ble inhibition of fluorocytosine efficacy during therapy with cytarabine. this may be due to potential competitive inhibition of its uptake.

cytarabine) has been reported following some experimental cytarabine dose schedules. these reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction, including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. rarely, severe skin rash, leading to desquamation has been reported. complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. if experimental high dose therapy is used, do not use a diluent containing benzyl alcohol. cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. a syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. the outcome of this syndrome can be fatal. two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients. use in pregnancy : cytarabine injection can cause fetal harm when administered to a pregnant woman. cytarabine causes abnormal cerebellar development in the neonatal hamster and is teratogenic to the rat fetus. there are no adequate and well-controlled studies in pregnant women. women of childbearing potential should be advised to avoid becoming pregnant.

f an administered dose. in particular, patients with renal or hepatic function impairment may have a higher likelihood of cns toxicity after high-dose cytarabine treatment. use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor. periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine injection. like other cytotoxic drugs, cytarabine injection may induce hyperuricemia 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 pharmacologic measures as might be necessary to control this problem. acute pancreatitis has been reported to occur in a patient receiving cytarabine by continuous infusion and in patients being treated with cytarabine who have had prior treatment with l-asparaginase.

drug by rapid intravenous injection as compared with slow infusion. this phenomenon is related to the drug's rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either. in the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m 2 /day by continuous intravenous infusion (days 1-7) or 100 mg/m 2 intravenous every 12 hours (days 1-7). the literature should be consulted for the current recommendations for use in acute lymphocytic leukemia. intrathecal use in meningeal leukemia : cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m 2 to 75 mg/m 2 of body surface area. the frequency of administration varied from once a day for 4 days to once every 4 days. the most frequently used dose was 30 mg/m 2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. the dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy. if used intrathecally, do not use a solution containing benzyl alcohol. this pharmacy bulk package is not intended to be used for the preparation of intrathecal doses. cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. modification of other anti-leukemia therapy may be necessary. major toxicity is rare. the most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. paraplegia has been reported. necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. isolated neurotoxicity has been reported. blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine. when cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician. focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may better be treated with radiotherapy. chemical stability of infusion solutions : chemical stability studies were performed by a stability indicating hplc assay on cytarabine injection in infusion solutions. these studies showed that when cytarabine injection was diluted with water for injection, 5% dextrose injection or sodium chloride injection, in both glass and plastic infusion bags, 97-100% of the cytarabine was present after 8 days storage at room temperature. this chemical stability information in no way indicates that it would be acceptable practice to infuse a cytarabine admixture well after the preparation time. good professional practice suggests that administration of an admixture should be as soon after preparation as feasible. parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. handling and disposal : procedures for proper handling and disposal of anti-cancer drugs should be considered. several guidelines on this subject have been published. 1-7 there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. direction for dispensing from pharmacy bulk package : the 50 ml pharmacy bulk package is for use in the pharmacy admixtures service only. the vials should be inserted into the plastic handling device provided, suspended as a unit in the laminar flow hood. a single entry through the vial closure should be made with a sterile dispensing set or transfer device. transfer individual doses to appropriate intravenous infusion solutions. use of a syringe with needle is not recommended. multiple entries will increase the potential of microbial and particulate contamination. the above process should be carried out under a laminar flow hood using aseptic technique. care should be exercised to protect personnel from aerosolized drug (see dosage and administration , references ). discard any unused portion within 4 hours after initial closure entry.

