Cytarabine

243.22

243.22

205-705-9

04079A1RDZ

DTXSID3022877

C408

Prisms from 50% ethanol|WHITE TO OFF-WHITE CRYSTALLINE POWDER

L01XY01|L01BC01|L - Antineoplastic and immunomodulating agents

29349990

129

-2.1

crystalline

1.9±0.1 g/cm3

212-213 °C

545.7ºC at 760 mmHg

274.1±32.9 °C

1.756

H2O: almost transparency;H2O: 50 mg/mL, clear, colorless

2-8°C

8.74X10-12 mm Hg at 25 deg C (est)

Oral-rat LD50: > 5000 mg/kg; Oral-Mouse LD50: 3150 mg/kg

Flammable; burning produces toxic nitrogen oxide fumes

D24 +153° (c = 0.5 in water)

ODORLESS

Henry's Law constant = 1.57X10-19 atm-cu m/mol at 25 °C (est)

pKa = 4.22

150.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

NON-HYGROSCOPIC @ 40 °C|Hydroxyl radical reaction rate constant = 1.23X10-10 cu cm/molec-sec at 25 °C (est)

Water soluble.

Alcohols and Polyols

NONH for all modes of transport

3

43-63-36/37/38-20/21/22

36/37-37/39-36-26

HA5425000

Xn,Xi

Treasury is ventilated, low temperature and dry; stored separately from food materials

Skin allergy

The manufacturer also recommends that any unused portion of cytarabine injection in pharmacy bulk packages be discarded within 4 hr after initial entry through the closure into the container.

P280

H317-H361

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for CYTARABINE (8 total), please visit the HSDB record page.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Weisburger EK; Bioassay Program for Carcinogenic Hazards of Cancer Chemotherapeutic Agents; Cancer 40: 1935-49 (1977). Route: intraperitoneal injection; Species: rats and mice.

STORAGE PRECAUTIONS: You should protect this material from exposure to light, and store it in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for CYTARABINE (19 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

moderately toxic

Cytarabine syndrome may develop - it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise.|/HUMAN EXPOSURE STUDIES/ The principal toxicity of standard induction regimens for acute non-lymphocytic leukemia (ANLL) [including cytarabine (ARA-C) 100 mg/sq m for 7 days plus an anthracycline] is myelotoxicity, leading to death in at least 25% of cases during induction in non-selected patients. The complete remission rate is less than 35% in patients over 65 years of age, due in part to an age-related increase of myelotoxicity. The other important adverse effect of standard-dose cytarabine is gastrointestinal toxicity, especially oral mucositis, diarrhea, intestinal ulceration, ileus and subsequent Gram-negative septicaemia. Idiosyncratic reactions like exanthema, fever and elevation of hepatic enzymes are relatively frequent, but do not represent therapeutic problems. Intermittent high-dose cytarabine (3 g/sq m in 8 to 12 doses) is extremely myelosuppressive. Similarly, the gastrointestinal toxicity is formidable and dose-limiting. Severe, and sometimes irreversible, cerebellar/cerebral toxicity in 5 to 15% of courses of treatment limits the peak dose of cytarabine. The pathogenesis, prophylactic and therapeutic measures are unknown. These major toxicities are age-related and prohibitive to the use of high-dose cytarabine therapy in patients older than 55 to 60 years. Subacute noncardiogenic pulmonary edema occurs in some patients, with an incidence of about 20%, and seems to have an intriguing coincidence with precedent streptococcal septicaemia; high-dose systemic steroids may be beneficial. Corneal toxicity is very frequent in high-dose cytarabine therapy but is always reversible. It is largely preventable with prophylactic steroid or 2-deoxycytidine eyedrops. Fever, exanthema and hepatic toxicity have an incidence similar to that in standard dosage. The maximum tolerable cumulated dose of cytarabine is significantly lower when the agent is administered as a continuous infusion, due to myelosuppression and gastrointestinal toxicity. Conversely, continuous infusion may be less neurotoxic. The antileukemic effect of continuous infusion high-dose cytarabine is less well established. The only significant toxicity of low-dose cytarabine is myelosuppression. Given the generally poor condition of leukemia patients, low-dose cytarabine therapy is well tolerated, although occasional cases of diarrhoea, reversible cerebellar symptoms, peritoneal and pericardial reactions, and ocular toxicity have been reported. Continuous infusion may be more toxic than the usual intermittent dosage. It is concluded that the toxicity of the standard induction regimen for ANLL is acceptable in patients younger than 60 to 65 years with no concurrent disease. Low dose cytarabine is tolerable for virtually all ANLL patients, but the overall therapeutic efficacy still needs to be defined and compared to standard therapy in the relevant age groups.

