Baxter Oncology


Full Prescribing Info
A cytostatic drug from the group of alkylating agents.
Pharmacology: Cyclophosphamide is inactive under in vitro conditions and is converted into its active form in the body. The cytostatic action of cyclophosphamide and its metabolites is due to intervention in the G2- and S-phase. Whether alkylation of the DNA is the only cause of the cytostatic effect or whether this can be explained in some other way (inhibition of the chromatin transformation processes, inhibition of DNA-polymerases) still needs to be elucidated.
Leukaemias, acute or chronic lymphatic and myeloid leukaemia. Malignant lymphomas. Paraproteinaemias eg, plasmacytoma. Waldenstroem's disease. Malignant solid tumours especially carcinoma of the ovaries or breast, small-cell bronchial carcinoma, neuroblastoma, seminoma, Ewing's sarcoma. Postoperative adjuvant treatment of chemosensitive tumours.
"Autoimmune diseases" including rheumatoid arthritis (progressive chronic polyarthritis, arthropathia psoriatica), lupus erythematosus, scleroderma, systemic vasculitides (eg, with nephrotic syndrome), certain types of glomerulonephritis (eg, with nephrotic syndrome), myasthenia gravis, autoimmune haemolytic anaemia, cold agglutination diseases. Organ and bone marrow transplantations. Endoxan should be used in nonmalignant conditions only in case of a vital indication and only if conventional treatment has failed.
Dosage/Direction for Use
Initial Treatment: Generally by IV injections. Dosage must be strictly individual, taking into consideration the general state of the patient and his WBC. Initial treatment is recommended with:
a) Daily IV injections of 3-6 mg/kg body weight (120-240 mg/m2) or;
b) Massive-Intermittent Therapy: 10-15 mg/kg body weight (400-600 mg/m2), with therapy-free intervals of 2 or 5 days, or;
c) Massive-Intermittent Therapy: 20-40 mg/kg body weight (800-1600 mg/m2), with therapy-free intervals of 10-20 days.
Endoxan should be given in the morning with liberal amounts of liquids, during and immediately after administrations. For continuation or maintenance therapy, 50-200 mg/day may be given orally.
Preparation of Solutions: Dissolve 200 mg in 10 mL of Water for Injection (double-distilled water). Do not use physiological saline as a solvent. The solutions should be used within 24 hrs after preparation. The substance dissolves readily when the vial is shaken vigorously for ½-1 min after addition of the solvent. If complete dissolution is not achieved immediately, allow the solution to stand for some minutes until it is thoroughly clear.
There is no known antidote specific for Endoxan. Overdosage is likely to result in dose-related side effects (see Side Effects). Management of overdosage would include general supportive measures to sustain the patient through any period of toxicity that might occur eg, dialysis, forced diuresis, monitoring and support of vital functions.
Known hypersensitivity; severe impairment of bone marrow and renal function, acute infection, inflammation of the bladder (cystitis), obstruction of the lower urinary tract, pregnancy.
Special Precautions
Patients of both sexes in the reproductive age should take contraceptives during therapy and for the following 6 months. Before the onset of therapy, all conditions of hampered urinary flow in the efferent urinary passages should be excluded, possible infections have to be cured, and disturbances of the electrolyte balance should be corrected, if necessary.
In general, cyclophosphamide, like all other cytostatics, should be used with care in weakened or elderly patients and in patients who have had previous radiotherapy. Patients with a weakened immune system eg, those with diabetes mellitus, chronic hepatic or renal impairments, also require special care.
Use In Pregnancy & Lactation
This drug is contraindicated during pregnancy.
Side Effects
The following dose-dependent side effects can occur, which in most cases are reversible.
Blood: Leucocytopenia, with the risk of life-threatening infections; thrombocytopenia, with the risk of bleeding; and anaemia, with a haemoglobin decrease of >2 g/100 mL compared to the initial value. The lowest leucocyte and thrombocyte counts normally occur 1-2 weeks after start of treatment and recover within 3-4 weeks.
A combination treatment with other myelosuppressive agents may require dose adjustments. Therefore, the doctor should refer to the relevant tables on dose adjustment of cytotoxic drugs to the blood counts at the beginning of the cycle and the nadir-adjusted dosage of cytostatic agents.
Gastrointestinal Side Effects: Frequently, nausea and vomiting; seldom anorexia, diarrhoea, constipation and stomatitis.
