Yes

Antineoplastic Agent, Antimetabolite

Ara-C is one of the most active agents in leukemia; also active against lymphoma, meningeal leukemia, and meningeal lymphoma; has little use in the treatment of solid tumors

D

Hypersensitivity to cytarabine or any component

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution in pregnant women or women of childbearing age and in infants; must monitor drug tolerance, protect and maintain a patient compromised by drug toxicity that includes bone marrow suppression with leukopenia, thrombocytopenia and anemia along with nausea, vomiting, diarrhea, abdominal pain, oral ulceration and hepatic impairment; marked bone marrow suppression necessitates dosage reduction by a decrease in the number of days of administration.

>10%:

High-dose therapy toxicities: Cerebellar toxicity, conjunctivitis (make sure the patient is on steroid eye drops during therapy), corneal keratitis, hyperbilirubinemia, pulmonary edema, pericarditis, and tamponade

Central nervous system: Has produced seizures when given I.T.; cerebellar syndrome (or cerebellar toxicity), manifested as ataxia, dysarthria, and dysdiadochokinesia, has been reported to be dose-related. This may or may not be reversible.

Dermatologic: Oral/anal ulceration, rash

Gastrointestinal: Nausea, vomiting, diarrhea, and mucositis which subside quickly after discontinuing the drug; GI effects may be more pronounced with divided I.V. bolus doses than with continuous infusion

Emetic potential:

<500 mg: Moderately low (10% to 30%)

500 mg to 1500 mg: Moderately high (60% to 90%)

>1-1.5 g: High (>90%)

Time course of nausea/vomiting: Onset: 1-3 hours; Duration: 3-8 hours

Hematologic: Bleeding

Myelosuppressive: Occurs within the first week of treatment and lasts for 10-14 days; primarily manifested as granulocytopenia, but anemia can also occur

WBC: Severe

Platelets: Severe

Onset (days): 4-7

Nadir (days): 14-18

Recovery (days): 21-28

Hepatic: Hepatic dysfunction, mild jaundice and acute increase in transaminases can be produced

Local: Thrombophlebitis

1% to 10%:

Cardiovascular: Cardiomegaly

Central nervous system: Dizziness, headache, somnolence, confusion, neuritis, malaise

Dermatologic: Skin freckling, itching, alopecia, cellulitis at injection site

Genitourinary: Urinary retention

Neuromuscular & skeletal: Myalgia, bone pain, peripheral neuropathy

Respiratory: Syndrome of sudden respiratory distress progressing to pulmonary edema, pneumonia

Miscellaneous: Sepsis

Symptoms of overdose include myelosuppression, megaloblastosis, nausea, vomiting, respiratory distress, pulmonary edema. A syndrome of sudden respiratory distress progressing to pulmonary edema and cardiomegaly has been reported following high doses.

Decreased effect of gentamicin, flucytosine; decreases digoxin oral tablet absorption

Increased toxicity: Alkylating agents and radiation; purine analogs; methotrexate

Store intact vials of powder at room temperature 15°C to 30°C (59°F to 86°F)

Reconstitute with SWI, D₅W or NS; dilute to a concentration of 100 mg/mL as follows; reconstituted solutions are stable for 48 hours at 15°C to 30°C

100 mg vial = 1 mL

500 mg vial = 5 mL

1 g vial = 10 mL

2 g vial = 20 mL

Further dilution in D₅W or NS is stable for 8 days at room temperature (25°C)

Standard I.V. dilution:

I.V. push: Dose/syringe (concentration: 100 mg/mL)

Maximum syringe size for IVP is 30 mL syringe and syringe should be less than or equal to 75% full

IVPB: Dose/100 mL D₅W or NS

CIV: Dose/250-1000 mL D₅W or NS

Compatible with calcium, idarubicin, magnesium, potassium chloride, and vincristine

Incompatible with 5-FU, gentamicin, heparin, insulin, methylprednisolone, nafcillin, oxacillin, penicillin G sodium

Intrathecal solutions in 3-20 mL lactated Ringer's are stable for 7 days at room temperature (30°C); however, should be used within 24 hours due to sterility concerns

Standard intrathecal dilutions: Dose/3-5 mL lactated Ringer's ± methotrexate (12 mg) ± hydrocortisone (15-50 mg)

Compatible with methotrexate and hydrocortisone in lactated Ringer's or NS for 24 hours at room temperature (25°C)

Inhibition of DNA synthesis; cell cycle-specific for the S phase of cell division; cytosine gains entry into cells by a carrier process, and then must be converted to its active compound; cytosine acts as an analog and is incorporated into DNA; however, the primary action is inhibition of DNA polymerase resulting in decreased DNA synthesis and repair; degree of its cytotoxicity correlates linearly with its incorporation into DNA; therefore, incorporation into the DNA is responsible for drug activity and toxicity

