CYTARABINE

By intravenous infusion or injection or subcutaneous injection. Only general recommendations can be given, as acute leukaemia is almost exclusively treated with combinations of cytostatics. Dosage recommendation may be converted from those in terms of bodyweight to those related to surface area by means of nomograms.

1) Remission induction: Adult a) Continuous treatment: i) Rapid injection - 2 mg/kg/day is a judicious starting dose. Administer for 10 days. Obtain daily blood counts. If no antileukaemic effect is noted and there is no apparent toxicity, increase to 4 mg/kg/day and maintain until therapeutic response or toxicity is evident.

Almost all patients can be carried to toxicity with these doses. 0 mg/kg/day may be given in an infusion of up to 24 hours duration. Results from one-hour infusions have been satisfactory in the majority of patients. After 10 days this initial daily dose may be increased to 2 mg/kg/day subject to toxicity.

Continue to toxicity or until remission occurs. b) Intermittent treatment: i) 3-5 mg/kg/day are administered intravenously on each of five consecutive days. After a two to nine day rest period, a further course is given. Continue until response or toxicity occurs.

The first evidence of 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 toxicity nor remission after a fair trial, the cautious administration of higher doses is warranted.

As a rule, patients have been seen to tolerate higher doses when given by rapid intravenous injection as compared with slow infusion. This difference is due to the rapid metabolism of Cytarabine and the consequent short duration of action of the high dose.

2) Maintenance therapy: Remissions which have been induced by cytarabine, or by other drugs, may be maintained by intravenous or subcutaneous injection of 1 mg/kg once or twice weekly.

Paediatric population:

Children appear to tolerate higher doses of cytarabine than adults, and where the range of doses is given, children should receive the higher dose. 4). Cytarabine can be dialyzed. Therefore, Cytarabine should not be administered immediately before or after a dialysis.

Elderly Patients:

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 leukopenia, thrombocytopenia, and anaemia, with appropriate initiation of supportive therapy when indicated.

4) Most frequent adverse reactions include nausea, vomiting, diarrhoea, fever, rash, anorexia, oral and anal inflammation or ulceration, and hepatic dysfunction.

Blood and lymphatic system disorders:

Because cytarabine is a bone marrow suppressant, anaemia, leukopenia, thrombocytopenia, megaloblastosis and reduced reticulocytes can be expected as a result of its administration. The severity of these reactions are dose and schedule dependent.

Cellular changes in the morphology of bone marrow and peripheral smears can be expected.

Infections and infestations:

Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body, may be associated with the use of Cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity.

These infections may be mild, but can be severe and at times fatal.

Musculoskeletal and connective tissue disorders:

A Cytarabine syndrome has been described. It is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6 - 12 hours following drug administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome.

If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated as well as continuation of therapy with cytarabine. The reported adverse reactions are listed below by MedDRA System Organ Class and by frequency.

4) are included in the following table: Adverse Reactions Table (High Dose Therapy) Infections and Infestations: Frequency not known Liver abscess, sepsis Psychiatric Disorders: Frequency not known Personality changea Nervous System Disorders: Very common Cerebral disorder, cerebellar disorder, somnolence Frequency not known Coma, convulsion, peripheral motor neuropathy, peripheral sensory neuropathy Eye Disorders: Very common Corneal disorder Cardiac Disorders: Frequency not known Cardiomyopathyb Respiratory, Thoracic and Mediastinal Disorders: Very common Acute respiratory distress syndrome, pulmonary oedema Gastrointestinal Disorders: Common Necrotising colitis Frequency not known Gastrointestinal necrosis, gastrointestinal ulcer, pneumatosis intestinalis, peritonitis Hepatobiliary Disorders: Frequency not known Liver injury, hyperbilirubinaemia Adverse Reactions Table (High Dose Therapy) Skin and Subcutaneous Tissue Disorders: Common Skin exfoliation, aPersonality change was reported in association with cerebral and cerebellar dysfunction.

bWith subsequent death Other adverse reactions A diffuse interstitial pneumonitis without clear cause that may have been related to cytarabine was reported in patients treated with experimental intermediate doses of cytarabine (1g/m2) with and without other hemotherapeutic agents (meta-AMSA, daunorubicin, VP-16).

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and a radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia; fatal outcome has been reported.

Nervous system disorders:

After treatment with high doses of cytarabine, symptoms of cerebral or cerebellar influence like personality changes, affected alertness, dysarthria, ataxia, tremor, nystagmus, headache, confusion, somnolence, dizziness, coma, convulsions, etc.

appear in 8-37 % of treated patients. The incidence in elderly (>55 years) may […]

General:

Only physicians experienced in cancer chemotherapy should use cytarabine.

Warnings:

Haematologic Effects: 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, hemoglobin and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia, anaemia, megaloblastosis and reduced reticulocytes. 8). 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. Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defences, and haemorrhage secondary to thrombocytopenia).

Anaphylactic reactions have occurred with cytarabine treatment. Anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. 8).

High Dose Schedules:

Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of Cytarabine) has been reported following some experimental high dose (2-3 g/m2) schedules with Cytarabine. 8). Cytarabine has been shown to be carcinogenic in animals.

The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.

Precautions:

Patients receiving Cytarabine must be monitored closely. Frequent hemoglobin, platelet and leucocyte counts are mandatory. Suspend or modify therapy when drug- induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte 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, restart therapy 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. Peripheral motor and sensory neuropathies after consolidation with high doses of cytarabine, daunorubicin, and asparaginase have occurred in adult patients with acute non lymphocytic leukemia.

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 experimental high dose schedules with cytarabine therapy.

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.

Conventional Dose Schedules:

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.

Hepatic and/or Renal Function:

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

Use the drug with caution and at reduced dose in patients whose liver function is poor. Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

Neurological:

Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given intravenous cytarabine in combination with intrathecal methotrexate.

The safety of this drug for use in infants is not established.

Tumour Lysis Syndrome:

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.

Pancreatitis:

Cases of pancreatitis have been observed with the induction of cytarabine. Immunosuppressant Effects/Increased Susceptibility to Infections: […]

Therapy with cytarabine should not be considered in patients with severe bone marrow suppression. Cytarabine should not be used in the management of non- malignant disease, except for immunosuppression. 1 Degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionising radiation