Cyclophosphamide, although effective as a single agent in certain malignancies, is more commonly used in combination or sequentially with other antineoplastic agents. The following malignancies are often responsive to cyclophosphamide therapy:

• Malignant lymphomas (Stages III and IV of the Ann Arbor classification), including Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell lymphoma, histiocytic lymphoma, and Burkitt’s lymphoma.
• Multiple myeloma.
• Leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (generally ineffective during acute blastic crisis), acute myelogenous and monocytic leukemia, and acute lymphoblastic (stem-cell) leukemia in children (cyclophosphamide administered during remission helps prolong its duration).
• Mycosis fungoides (advanced stage).
• Neuroblastoma (disseminated disease).
• Adenocarcinoma of the ovary.
• Retinoblastoma.
• Carcinoma of the breast.

Nonmalignant Disease: Biopsy-proven “minimal change” nephrotic syndrome in children:
Cyclophosphamide may be beneficial in selected cases of biopsy-confirmed minimal change nephrotic syndrome in children; however, it should not be used as first-line therapy. It may induce remission in children who do not respond adequately to corticosteroid therapy or who develop significant adverse effects from such treatment. Cyclophosphamide is not indicated for nephrotic syndrome in adults or for other renal diseases.

Cyclophosphamide is metabolized mainly in the liver into active alkylating metabolites through a microsomal enzyme system. These metabolites interfere with the growth and multiplication of rapidly dividing cancer cells. The drug works primarily by forming cross-links within tumor cell DNA, which disrupts DNA replication and leads to the death of malignant cells. Cyclophosphamide is well absorbed after oral administration, with a bioavailability of more than 75%. The elimination half-life of the unchanged drug ranges from approximately 3 to 12 hours. Most of the drug is excreted in the urine as metabolites, while about 5–25% of the dose may be eliminated unchanged. Peak concentrations of active metabolites in the blood usually occur 2–3 hours after intravenous administration. The parent drug has low plasma protein binding, although some metabolites may bind to plasma proteins to a greater extent. Although higher levels of metabolites have been observed in patients with kidney failure, this does not necessarily lead to increased clinical toxicity.

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/mm³ (following short courses) or more persistent reduction to 3000 cells/mm³ (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.

Cyclophosphamide metabolism and its ability to cause leukopenia may increase when high doses of Phenobarbital are used for a long period. Physicians should remain aware of possible interactions when Cyclophosphamide is used together with other medications, including other cytotoxic drugs. Cyclophosphamide can significantly inhibit cholinesterase activity, which may enhance the effect of Succinylcholine Chloride, a muscle relaxant commonly used during anesthesia. Therefore, if a patient has received Cyclophosphamide within 10 days before general anesthesia, the anesthesiologist should be informed.

Continued use of cyclophosphamide is contraindicated in patients with severely suppressed bone marrow function. It is also contraindicated in patients with a known history of hypersensitivity to cyclophosphamide.

Digestive System: Nausea and vomiting are common during treatment with Cyclophosphamide. Loss of appetite, abdominal discomfort, pain, and diarrhea may also occur. Rarely, hemorrhagic colitis, oral ulcers, and jaundice have been reported.

Skin and Hair: Hair loss (alopecia) is common during therapy. Hair usually grows back after treatment, although the texture or color may change. Skin rashes, skin pigmentation changes, and nail changes may occur. Rare severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported.

Blood and Bone Marrow: Leukopenia is the most common blood-related effect and is dose-dependent. In some cases, thrombocytopenia or anemia may develop. Blood cell counts generally recover within 7–10 days after stopping treatment.

Urinary System: Hemorrhagic ureteritis and kidney tubular damage have occasionally been reported but often resolve after discontinuing therapy.

Respiratory System: Interstitial pneumonitis and pulmonary fibrosis have been reported in patients receiving high or prolonged doses.

Other Reactions: Severe allergic reactions (anaphylaxis), SIADH (Syndrome of Inappropriate ADH Secretion), weakness, and fatigue may also occur.

Cyclophosphamide is classified as Pregnancy Category D. It can pass into breast milk and may cause serious adverse effects in infants. A decision should be made whether to stop breastfeeding or discontinue the drug depending on the mother’s treatment needs.

Special care is required when using Cyclophosphamide in patients with:

• Leukopenia
• Thrombocytopenia
• Tumor infiltration in bone marrow
• Previous radiation therapy
• Previous cytotoxic chemotherapy
• Liver dysfunction
• Kidney impairment

Pediatric use: The safety profile of cyclophosphamide in children is comparable to that observed in adults.

Geriatric use: Available clinical data on cyclophosphamide use in patients aged 65 years and older for conditions such as malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are limited, making it difficult to determine whether their response differs from younger patients. In clinical studies comparing cyclophosphamide with paclitaxel, each combined with cisplatin for advanced ovarian carcinoma, 154 out of 552 patients (28%) receiving cyclophosphamide with cisplatin were aged 65 years or older. Subgroup analyses, published clinical reports, and post-marketing experience indicate that elderly patients may have increased susceptibility to cyclophosphamide toxicity. Therefore, dose selection in elderly patients should be approached cautiously, typically starting at the lower end of the dosing range and adjusting according to individual response.

There is no specific antidote for an overdose of Cyclophosphamide. Treatment involves supportive care and management of complications such as infection, bone marrow suppression, or cardiac toxicity.

Cytotoxic Chemotherapy

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