Absorption: Because high concentrations of cytidine deaminase are in the GI mucosa and liver, 3-10 fold higher doses than I.V. would need to be given orally; therefore, the oral route is not used

Distribution: V_d = total body water. Widely and rapidly distributed since it enters the cells readily; crosses the blood-brain barrier, and CSF levels of 40% to 50% of the plasma level are reached

Metabolism: Primarily in the liver; Ara-C must be metabolized to Ara-CTP to be active

Half-life: Initial: 7-20 minutes; Terminal: 0.5-2.6 hours

Elimination: ~80% of dose excreted in the urine as metabolites within 36 hours

I.V. bolus, IVPB, and CIV doses of cytarabine are very different. Bolus doses are relatively well tolerated since the drug is rapidly metabolized; bolus doses are associated with greater gastrointestinal and neurotoxicity; continuous infusion uniformly results in myelosuppression. Refer to individual protocols.

Induction remission:

I.V.: 200 mg/m²/day for 5 days at 2-week intervals

100-200 mg/m²/day for 5- to 10-day therapy course or every day until remission

I.T.: 5-75 mg/m² every 4 days until CNS findings normalize

or

<1 year: 20 mg

1-2 years: 30 mg

2-3 years: 50 mg

>3 years: 70 mg

Maintenance remission:

I.V.: 70-200 mg/m²/day for 2-5 days at monthly intervals

I.M., S.C.: 1-1.5 mg/kg single dose for maintenance at 1- to 4-week intervals

High-dose therapies:

Doses as high as 1-3 g/m² have been used for refractory or secondary leukemias or refractory non-Hodgkin's lymphoma

Doses of 3 g/m² every 12 hours for up to 12 doses have been used

Bone marrow transplant: 1.5 g/m² continuous infusion over 48 hours

Dosage adjustment of high-dose therapy in patients with renal insufficiency: In one study, 76% of patients with a Cl_cr <60 mL/minute experienced neurotoxicity; dosage adjustment should be considered in these patients

Hemodialysis: Supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

Dose may need to be adjusted in patients with liver failure since cytarabine is partially detoxified in the liver

Liver function tests, CBC with differential and platelet count, serum creatinine, BUN, serum uric acid

May cause sedation or confusion

May cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

This drug can only be given by infusion or injection. During therapy maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). You will be more susceptible to infection; avoid crowds and exposure to infection. Do not have any vaccinations without consulting prescriber. Small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may reduce incidence of nausea or vomiting or loss of appetite. If these measures are ineffective, consult prescriber for antiemetic medication. Report immediately any signs of CNS changes or change in gait, easy bruising or bleeding, yellowing of eyes or skin, change in color of urine or blackened stool, respiratory difficulty, or palpitations. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures during and 4 months after therapy to prevent possible harm to the fetus. Breast-feeding is not recommended.

Administer corticosteroid eye drops around the clock prior to, during, and after high-dose Ara-C for prophylaxis of conjunctivitis; pyridoxine has been administered on days of high-dose Ara-C therapy for prophylaxis of CNS toxicity. Can be administered I.M., IVP, I.V. infusion, or S.C. at a concentration not to exceed 100 mg/mL; high-dose regimens are usually administered by I.V. infusion over 1-3 hours or as I.V. continuous infusion; for I.T. use, reconstitute with preservative free saline or preservative free lactated Ringer's solution.

Powder for injection, as hydrochloride: 100 mg, 500 mg, 1 g, 2 g

Powder for injection, as hydrochloride (Cytosar-U®): 100 mg, 500 mg, 1 g, 2 g

Capizzi RL, "Curative Chemotherapy for Acute Myeloid Leukemia: The Development of High-Dose Ara-C From the Laboratory to Bedside," Invest New Drugs, 1996, 14(3):249-56.

Capizzi RL, White JC, Powell BL, et al, "Effect of Dose on the Pharmacokinetic and Pharmacodynamic Effects of Cytarabine," Semin Hematol, 1991, 28(3 Suppl 4):54-69.

Grossman L, Baker MA, Sutton DM, et al, "Central Nervous System Toxicity of High-Dose Cytosine Arabinoside," Med Pediatr Oncol, 1983, 11(4):246-50.

Hiddemann W, "Cytosine Arabinoside in the Treatment of Acute Myeloid Leukemia: The Role and Place of High-Dose Regimens," Ann Hematol, 1991, 62(4):119-28.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Stasi R, Venditti A, Del Poeta G, et al, "High-Dose Chemotherapy in Adult Acute Myeloid Leukemia: Rationale and Results," Leuk Res, 1996, 20(7):535-49.

Stentoft J, "The Toxicity of Cytarabine," Drug Saf, 1990, 5(1):7-27.