CYTARABINE

Chemistry - A synthetic pyrimidine nucleoside antimetabolite, cytarabine occurs as an odorless, white to off-white, crystalline powder with a pKa of 4.35. It is freely soluble in water and slightlysoluble in alcohol. Cytarabine is also commonly known as ARA-C or Cytosine Arabinoside. It mayalso be known as 1-beta-D-Arabinofuranosylcytosine or Arabinosylcytosine.

Storage, Stability, Compatibility

Cytarabine sterile powder for injection should be stored atroom temperature (15-30°C). After reconstituting with bacteriostatic water for injection, solutionsare stable for at least 48 hours when stored at room temperature. One study however, demonstratedthat the reconstituted solution retains 90% of its potency for up to 17 days when stored at roomtemperature. If the solution develops a slight haze, the drug should be discarded.
Cytarabine is reportedly compatible with the following intravenous solutions and drugs: aminoacids 4.25%/dextrose 25%, dextrose containing solutions, dextrose-saline combinations, dextrose-lactated Ringer's injection combinations, Ringer's injection, lactated Ringer's injection, sodiumchloride 0.9%, sodium lactate 1/6 M, corticotropin, lincomycin HCl, methotrexate sodium, metoclopramide HCl, potassium chloride, prednisolone sodium phosphate, sodium bicarbonate, andvincristine sulfate.
Cytarabine compatibility information conflicts or is dependent on diluent or concentrationfactors with the following drugs or solutions: cephalothin sodium, gentamicin sulfate, hydrocortisone sodium succinate, and methylprednisolone sodium succinate. Compatibility is dependentupon factors such as pH, concentration, temperature and diluents used. It is suggested to consultspecialized references for more specific information (e.g., Handbook on Injectable Drugs by
Trissel; see bibliography).
Cytarabine is reportedly incompatible with the following solutions or drugs: carbenicillin disodium, fluorouracil, regular insulin, nafcillin sodium, oxacillin sodium, and penicillin G sodium.

Pharmacology - CYTARABINE

Cytarabine is converted intracellularly into cytarabine triphosphate which apparently competes with deoxycytidine triphosphate, thereby inhibiting DNA polymerase with resulting inhibition of DNA synthesis. Cytarabine is cel phase specific, and acts principally duringthe S-phase (DNA synthesis). It may also, under certain conditions, block cells from the G1 phaseto the S phase.
Uses, Indications - In veterinary medicine, cytarabine is used primarily in small animals as an antineoplastic agent for lymphoreticular neoplasms, myeloproliferative disease and CNS lymphoma. Refer to the Dosages below or the Protocols (at the end of this section), for more information.

Pharmacokinetics - CYTARABINE

Cytarabine has very poor systemic availability after oral administration and isonly used parenterally. Following IM or SQ injections, the drug peaks in the plasma within 20-60minutes, but levels attained are much lower than with an equivalent IV dose.
Cytarabine is distributed widely throughout the body, but crosses into the CNS in only a limitedmanner. If given via continuous IV infusion, CSF levels are higher than with IV bolus injection andcan reach 40-60% of those levels found in the plasma. In humans, cytarabine is only about 13%bound to plasma proteins. The drug apparently crosses the placenta, but it is not known if it entersmilk.
Circulating cytarabine is rapidly metabolized by the enzyme cytidine deaminase, principally in theliver, but also in the kidneys, intestinal mucosa, and granulocytes, to the inactive metabolite ara-U(uracil arabinoside). About 80% of a dose is excreted in the urine within 24 hours as both ara-U(»90%) and unchanged cytarabine (»10%).

Contraindications, Precautions, Reproductive Safety

Cytarabine is contraindicated in patientshypersensitive to it. Because of the potential for development of serious adverse reactions, cytarabine should only be used in patients who can be adequately and regularly monitored.
The person preparing or administering cytarabine for injection, need not observe any specialhandling precautions other than wearing gloves. However, should any contamination occur, thoroughly wash off the drug from skin or mucous membranes.
Cytarabine's safe use in pregnancy has not been established and it is potentially teratogenic andembryotoxic.

Adverse Effects, Warnings

The principal adverse effects of cytarabine is myelosuppression(with leukopenia being most prevalent), but anemia and thrombocytopenia can also be seen.
Myelosuppressive effects are more pronounced with IV administration and reach a nadir at 5-7days, and generally recover at 7-14 days.
GI disturbances (anorexia, nausea, vomiting, diarrhea), conjunctivitis, oral ulceration, hepatotoxicityand fever may also be noted with cytarabine therapy. Anaphylaxis has been reported, but is believedto occur very rarely.
Cytarabine is a mutagenic and potentially carcinogenic agent.

Overdosage, Acute Toxicity

Cytarabine efficacy and toxicity (see Adverse Effects) are dependent not only on the dose, but also the rate the drug is given. In dogs, the IV LD50 is 384 mg/kgwhen given over 12 hours and 48 mg/kg when infused IV over 120 hours. Should an inadvertentoverdose occur, supportive therapy should be instituted.

Drug Interactions

Presumably due to causing alterations in the intestinal mucosa, cytarabinemay decrease the amount of digoxin (tablets only) that is absorbed after oral dosing. This effectmay persist for several days after cytarabine has been discontinued.
Limited studies have indicated that cytarabine may antagonize the anti-infective activity of gentamicin or flucytosine. Animals receiving either of these drugs with cytarabine should be closely monitored for decreased anti-infective efficacy.
Drug/Laboratory Interactions - None reported.