Haemorrhagic colitis and ulcerations on the buccal mucosa have been reported in isolated cases.
Urogenital Tract: Therapy-dependent cystitis after administration of Endoxan is a frequent side effect requiring an interruption of treatment.
After elimination into the urine, cyclophosphamide and its metabolites lead to changes in the bladder eg, bladder-wall oedema, suburothelial bleedings, interstitial inflammations with fibrosis and, eventually, to a rigidity of the bladder wall. Cystitis is initially sterile, but secondary microbial invasion may occur. In isolated cases, haemorrhagic cystitis with subsequent death has been reported. Renal lesions (in particular with a history of impaired renal function) are rare side effects after high doses.
Note: Treatment with Uromitexan (mesna), adequate hydration and alkalinisation of the urine can markedly reduce the frequency and severity of these urotoxic side effects.
In case of concomitant diuretic treatment, urinary alkalinisation is not allowed due to the risk of an increased bladder toxicity.
Hepatotoxicity: In rare cases, impaired liver function has been reported, identified by an increase of the relevant laboratory parameters (SGOT, SGPT, γ-GT, alkaline phosphatase, bilirubin).
Cardiovascular System: Secondary cardiomyopathy induced by cytotoxic drugs has particularly been reported after high doses of cyclophosphamide (120-240 mg/kg body weight). There are signs indicating an enhanced cardiotoxicity of cyclophosphamide after previous radiotherapy of the cardiac region and concomitant anthracycline treatment.
Secondary Tumours: As with cytotoxic therapy in general, treatment with cyclophosphamide involves the risk of secondary tumours and their precursors as late sequelae. The risk of developing urinary tract cancer as well as myelodysplastic alterations partly progressing to acute leukaemias is increased. Animal studies prove that the risk of bladder cancer can be markedly reduced by giving an adequate dose of Uromitexan (mesna).
Other Side Effects: Alopecia, a frequent side effect, is in general reversible. Cases of pigment changes of the palms, finger nails and the soles have also been reported. In addition, the following side effects were observed:
Partly irreversible impairment of spermatogenesis, with resulting azoospermia or persistent oligospermia. Less frequently irreversible ovulation disturbances with resulting amenorrhea.
Chronic interstitial lung fibrosis.
Syndrome of inappropriate ADH secretion (Schwarz-Bartter syndrome) with hyponatraemia and water retention.
Inflammation of the skin and mucous membrane.
Hypersensitivity reactions, in isolated cases progressing to shock.
Blurred vision and episodes of dizziness.
Note: Attention should be paid to meticulous oral hygiene. Regular blood counts are indicated during treatment: Intervals of 5-7 days at initial therapy, intervals of 2 days in case the level of white cells decreases <3000/mm3, eventually daily. Checks every 2 weeks are generally sufficient in case of long-term therapy. The urinary sediment should be checked regularly for erythrocytes.
Drug Interactions
Apart from a variety of drug interactions that have been observed only in experimental situations, clinically significant interactions have been described between cyclophosphamide and allopurinol (increased incidence of bone marrow depression), antidiabetic agents (potentiation of hypoglycaemic effect) and suxamethonium (prolongation of apnoea).
Caution For Usage
Physiological saline should not be used as a solvent to avoid hyperosmolarity.
Endoxan vials with dry injectable powder are stored at room temperature not exceeding 25°C. After preparation, the injectable solution is used within 24 hrs. In this period, the solution is kept in the refrigerator, at temperatures lower than 8°C.
During transport or storage of Endoxan, temperature influences can lead to melting of the active ingredient cyclophosphamide. Vials containing melted substance can easily be optically differentiated from those containing the intact active ingredient: Melted cyclophosphamide is clear or yellowish viscous liquid (usually found as connected phase or in droplets in the affected vials). Do not use injection vials with the melted content. With doses of ≥10 mg/kg and in high-risk patients (previous cystitis during earlier treatment with Endoxan or similar drugs, previous irradiation of the small pelvis and in preexisting urinary tract damage) Uromitexan (mesna) should always be given to protect the bladder.
The known procedures of safe handling of cytotoxic drugs should be followed.
Do not store at temperatures above +25°C.
ATC Classification
L01AA01 - cyclophosphamide ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.
Coated tab 50 mg x 50's, 1000's. Powd for inj (vial) 1000 mg x 1's.
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