10 days. infectious complications : infection : 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. the cytarabine (ara-c) syndrome : a cytarabine syndrome has been described by castleberry. it is characterized 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 deemed treatable, corticosteroids should be contemplated as well as continuation of therapy with cytarabine injection. most frequent adverse reactions : anorexia, hepatic dysfunction, nausea, fever, vomiting, rash, diarrhea, thrombophlebitis, oral and anal inflammation or ulceration, bleeding (all sites). nausea and vomiting are most frequent following rapid intravenous injection. less frequent adverse reactions : sepsis, abdominal pain, pneumonia, freckling, cellulitis at injection site, jaundice, skin ulceration, conjunctivitis (may occur with rash), urinary retention, dizziness, renal dysfunction, alopecia, neuritis, anaphylaxis (see warnings ), neural toxicity, allergic edema, sore throat, pruritus, esophageal ulceration, shortness of breath, esophagitis, urticaria, chest pain, pericarditis, headache, bowel necrosis, pancreatitis, sinus bradycardia. experimental doses : 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 dose schedules of cytarabine. these reactions include reversible corneal toxicity and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction, including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia; bowel necrosis; and necrotizing colitis. rarely, severe skin rash, leading to desquamation has been reported. complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. if experimental high dose therapy is used, do not use a diluent containing benzyl alcohol. cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation. this cardiac toxicity may be schedule dependent. a syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. the outcome of this syndrome can be fatal. two patients with adult acute non-lymphocytic leukemia developed peripheral motor and sensory neuropathies after consolidation with high-dose cytarabine, daunorubicin, and asparaginase. patients treated with high-dose cytarabine should be observed for neuropathy since dose schedule alterations may be needed to avoid irreversible neurologic disorders. ten patients treated with experimental intermediate doses of cytarabine (1 g/m 2 ) with and without other chemotherapeutic agents (meta-amsa, daunorubicin, etoposide) at various dose regimens developed a diffuse interstitial pneumonitis without clear cause that may have been related to the cytarabine. two cases of pancreatitis have been reported following experimental doses of cytarabine and numerous other drugs. cytarabine could have been the causative agent.

ble inhibition of fluorocytosine efficacy during therapy with cytarabine. this may be due to potential competitive inhibition of its uptake.

; it is inactivated by a pyrimidine nucleoside deaminase which converts it to the nontoxic uracil derivative. it appears that the balance of kinase and deaminase levels may be an important factor in determining sensitivity or resistance of the cell to cytarabine. human pharmacology : cytarabine is rapidly metabolized and is not effective orally; less than 20 percent of the orally administered dose is absorbed from the gastrointestinal tract. following rapid intravenous injection of cytarabine, labeled with tritium, the disappearance from plasma is biphasic. there is an initial distributive phase with a half-life of about 10 minutes, followed by a second elimination phase with a half-life of about 1 to 3 hours. after the distributive phase, more than 80 percent of plasma radioactivity can be accounted for by the inactive metabolite 1- β -d-arabinofuranosyluracil (ara-u). within 24 hours about 80 percent of the administered radioactivity can be recovered in the urine, approximately 90 percent of which is excreted as ara-u. relatively constant plasma levels can be achieved by continuous intravenous infusion. after subcutaneous or intramuscular administration of cytarabine labeled with tritium, peak-plasma levels of radioactivity are achieved about 20 to 60 minutes after injection and are considerably lower than those after intravenous administration. cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single intravenous injection. however, in one patient in whom cerebrospinal levels were examined after 2 hours of constant intravenous infusion, levels approached 40 percent of the steady state plasma level. with intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours. because cerebrospinal fluid levels of deaminase are low, little conversion to ara-u was observed. immunosuppressive action : cytarabine is capable of obliterating immune responses in man during administration with little or no accompanying toxicity. suppression of antibody responses to e. coli-vi antigen and tetanus toxoid have been demonstrated. this suppression was obtained during both primary and secondary antibody responses. cytarabine also suppressed the development of cell-mediated responses such as delayed hypersensitivity skin reaction to dinitrochlorobenzene. however, it had no effect on already established delayed hypersensitivity reactions. following 5-day courses of intensive therapy with cytarabine, the immune response was suppressed, as indicated by the following parameters: macrophage ingress into skin windows; circulating antibody response following primary antigenic stimulation; lymphocyte blastogenesis with phytohemagglutinin. a few days after termination of therapy there was a rapid return to normal.