Serum aminotransferase elevations occur in 5% to 10% of patients on conventional doses of cytarabine and a greater proportion (9% to 75%) at higher doses. However, the serum enzyme elevations are rarely associated with symptoms and are generally self-limited and resolve rapidly, rarely requiring dose modification. Cases of clinically apparent liver injury attributed to cytarabine have been reported but are uncommon. The time to onset was usually within the first few cycles of therapy, and the pattern of serum enzyme elevations ranged from cholestatic to hepatocellular. Immunoallergic and autoimmune features were generally not present. Antineoplastic regimens, including cytarabine, have been implicated in cases of sinusoidal obstruction syndrome and peliosis, but the role of cytarabine in these reactions was unclear. Many examples of liver injury attributed to cytarabine in the literature were typical of jaundice of sepsis rather than acute hepatocellular or cholestatic injury, although high doses of cytarabine may cause hyperbilirubinemia independent of hepatic injury.

GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination chemotherapy regimens (including regimens containing cytarabine), possibly as a result of temporary damage to intestinal mucosa caused by the cytotoxic agents. Plasma concentrations of digoxin should be carefully monitored in patients receiving such combination chemotherapy regimens. Use of digoxin oral elixir or liquid-filled capsules may minimize the potential interaction, since the drug is rapidly and extensively absorbed from these dosage forms. Limited data suggest that the extent of GI absorption of digitoxin (no longer commercially available in the US) is not substantially affected by concomitant administration of combination chemotherapy regimens known to decrease absorption of digoxin.|One in vitro study indicates that cytarabine may antagonize the activity of gentamicin against Klebsiella pneumoniae. Patients receiving concurrent cytarabine and aminoglycoside therapy for the treatment of infections caused by K. pneumoniae should be closely monitored; if therapeutic response is not achieved, reevaluation of anti-infective therapy may be necessary.|Limited data suggest that cytarabine may antagonize the anti-infective activity of flucytosine, possibly by competitive inhibition of the anti-infective's uptake by fungi.|The incidence of toxicity may be increased when liposomal cytarabine is used concurrently with systemic chemotherapy in patients withneoplastic meningitis. Increased neurotoxicity has been observed in patients recievingconcomitant intrathecal administration of conventionalcytarabine and other cytotoxic agents.|For more Interactions (Complete) data for CYTARABINE (15 total), please visit the HSDB record page.

LD50 Mouse ip 3779 mg/kg|LD50 Mouse oral 3150 mg/kg

13%

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The danger to health-care personnel from handling a hazardous drug stems from a combination of its inherent toxicity and the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/|NIOSH (NOES Survey 1981-1983) has statistically estimated that 18,673 workers (12,859 of these are female) are potentially exposed to cytarabine in the US(1).

For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia.|FDA Label|Vyxeos liposomal is indicated for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC).|Intrathecal treatment of lymphomatous meningitis. In the majority of patients such treatment will be part of symptomatic palliation of the disease.|Treatment of acute myeloid leukaemia|Drug: Ade|Drug: Cytarabine

Cytarabine is a cytosine analogue and antineoplastic agent used largely in the therapy of acute leukemia. Cytarabine is associated with a low rate of transient serum enzyme and bilirubin elevations during therapy, but has only rarely been implicated in cases of clinically apparent acute liver injury with jaundice.

Antineoplastic Agents

Antimetabolites, Antineoplastic; Antiviral Agents; Immunosuppressive Agents; Teratogens|DepoCyt (cytarabine liposome injection) is indicated for the intrathecal treatment of lymphomatous meningitis. This indication is based on demonstration of increased complete response rate compared to unencapsulated cytarabine. There are no controlled trials that demonstrate a clinical benefit resulting from this treatment, such as improvement in disease-related symptoms, or increased time to disease progression, or increased survival. /Cytarabine liposome injection/|Cytarabine is indicated, in combination with other antineoplastic agents, for treatment of acute nonlymphocytic leukemia in adults and children. /Included US product label/|Cytarabine is indicated for treatment of acute lymphocytic leukemia and chronic myelocytic leukemia (blast phase). /Included in US product label/|For more Therapeutic Uses (Complete) data for CYTARABINE (10 total), please visit the HSDB record page.

