ENDOXAN

What it is

Cyclonex® (Cyclophosphamide) is supplied as film-coated tablets containing cyclophosphamide monohydrate equivalent to 50 mg cyclophosphamide. The tablets are brown to pinkish round convex film coated tablets. Cyclophosphamide is an alkylating antineoplastic agent that is not itself an alkylating agent but is converted by a series of reactions in the liver to its active form, which interferes with the growth of susceptible neoplasms and to a certain extent, with normal tissue regeneration.

Approved indications —

Malignant lymphomas (stages III and IV) — Multiple myeloma — Leukaemias — Mycosis fungoides (advanced disease) — Neuroblastoma (patients with disseminated disease) — Adenocarcinoma of the ovary — Retinoblastoma — Carcinoma of the breast — Malignant neoplasm of the lung Cyclophosphamide has also been used in the treatment of autoimmune diseases and immunopathies of unspecified type, such as Wegener's granulomatosis, when these diseases have been resistant to conventional first and second line treatment, and for the prevention of transplant rejection. Cyclophosphamide can be recommended for use in the treatment of non-malignancies only when in the opinion of the physician the benefits to the patient outweigh the risk of treatment.

Dosing overview

For antineoplastic induction therapy, the usual initial intravenous loading dose for patients with no haematological deficiency is 40–50 mg/kg, usually given in divided doses over a period of two to five days. Patients with previous treatment that may have compromised bone marrow function, or patients with tumour infiltration of the bone marrow, may require reduction of the initial loading dose by one third to one half. If initial therapy is given orally, a dose of 1–5 mg/kg/day can be administered depending on tolerance by the patient. For maintenance therapy, a variety of schedules have been used: 1–5 mg/kg orally daily; 10–15 mg/kg intravenous every 7 to 10 days; or 3–5 mg/kg intravenous twice weekly. For immunosuppressive therapy, doses used have been in the order of 1–3 mg/kg orally depending upon response and toxicity.

Key safety warnings

Sterile haemorrhagic cystitis is a severe adverse reaction that has been reported with cyclophosphamide therapy. To prevent this toxic effect patients should be instructed to increase their fluid intake for a period of 24 hours before, during and at least 24 hours after receiving cyclophosphamide therapy, and should void frequently for 24 hours after receiving the drug. Frequent voiding helps prevent the development of cystitis, but when it occurs, it is necessary to interrupt cyclophosphamide therapy. Urine should be examined regularly for the presence of red cells, which may precede haemorrhagic cystitis. Since this complication may be severe and fatal, the drug should be discontinued in patients who develop this complication. One of the major toxicities of cyclophosphamide is bone marrow suppression. Leucopoenia and neutropenia are expected to occur following therapeutic doses and they may be severe. Leucopoenia may occur with or without fever and carries the risk of secondary and potentially life-threatening infections. Weekly clinical and haematological examinations should be made, with total and differential blood cell counts and estimation of haemoglobin levels being essential. Cyclophosphamide therapy has immunosuppressive activity that can potentially lead to serious or fatal infections. The patient should be carefully monitored for any sign or symptom of infection, and interruption or modification of dosage should be considered for patients who develop bacterial, fungal, protozoal, helminthic or viral infections. This is especially true for patients receiving or who have recently received concomitant steroid therapy. Cardiotoxicity has been rarely reported in patients receiving cyclophosphamide. Monitoring of cardiac functions is recommended in patients with pre-existing cardiac disturbances or impairments. Special attention is required when using cyclophosphamide in combination with other potentially cardiotoxic drugs such as anthracyclines and fluorouracil. Some patients receiving cyclophosphamide have developed secondary malignancies, most frequently urinary bladder, myeloproliferative and lymphoproliferative malignancies. Secondary malignancies have occurred mainly in patients treated with cyclophosphamide for primary haematological malignancies or primary non-malignant diseases in which immune processes are believed to be involved.

Contraindications

Cyclophosphamide is contraindicated in patients who have demonstrated previous hypersensitivity to it and in the presence of active infections, which may lead to fatal complications as a result of immunosuppression induced by the cytotoxic treatment. Cyclophosphamide is contraindicated in patients with evidence of cystitis, acute systemic or urinary infection, urinary outflow obstruction, drug or radiation induced haemorrhagic cystitis. It is contraindicated in patients with severely depressed bone marrow function, particularly in patients who have been pre-treated with cytotoxic agents and/or radiotherapy. Cyclophosphamide is contraindicated in the first trimester of pregnancy. Cyclophosphamide therapy should not be commenced for 4 to 8 days after major surgery.

Regulatory history

ENDOXAN cyclophosphamide powder for injection was first approved on 4 June 2002.