Cytarabine

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.

/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/

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.

/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.

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/

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.

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.

Myelosuppression is the most dreaded adverse effect of cytarabine and can present as acute and severe pancytopenia with striking megaloblastic changes. Other, less life-threatening symptoms include irritation at the site of administration, gastrointestinal disturbances, stomatitis, conjunctivitis, reversible hepatic enzyme elevation, and dermatitis. Severe hypersensitivity, such as anaphylaxis, occurs on rare occasions but is a strong indication for discontinuation of cytarabine therapy. Cerebral and cerebellar toxicity may follow an intrathecal administration of cytarabine. Manifestations of cerebellar toxicity include ataxia and slurred speech, while that of cerebral toxicity are seizures and dementia.

/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.

Toxicity caused by cytarabine can classify into either low dose or high dose toxicity. The only noteworthy low-dose toxicity is myelosuppression, while corneal toxicity is frequent with high doses of cytarabine. Continuous infusion may prove more toxic than the typical intermittent dosage. Considerable cardiac toxicity has been observed only in the standard induction schedules.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=147-94-4]

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /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.

AEROBIC: Cytarabine, present at 12.5 mg/L, was shown to biodegrade up to 70% but did not reach a constant value within 10 days using an activated sludge inoculum and the OECD confirmatory test, detection limit = 0.2 mg/L(1). Biodegradation was noted at approximately 60% in 14 days when presented as a mixture with other cytostatic compounds(1).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Cytarabine

vMost-DILI-concern

3

Box warning

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Single subconjunctival injections of 37.5 mg/kg in rabbits have caused an inflammatory response in the conjunctiva lasting less than 24 hours, without disturbance of other parts of the eye.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Ara-c ip admin in pregnant rats on day 11 produced preaxial polydactyly (87.9%) and on day 12 or 13 led to oligodactyly formation (day 12, 57.3%; day 13, 86.8%) in the hindlimb. However, the repeated treatments on 2 days 11 and 12 or 11 and 13 not only converted the polydactyly-inducing effect into the oligodactyly-inducing effect, but also reduced (49.2%, on days 11 and 12) or incr (100%, on days 11 and 13) the incidence of total digital malformations compared with that of single treatment on day 11, 12, or 13. This might be due to the different susceptibility of the ectodermal and mesodermal cells to the teratogen, because the stage of cellular differentiation was different between the ectoderm and the mesoderm of the hindlimb bud.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Correlations were observed between the necrotic patterns induced by cytosine arabinoside in fetal mouse limb buds (when the drug was given ip to the pregnant mothers and the results observed 6-54 hr later) and the skeletal defects observed in full-term fetuses submitted to the same treatments. The drug exerted its deleterious effect on limb morphogenesis by causing abnormal cell death within the undifferentiated limb bud mesoderm. Observations after the teratogenic treatment suggested the final skeletal pattern observed in full-term fetuses was the result of a compromise between the number of dead mesodermal cells and the regulatory capacities of the remaining healthy mesoderm.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant Jcl:ICR mice were given a single ip dose of 2.5, 5, or 10 mg/kg cytosine arabinoside (Ara-C) on day 9.5 or 10.5 of gestation (gd). The treatment groups consisted of over 20 animals per group. The dams were killed on gd 18 and live fetuses were examined for digit anomalies. Oligodactyly of the hindlimbs was most frequent in male fetuses at the 10 mg/kg Ara-C dose on gd 9.5. In the 5 mg/kg Ara-C group treated on gd 10.5, oligodactyly of the forelimbs were observed more frequently in male fetuses, while polydactyly occurred more frequently in female fetuses.

For more Non-Human Toxicity Excerpts (Complete) data for CYTARABINE (11 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).

THERAP CAT: Antineoplastic; antiviral

MEDICATION (VET)

MEDICATION

Use (kg; approx.) in Germany (2009): >100

For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia.

Cytidine is reacted with fuming nitric acid and resulting cytidine 2',3',5'-trinitrate is boiled in alcohol containing dilute alkali hydroxide to form inverted 2'-hydroxy compound. Remaining nitrate groups are removed via saponification.

Preparation: J. H. Hunter, US 3116282 (1963 to Upjohn)

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/