CYTARABINE - cytarabine injection, powder, lyophilized, for solution
Bedford Laboratories
Cytarabine for Injection USP
For Intravenous, Intrathecal, or Subcutaneous Use Only
Rx ONLY.
WARNINGS
Only physicians experienced in cancer chemotherapy should use Cytarabine for Injection USP.
For induction therapy, patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia, and anemia. Less serious toxicity includes nausea, vomiting, diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction.
The physician must judge possible benefit to the patient against known toxic effects of this drug in considering the advisability of therapy with cytarabine. Before making this judgement or beginning treatment, the physician should be familiar with the following text.
DESCRIPTION
Cytarabine for Injection USP, commonly known as ara-C, an antineoplastic for intravenous, intrathecal, or subcutaneous administration, contains sterile lyophilized cytarabine (1-ß-D-Arabinofuranosylcytosine). Cytarabine is an odorless, white to off-white, crystalline powder which is freely soluble in water and slightly soluble in alcohol and in chloroform. Cytarabine is a synthetic nucleoside which differs from the normal nucleosides cytidine and deoxycytidine in that the sugar moiety is arabinose rather than ribose or deoxyribose. Its structural formula is:
C9H13N3O5 M.W.=243.22
Cytarabine for Injection USP is available in vials containing 100 mg, 500 mg, 1 g, and 2 g cytarabine. When necessary, the pH of Cytarabine for Injection USP was adjusted with hydrochloric acid and/or sodium hydroxide. Reconstitute with Bacteriostatic Water for Injection USP with benzyl alchohol for intravenous and subcutaneous use only. Do not use this diluent intrathecally. See “WARNINGS" Section.
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 G1 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, has 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 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 when taken orally; less than 20% 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% of pl
