CYTARABINE

Cytarabine 20 mg/ml solution for injection/infusion is intended for intravenous, intramuscular, subcutaneous or intrathecal use. Subcutaneous injection is generally well tolerated, and may be recommended when used in maintenance therapy.

Cytarabine 20 mg/ml solution for injection/infusion can be diluted with Sterilised Water for Injections, Glucose Intravenous Infusion or Sodium Chloride Intravenous Infusion. Treatment with cytarabine should be initiated by, or be in consultation with, a doctor with extensive experience in treatment with cytostatics.

Only general recommendations can be given, as acute leukaemia is almost exclusively treated with combinations of cytostatics. Dosage recommendations, may be made according to body weight (mg/kg) or according to BSA(mg/m2). Dose recommendation may be converted from those in terms of bodyweight to those related to surface area by means of nomograms.

Remission Induction:

Continuous treatment: The usual dose in leukaemia is 2 mg/kg/day by rapid intravenous injection daily for ten days. If after ten days neither therapeutic response nor toxicity has been observed, the dose may be increased to 4 mg/kg/day until a therapeutic response or toxicity is evident.

Almost all patients can be carried to toxicity with these doses. 5 to 1 mg/kg/day may be infused daily in 1-24 hours for ten days, and then at a rate of 2 mg/kg/day until toxicity is observed. Continue to toxicity or until remission occurs.

Results from one hour infusions have been satisfactory in the majority of patients.

Intermittent treatment:

Cytarabine may be given as intermittent intravenous doses of 3-5 mg/kg daily, for five consecutive days. This course of treatment can be repeated after 2 to 9 days rest period, and repeated until the therapeutic response or toxicity is exhibited.

Evidence of bone marrow improvement has been reported to occur 7-64 days (mean 28 days) after the beginning of therapy. In general, if a patient shows neither remission nor toxicity after a trial period, the cautious administration of higher doses is warranted.

Generally patients tolerate higher doses given by rapid intravenous injection rather than slow infusion. This difference is due to the rapid metabolism of Cytarabine and the consequent short duration of action of the high dose. Cytarabine has been given in doses of 100-200 mg/m2/24 hours by continuous infusion for 5-7 days alone or combination with other cytostatics including for instance an anthracycline has been used.

Additional cycles may be administered at intervals of 2-4 weeks, until remission is achieved or unacceptable toxicity occurs.

Maintenance therapy:

To maintain remission, doses of 1 mg/kg may be given intravenously or subcutaneously, once or twice weekly. Cytarabine has also been administered in doses of 100-200 mg/m², as continuous infusion for 5 days at monthly intervals as monotherapy or in combination with other cytostatics.

Intrathecally Doses between 5 and 30 mg/m² BSA have been administered. For the treatment of meningeal leukaemia, usually a dose of 30 mg/m² BSA is given once every 4 days until cerebrospinal fluid findings are normal, followed by one additional dose.

The injection should be slow. 8.

High dosage:

Cytarabine, under strict medical surveillance, is administered as monotherapy or in combination with other cytostatics, 2-3 g/m², as intravenous infusion, for 1-3 hours every 12 hours for 2-6 days (total of 12 doses per cycle). A total treatment dose of 36 g/m2 should not be exceeded.

Frequency of treatment cycles depends on the response to treatment and haematological and non-haematogological toxicity. 4) for treatment stopping requirements.

Paediatric patients:

Children appear to tolerate higher doses than adults and, where dose ranges are quoted, the children should receive the higher dose and the adults the lower.

Patients with hepatic and renal impairment:

Patients with impaired hepatic or renal function: Dosage should be reduced. Cytarabine can be dialyzed. Therefore, Cytarabine should not be administered immediately before or after a dialysis.

Elderly patients:

High dose therapy in patients > 60 years should be administered only after careful risk benefit-evaluation. There is no information to suggest that a change in dosage is warranted in the elderly. Nevertheless, the elderly patient does not tolerate drug toxicity as well as the younger patient, and particular attention should thus be given to drug induced leucopenia, thrombocytopenia, and anaemia, with appropriate initiation of supportive therapy when indicated.

6.

8.

High dosage:

Cytarabine, under strict medical surveillance, is administered as monotherapy or in combination with other cytostatics, 2-3 g/m², as intravenous infusion, for 1-3 hours every 12 hours for 2-6 days (total of 12 doses per cycle). A total treatment dose of 36 g/m2 should not be exceeded.

Frequency of treatment cycles depends on the response to treatment and haematological and non-haematogological toxicity. 4) for treatment stopping requirements.

Paediatric patients:

Children appear to tolerate higher doses than adults and, where dose ranges are quoted, the children should receive the higher dose and the adults the lower.

Patients with hepatic and renal impairment:

Patients with impaired hepatic or renal function: Dosage should be reduced. Cytarabine can be dialyzed. Therefore, Cytarabine should not be administered immediately before or after a dialysis.

Elderly patients:

High dose therapy in patients > 60 years should be administered only after careful risk benefit-evaluation. There is no information to suggest that a change in dosage is warranted in the elderly. Nevertheless, the elderly patient does not tolerate drug toxicity as well as the younger patient, and particular attention should thus be given to drug induced leucopenia, thrombocytopenia, and anaemia, with appropriate initiation of supportive therapy when indicated.

6. 1. g. bone marrow aplasia), unless the benefits outweigh the risk. Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation. 6). 4 Special warnings and precautions for use General: Only physicians experienced in cancer chemotherapy should use cytarabine.

Cytarabine should only be used with great caution in patients who have recently received radiotherapy or other cytotoxic agents. Cytarabine should only be administered with caution under the direction of a specialist oncology service having the facilities for regular monitoring of clinical biochemical and haematological effects during and after administration.