The patient's hematologic status must be carefully monitored. Leukocyte and platelet counts should be performed frequently during cytarabine therapy. The manufacturers state that leukocyte and platelet counts should be determined daily during remission induction therapy of acute leukemia. The manufacturers also recommend frequent bone marrow examinations after blast cells have disappeared from the peripheral blood.|Patients who receive myelosuppressive drugs experience an increased frequency of infections (e.g., viral, bacterial, fungal) as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. ...Treatment with cytarabine should be initiated only with extreme caution in patients with preexisting drug-induced bone marrow suppression.|The manufacturers recommend that periodic determinations of renal function be performed in patients receiving cytarabine. Periodic determinations of hepatic function should also be performed in patients receiving cytarabine, and the manufacturers state that the drug should be used with caution and in reduced dosage in patients with poor hepatic function.|Cytarabine is contraindicated in patients with known hypersensitivity to the drug.|For more Drug Warnings (Complete) data for CYTARABINE (30 total), please visit the HSDB record page.

Several biochemical mechanisms have been identified in AraC-resistant subpopulations in various murine and human tumor cell lines. Most commonly encountered is deficiency of deoxycytidine kinase ... Another mechanism of resistance is marked expansion of the dCTP pool due to incr CTP synthase activity ... The incr concn of intracellular dCTP presumably can block the actions of AraCTP on DNA synthesis. Other mechanisms include incr cytidine deaminase activity and reduced affinity of DNA polymerase for AraCTP ... While specific steps in AraC activation and degradation exert a strong influence ... the cellular response to AraC-mediated DNA damage also governs whether or not the genotoxic insult results in cell death ... Overexpression of Bcl-2 and Bcl-XL in leukemic blasts have been associated with in vitro resistance to AraC-mediated apoptosis ... Phosphorylation of DNA-damage response factors or transcription factors also may influence the cellular response to AraC toxic insult. Recent studies have shown that phosphorylation of Bcl-2 or the AP-1 transcription factor is associated with AraC resistance in human myeloid leukemia cell lines in vitro ... At the clinical level, AraC resistance is poorly understood.

Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA. The latter mechanism is probably the most important. Cytotoxicity is highly specific for the S phase of the cell cycle.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)|Antimetabolites that are useful in cancer chemotherapy. (See all compounds classified as Antimetabolites, Antineoplastic.)|Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)

Less than 20% of the orally administered dose is absorbed from the gastrointestinal tract.|The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U.|Less than 20% of a dose of conventional cytarabine is absorbed from the GI tract, and the drug is not effective when administered orally. Following subcutaneously or im injection of conventional cytarabine H 3, peak plasma concentrations of radioactivity occur within 20-60 min and are considerably lower than those attained after iv administration. Continuous iv infusions of conventional cytarabine produce relatively constant plasma concn of the drug in 8-24 hr.|Cytarabine is rapidly and widely distributed into tissues and fluids, including liver, plasma, and peripheral granulocytes. Following rapid IV injection of cytarabine in one study, approximately 13% of the drug was bound to plasma proteins.|Cytarabine crosses the blood-brain barrier to a limited extent. During a continuous IV or subcutaneous infusion, cytarabine concentrations in the CSF are higher than those attained after rapid IV injection and are about 40-60% of plasma concentrations. Most of an intrathecal dose of cytarabine diffuses into the systemic circulation but is rapidly metabolized and usually only low plasma concentrations of unchanged drug occur.|The drug apparently crosses the placenta. It is not known if cytarabine or ara-U is distributed into milk.|For more Absorption, Distribution and Excretion (Complete) data for CYTARABINE (7 total), please visit the HSDB record page.

