomide. Such lesions usually resolve following cessation of therapy. Respiratory System : Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of Cyclomide over a prolonged period. 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. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of Cyclomide. Malaise and asthenia have been reported as part of the postmarketing experience.
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.
The rate of metabolism and the leukopenic activity of Cyclomide 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 Cyclomide even though Cyclomide has been used successfully concurrently with other drugs, including other cytotoxic drugs. Cyclomide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride. If a patient has been treated with Cyclomide within 10 days of general anesthesia, the anesthesiologist should be alerted.
Special attention to the possible development of toxicity should be exercised in patients being treated with Cyclomide if any of the following conditions are present. Leukopenia Thrombocytopenia Tumor cell infiltration of bone marrow Previous X-ray therapy Previous therapy with other cytotoxic agents Impaired hepatic function Impaired renal function