COMPOSITION: Vials containing 200 mg, 500 mg, and 1 g cyclophosphamide as powder per vial.
Tablets containing 50 mg cyclophosphamide per tablet
PHARMACOLOGICAL CLASSIFICATION: A 26 Cytostatic agents
PHARMACOLOGICAL ACTION: ENDOXAN (cyclophosphamide) is a cyclic propylene phosphamide ester of nitrogen mustard.
The main advantage of chemotherapy is complete penetration of the tissues, reaching the most widely spread malignant cells. The difficulty lies in the necessity of achieving a specific cancerotoxic effect on the neoplastic cells without affecting healthy tissue too severely. In this respect ENDOXAN TABLETS and INJECTION represent distinct progress in the chemotherapy of cancer. It is one of the most useful cytotoxics available today.
ENDOXAN is a "transport form" and as such it has a selective tumour affinity. It consists of a carrier molecule, a blocking group to make it inactive during the transport stage, and the active nitrogen mustard group. It is inactive in vitro.
The cytotoxic action is presumably based on binding and inactivation of the cellular DNA. This transport principle has resulted in markedly reduced toxicity and increased tumour selectivity. ENDOXAN has a quickly reversible leucotoxic effect which is utilised to determine dosage and intervals between doses.
INDICATIONS: Active treatment of all neoplastic diseases of the reticulo-endothelial system, e.g. lymphomas, lymphosarcomas, reticulo-sarcomas. Hodgkin's disease, chronic lymphatic leukaemias, multiple myelomas.
In combination with other cytostatics for various forms of carcinoma
Adjuvant therapy in surgery and/or radiotherapy for cancer
Palliation of inoperable malignancies
It is strongly recommended to conduct cancer surgery under protection of chemotherapy with ENDOXAN TABLETS and INJECTION to help prevent acute dissemination of malignant cells during surgery and thus to curb subsequent metastases.
CONTRA-INDICATIONS: Known hypersensitivity to cyclophosphamide and severe bone-marrow depression. Contra-indicated in the first trimester of pregnancy.
WARNINGS: In male and female patients of reproductive age contraceptive measures should be carried out during, and for up to at least three months after the end of cyclophosphamide therapy.
Cyclophosphamide should not be used during the first trimester, and only if absolutely necessary during the second half of pregnancy.
In view of the possible absorption of cyclophosphamide through the skin and by inhalation, it is recommended to wear face masks and PVC gloves for protection when handling the injection.
DOSAGE AND DIRECTIONS FOR USE: ENDOXAN INJECTION should be dissolved in sterile distilled water.
The injections should be given intravenously, although intramuscular, intrapleura, or intraperitoneal routes may also be used.
Dosage has to be adjusted individually. It has been found that the cytotoxic effect largely depends on an effective concentration of cyclophosphamide in the tissues. The highest tolerated dosage should therefore be given intravenously. The established maximum dosage is 50 mg per kg body mass; in exceptional cases higher single dosages have been given.
Tumour resistance to chemotherapy may develop from insufficient dosage.
1. Active treatment
The individually adjusted dose is given intravenously as rapidly as possible as a bolus. Regular leucocyte counts are necessary. If the leucocyte count does not drop below 2 000 per mm3, a larger dose can be used. When the leucocytes have recovered, usually after ten to fourteen days, the next dose, if possible even higher, is given. This form of treatment is continued until remission is clinically complete. Thereafter, massive dosage ENDOXAN therapy should be discontinued and the patients condition closely observed. In cases of recurrence a second full course of ENDOXAN should be given without delay.
If the malignancy is resistant to ENDOXAN, this will become apparent after three to six weeks treatment. In this event ENDOXAN therapy should be discontinued.
2. In combination therapy
Smaller dosages, depending on the other agents used.
3. Adjuvant therapy
In surgery: A single high dose (see "Active treatment") should be given ten to fourteen days prior to surgery and a full course of ENDOXAN as soon as possible after the operation. Wound healing is not affected.
In radiotherapy: Treatment should be given as outlined above, in consultation with the radiotherapist.
4. Palliative therapy (inoperable malignancies)
This should be conducted on the same principles as the active therapy but often a more moderate dosage might be indicated.
In cases of good response, surgical intervention may again become possible.
5. Maintenance therapy
After an objective remission has been achieved maintenance therapy should be instituted by prolonging the time interval between injections to two or even four weeks but without reducing the individual dosages. If ENDOXAN TABLETS are preferred at this stage, one to four tablets daily or four to eight tablets one to three times a week, are usually considered sufficient. Also during maintenance therapy it is necessary to check the patient's leucocyte count at frequent intervals. In patients with bone-marrow lesions, a more moderate dosage regimen is indicated.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Nausea and vomiting occur in most cases for a short period soon after injections, and should be treated with antiemetics.
Alopecia from slight to severe is frequently observed during cyclophosphamide treatment but hair grows again after a while.
Haemorrhagic cystitis may occur during high dosage cyclophosphamide treatment. Prophylactic high fluid intake and sodium bicarbonate instillations are recommended for relief of symptoms.
The leucotoxic effect described above is usually relatively mild; even severe leucopenias, when they do occur, tend to be quickly reversible.
Thrombocytopenias of below 100 000 are rare.
Haemopoiesis is practically never inhibited.
A teratogenic effect has been pharmacologically established.
Avoid skin contact. In case of accidental spillage, washing with large quantities of soap and water is recommended.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: In the event of overdosage, general supportive measures should be used, e.g. dialysis and forced diuresis.
IDENTIFICATION: Clear glass 15 mL, 50 mL and 75 mL vials, containing 200 mg, 500 mg and 1 g white crystalline powder respectively.
White sugarcoated tablet
PRESENTATION: Injections: 10 x 200 mg in clear glass vials
5 x 500 mg in clear glass vials and 10 x 500 mg in clear glass vials
1 x 1 g in clear glass vial and 5 x 1 g in clear glass vials
Tablets 50 mg: 50' and 250in securitainers
STORAGE INSTRUCTIONS: Prior to making up the solution, ENDOXAN INJECTION should be stored below 25°C but not in a freezer, otherwise adhesion of cyclophosphamide to the walls of the vials might impair the solubility of the substance in water. Do not use if sintered or melted. If necessary the solution of ENDOXAN INJECTION can be kept for two to three hours if stored in a refrigerator at 5°C.
ENDOXAN TABLETS: Storage should not exceed 25°C
Protect from moisture
KEEP OUT OF REACH OF CHILDREN.
H2771 (Act 101/1965)
H2769 (Act 101/1965)
H2772 (Act 101/1965)
Tablets 50 mg:
H2770 (Act 101/1965)
NAME AND BUSINESS ADDRESS OF THE APPLICANT: Hoechst Marion Roussel Limited
16th Road, Midrand.
DATE OF PUBLICATION OF THIS PACKAGE INSERT: 14 April 1975
Hoechst Marion Roussel Ltd.
Under licence to Asta Medica, AG, Frankfurt, Germany.