Cytarabine is a potent bone marrow suppressant; the severity depends on the dose of the drug and the schedule of administration. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression.

Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leucocyte and platelet counts performed daily. Periodic bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

Facilities should be available for management of complications, possibly fatal bone marrow suppression (infection resulting from granulocytopenia and other impaired body defences, and haemorrhage secondary to thrombocytopenia). Patients receiving cytarabine must be monitored closely.

Frequent platelet and leucocyte counts are mandatory. Therapy should be suspended or modified when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear count under 1,000 per cubic mm. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped, and reach lowest values after drug-free intervals of 12 to 24 days.

If indicated, therapy may be restarted when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until 'normal' peripheral blood values are attained may escape from control. Following 5-day constant infusions or acute injections of 50 mg/m2 to 600 mg/m2, white cell depression follows a biphasic course.

Regardless of initial count, dosage level, or schedule, there is an initial fall starting the first 24 hours with a nadir at days 7-9. This is followed by a brief rise which peaks around the twelfth day. A second and deeper fall reaches nadir at days 15-24.

Then there is rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at 5 days with a peak depression occurring between days 12-15. Thereupon, a rapid rise to above baseline occurs in the next 10 days. Anaphylactic reactions have occurred with cytarabine treatment.

Anaphylaxis that resulted in acute cardiopulmonary arrest and necessitated resuscitation has been reported. This occurred immediately after intravenous cytarabine was administered. Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

The human liver apparently detoxifies a substantial fraction of an administered dose of cytarabine. In particular, patients with renal or hepatic impairment may have a higher likelihood of CNS toxicity after high-dose treatment with cytarabine.

The drug should be used with caution and at reduced dose in patients whose liver function is poor. However, dosage reduction does not appear to be necessary in patients with impaired renal function. Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency have been reported.

Like other cytotoxic drugs, cytarabine may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacological measures as may be necessary to control this problem.

When intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours afterwards. This problem tends to be less severe when the drug is infused. […]

General:

Only physicians experienced in cancer chemotherapy should use cytarabine. Cytarabine should only be used with great caution in patients who have recently received radiotherapy or other cytotoxic agents. Cytarabine should only be administered with caution under the direction of a specialist oncology service having the facilities for regular monitoring of clinical biochemical and haematological effects during and after administration.

Cytarabine is a potent bone marrow suppressant; the severity depends on the dose of the drug and the schedule of administration. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression.

Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leucocyte and platelet counts performed daily. Periodic bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

Facilities should be available for management of complications, possibly fatal bone marrow suppression (infection resulting from granulocytopenia and other impaired body defences, and haemorrhage secondary to thrombocytopenia). Patients receiving cytarabine must be monitored closely.

Frequent platelet and leucocyte counts are mandatory. Therapy should be suspended or modified when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear count under 1,000 per cubic mm. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped, and reach lowest values after drug-free intervals of 12 to 24 days.

If indicated, therapy may be restarted when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until 'normal' peripheral blood values are attained may escape from control. Following 5-day constant infusions or acute injections of 50 mg/m2 to 600 mg/m2, white cell depression follows a biphasic course.

Regardless of initial count, dosage level, or schedule, there is an initial fall starting the first 24 hours with a nadir at days 7-9. This is followed by a brief rise which peaks around the twelfth day. A second and deeper fall reaches nadir at days 15-24.

Then there is rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at 5 days with a peak depression occurring between days 12-15. Thereupon, a rapid rise to above baseline occurs in the next 10 days. Anaphylactic reactions have occurred with cytarabine treatment.

Anaphylaxis that resulted in acute cardiopulmonary arrest and necessitated resuscitation has been reported. This occurred immediately after intravenous cytarabine was administered. Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

The human liver apparently detoxifies a substantial fraction of an administered dose of cytarabine. In particular, patients with renal or hepatic impairment may have a higher likelihood of CNS toxicity after high-dose treatment with cytarabine.

The drug should be used with caution and at reduced dose in patients whose liver function is poor. However, dosage reduction does not appear to be necessary in patients with impaired renal function. Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency have been reported.

Like other cytotoxic drugs, cytarabine may induce hyperuricaemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacological measures as may be necessary to control this problem.

When intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours afterwards. This problem tends to be less severe when the drug is infused. Cytarabine has been shown to be mutagenic and carcinogenic in animals.

The possibility of the above effects should be considered when cytarabine is used in long- term management of patients. Abdominal tenderness (peritonitis) and guaiac positive colitis, with concurrent neutropenia and thrombocytopenia, have been reported in patients treated with conventional doses of cytarabine in combination with other drugs.

Patients have responded to nonoperative medical management. Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intrathecal and intravenous cytarabine at conventional doses in combination with other drugs.

Immunosuppressant effects/Increased susceptibility to infections Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cytarabine, may result in serious or fatal infections.

Vaccination with a live vaccine should be avoided in patients receiving cytarabine. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

High dose therapy:

The risk of CNS toxicity increases if high dose cytarabine is given in combination with another CNS toxic treatment such as radiation therapy or in patients who have previously had CNS treatment as chemotherapy intrathecally. Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acute non lymphocytic leukaemia.

Patients treated with high doses of cytarabine should be observed for neuropathy since dose schedule alterations may be needed to avoid irreversible neurologic disorders. Severe and sometimes fatal pulmonary toxicity, adult respiratory distress syndrome and pulmonary oedema have occurred following high dose schedules with cytarabine therapy.

Cases of cardiomyopathy with subsequent death have been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. Paediatric population […]

1. g. bone marrow aplasia), unless the benefits outweigh the risk. Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation. 6).