cytarabine 50 MG/ML Injectable Suspension

INDICATIONS AND USAGE Cytarabine Injection in combination with other approved anti-cancer drugs is indicated for remission induction in acute non-lymphocytic leukemia of adults and pediatric patients. It has also been found useful in the treatment of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of Cytarabine Injection (preservative free preparations only) is indicated in the prophylaxis and treatment of meningeal leukemia.

DOSAGE AND ADMINISTRATION Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for intravenous infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only. Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. While Cytarabine Injection may be given by intravenous infusion or injection, or subcutaneously or intrathecally, THE PURPOSE OF THE PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF INTRAVENOUS INFUSIONS. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated. Patients can tolerate higher total doses when they receive the 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.

WARNINGS (See boxed WARNING ) Cytarabine is a potent bone marrow suppressant. 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. 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 hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine injection. Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine injection) has been reported following some experimental dose schedules for cytarabine injection. 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 treatment programs using cytarabine injection. If experimental high dose therapy is used, do not use a preparation containing benzyl alcohol. 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. 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 injection 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. A review of the literature has shown 32 reported cases where cytarabine injection was given during pregnancy, either alone or in combination with other cytotoxic agents: Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis. Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure. There were seven infants with various problems in the neonatal period, including pancytopenia, transient depression of WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased lgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis. Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue. Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on cytarabine should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

CONTRAINDICATIONS Cytarabine Injection is contraindicated in those patients who are hypersensitive to the drug.

CLINICAL PHARMACOLOGY Cell Culture Studies Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G 1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. Extensive chromosomal damage, including chromatoid breaks, have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. Deoxycytidine prevents or delays (but does not reverse) the cytotoxic activity. Cellular Resistance and Sensitivity Cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate, an effective inhibitor of DNA polymerase; it is inactivated by a pyrimidine nucleoside deaminase, which converts it to the non-toxic 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 fluid levels are 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 injection 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 injection also suppressed the development of cell-mediated immune 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 injection 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.