Hepatic.|Cytarabine is rapidly and extensively metabolized mainly in the liver but also in kidneys, GI mucosa, granulocytes, and to a lesser extent in other tissues by the enzyme cytidine deaminase, producing the inactive metabolite 1-ß-d-arabinofuranosyluracil (ara-U, uracil arabinoside). After the initial distribution phase, more than 80% of the drug in plasma is present as ara-U. In the CSF, only minimal amounts of cytarabine are converted to ara-U because of low CSF concentrations of cytidine deaminase. Intracellularly, cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to cytarabine triphosphate, the active metabolite of the drug. Cytarabine triphosphate is inactivated by a pyrimidine nucleoside deaminase, which produces the uracil derivative.|The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U (1-(beta)-D-arabinofuranosyluracil or uracilarabinoside), followed by urinary excretion of ara-U. In contrast to systemically administered cytarabine, which is rapidly metabolized to ara-U, conversion to ara-U in the CSF is negligible after intrathecal administration because of the significantly lower cytidine deaminase activity in the CNS tissues and CSF. The CSF clearance rate of cytarabine is similar to the CSF bulk flow rate of 0.24 mL/min. /Cytarabine liposome injection/|Cytarabine must be converted to the 5'-monophosphate nucleotide by deoxycytidine kinase to be active. Ara-cytidine diphosphate &/or ara-cytidine triphosphate are presumably the form that inhibit DNA polymerase & block ribonucleoside diphosphate reductase.

10 minutes|After rapid IV injection of cytarabine, plasma drug concentrations appear to decline in a biphasic manner with a half-life of about 10 minutes in the initial phase and about 1-3 hours in the terminal phase. Cytarabine reportedly undergoes triphasic elimination in some patients. After intrathecal injection, cytarabine concentrations in the CSF reportedly decline with a half-life of about 2 hours.|Peak levels were followed by a biphasic elimination profile with a terminal phase half-life of 100 to 263 hours over a dose range of 12.5 mg to 75 mg. In contrast, intrathecal administration of 30 mg of free cytarabine showed a biphasic CSF concentration profile with a terminal phase half-life of 3.4 hours. /Cytarabine liposome injection/|After iv admin, there is a rapid phase of disappearance of AraC (half-life = 10 min), followed by a slower phase of elimination with a half-time of about 2.5 hr ... After intrathecal admin of the drug at a dose of 50 mg/sq m ... peak concn of 1 to 2 mM are achieved, which decline slowly with a terminal half-life of approx 3.4 hr.

Cytarabine acts through direct DNA damage and incorporation into DNA. 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.|Cytarabine is converted intracellularly to the nucleotide, cytarabine triphosphate (ara-CTP, cytosine arabinoside triphosphate). Although the exact mechanism(s) of action of cytarabine has not been fully elucidated, cytarabine triphosphate appears to inhibit DNA polymerase by competing with the physiologic substrate, deoxycytidine triphosphate, resulting in the inhibition of DNA synthesis. Although limited, incorporation of cytarabine triphosphate into DNA and RNA may also contribute to the cytotoxic effects of the drug.|Cytarabine is a potent immunosuppressant which can suppress humoral and/or cellular immune responses; however, the drug does not decrease preexisting antibody titers and has no effect on established delayed hypersensitivity reactions.|Cytarabine liposome injection is a sustained-release formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF). Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5'-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA polymerase. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. /Cytarabine liposome injection/

ACUTE/CHRONIC HAZARDS: Very toxic. Hazardous decomposition products. May cause irritation on contact. Teratogen. Mutagen. Central nervous system effects. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

There is no antidote for overdose of intrathecal DepoCyt or unencapsulated cytarabine released from DepoCyt. Exchange of CSF with isotonic saline has been carried out in a case of intrathecal overdose of free cytarabine, and such a procedure may be considered in the case of DepoCyt overdose. Management of overdose should be directed at maintaining vital functions. /Cytarabine liposome injection/|Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation. Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. ...Very few specific treatments or antidotes are available. Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

