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Cytarabine Injection should not be administered by the intrathecal route. Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving the drug should be kept under close medical supervision. Leucocyte and platelet counts should be performed frequently and daily during induction. 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, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses and haemorrhage secondary to thrombocytopenia).
One case of anaphylaxis that resulted in cardiopulmonary arrest and necessitated resuscitation has been reported. This occurred immediately after intravenous cytarabine was administered.
Severe and at times fatal central nervous system (CNS), gastrointestinal (GI) and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some experimental cytarabine dose schedules. These reactions include reversible corneal toxicity; cerebral and cerebellar dysfunction, usually reversible; somnolence; convulsion; severe gastrointestinal ulceration including pneumatosis cysteroides intestinalis, leading to peritonitis; sepsis and liver abscess; and pulmonary oedema.
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. Rarely, neurological effects such as severe spinal cord toxicity even leading to necrotising encephalopathy, quadriplegia and paralysis and blindness have been reported with cytosine arabinoside and have been predominantly associated with intrathecal administration. Isolated cases have also been reported with high intravenous doses during combination chemotherapeutic regimens.
Delayed progressive ascending paralysis resulting in death has been reported in children with AML following intravenous cytarabine at conventional doses in combination with other drugs.
Cytarabine has been shown to be mutagenic and carcinogenic in animals. The possibility of a similar effect should be borne in mind when designing the long-term management of the patient.
Cytarabine should be administered only under constant supervision by physicians experienced in therapy with cytotoxic agents. Hyperuricaemia secondary to rapid lysis of neoplastic cells may occur in patients receiving cytarabine; serum uric acid concentrations should be monitored. The physician should be prepared to use such supportive and pharmacological measures as may be necessary to control this problem. Periodic determinations of renal and hepatic functions and bone marrow should also be performed, and the drug should be used with caution in patients with impaired hepatic function. However, dosage reduction does not appear to be necessary in patients with impaired renal function. The human liver apparently detoxifies a substantial fraction of the administered dose. The drug should be used with caution and at a reduced dose when liver function is poor. Frequent platelet and leucocyte counts are mandatory.
Therapy should be suspended or modified when drug-induced bone marrow depression results in a platelet count of less than 50,000 or a polymorphonuclear count of under 1000 per mm3. Counts may continue to fall after the therapy has been discontinued and may reach lowest values after five to seven days. Therapy may be restarted when the bone marrow appears to be recovering on successive bone marrow studies. Therapy should not wait until the normal blood values are obtained to be re-initiated. If treatment is not resumed before blood values return to normal, the disease can get out of control.
When intravenous doses are given quickly, patients may become nauseated and may vomit for several hours afterwards. The problem tends to be less severe when infused. 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. Concurrent granulocyte-transfusion should be avoided as severe respiratory insufficiency has been reported.
Immunosuppressant effects/Increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cytarabine, 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: 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 adjustments may be needed to avoid irreversible neurologic disorders. Severe and sometimes fatal pulmonary toxicity, adult respiratory distress syndrome, and pulmonary edema 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.
The safety of the drug has not been established in infants.
Patients receiving chemotherapy may have an impaired ability to drive or operate machinery and should be warned of the possibility and advised to avoid such tasks if so affected.
Carcinogenesis, Mutagenesis, Impairment of fertility: Extensive chromosomal damage, including chromatoid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported.
Fertility studies to assess the reproductive toxicity of cytarabine have not been conducted. Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking cytarabine therapy, especially in combination with alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Given that cytarabine has a mutagenic potential which could induce chromosomal damage in the human spermatozoa, males undergoing cytarabine treatment and their partner should be advised to use a reliable contraceptive method.