/HUMAN EXPOSURE STUDIES/ Limited information is available on the acute toxicity of conventional cytarabine. IV doses of cytarabine 4.5 g/sq m administered over 1 hr every 12 hours for 12 doses caused excessive toxicity, including irreversible CNS toxicity and death. single doses of cytarabine up to 3 g/sq m iv have been administered by rapid iv infusion without apparent toxicity. There is no known antidote for overdosage of conventional cytarabine.|/HUMAN EXPOSURE STUDIES/ Cytarabine ... has been tested for toxicity to the cornea in ... human beings. A solution of 0.1% cytarabine hydrochloride applied six times a day for six to ten days was not injurious, but concn of 0.5% or more, caused reversible changes in the corneal epithelium. Some patients with normal corneas treated in this way for seven days developed glittering opacities in the lower layers of the epithelium, usually without stainability by fluorescein. Some had pain and developed signs of iritis. The severity was related to the concentration used and the time of exposure. After the applications were discontinued, all corneas cleared gradually during three weeks. A number of patients who have been treated systemically for leukemia or lymphoma with high doses have developed similar signs and symptoms, with punctate epithelial keratitis and photophobia in up to 46% of those treated with the drug intravenously. ... Topical corticosteroid treatment has been disappointing. The keratitis has usually cleared in 1 to 2 weeks without this treatment.|/HUMAN EXPOSURE STUDIES/ The occurrence of fatal or nearly fatal pulmonary insufficiency in 5/22 pediatric patients with relapsed acute myelogenous leukemia (AML) treated with high dose cytosine arabinoside (Ara-C) is reported. Ara-C (1.0-1.5 g/sq m/day) was given as a 5 day continuous infusion to all patients. Four patients with persistent leukemia received a second 3- or 5-day course. The POG protocol included the admin of granulocyte colony stimulating factor for the priming of myeloblasts. Diagnostic criteria for pulmonary insufficiency included noncardiogenic pulmonary edema with exclusion of underlying cardiorespiratory, infectious, or metabolic conditions. autopsy material also was reviewed. Of the 22 patients, 5 died (23%), including 2 who received a second course of Ara-C as a results of pulmonary insufficiency that developed at a median of 8 days (range, 3-38 days) after the first course. Three patients died despite intubation and pressor support. Two patients were managed successfully with colloids, diuresis, and oxygen by face mask; remission was achieved in both. The postmortem exam of one patient disclosed airless lungs, profound pulmonary edema, and subpleural nodules, but no evidence of leukemia. Pulmonary insufficiency from high dose Ara-C varies in severity and may be fatal. It may occur during or after treatment. Awareness of this potential complication, careful attention to fluid status, and aggressive supportive care may optimize outcome.|/SIGNS AND SYMPTOMS/ A number of patients who have been treated systemically for leukemia or lymphoma with high doses have developed similar signs and symptoms, with punctate epithelial keratitis and photophobia in up to 46% of those treated with the drug intravenously. ... Topical corticosteroid treatment has been disappointing. The keratitis has usually cleared in 1 to 2 weeks without this treatment.|For more Human Toxicity Excerpts (Complete) data for CYTARABINE (18 total), please visit the HSDB record page.

Ara C

DepoCyt is available in 5 mL, ready-to-use, single-use vials containing 50 mg of cytarabine. DepoCyt is formulated as a sterile, nonpyrogenic, white to off-white suspension of cytarabine in Sodium Chloride 0.9% w/v in Water for Injection. DepoCyt is preservative-free. Cytarabine, the active ingredient, is present at a concentration of 10 mg/mL and is encapsulated in the particles. Inactive ingredients at their respective approximate concentrations are cholesterol, 4.1 mg/mL; triolein, 1.2 mg/mL; dioleoylphosphatidylcholine (DOPC), 5.7 mg/mL; and dipalmitoylphosphatidylglycerol (DPPG), 1.0 mg/mL. The pH of the product falls within the range from 5.5 to 8.5. /Cytarabine liposome injection/

Analyte: cytarabine; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: cytarabine; matrix: chemical identification; procedure: retention time of the major peak of the liquid chromatogram with comparison to standards|Analyte: cytarabine; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards|Analyte: cytarabine; matrix: pharmaceutical preparation (solid for injection); procedure: retention time of the major peak of the liquid chromatogram with comparison to standards (chemical identification)|Analyte: cytarabine; matrix: pharmaceutical preparation (solid for injection); procedure: liquid chromatography with detection at 254 nm and comparison to standards (chemical purity)

A HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD FOR THE DETERMINATION OF CYTARABINE AND ITS MAIN METABOLITE URACIL ARABINOSIDE IN HUMAN PLASMA AND CSF IS DESCRIBED.|A NOVEL, DUAL-COLUMN HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY METHOD FOR DETERMINATION OF ARA-C WAS DEVELOPED. THE PROCEDURE IS SENSITIVE TO 25 NG/ML AND CAN BE USED FOR PATIENT PLASMA SAMPLES.

Human drugs -> Orphan -> Vyxeos liposomal (previously known as Vyxeos) -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> DepoCyte -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients