VA Class:AN300

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Cytarabine

Chemical Name:

• 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one

Molecular Formula:

• C₉H₁₃N₃O₅

Cytarabine, a synthetic pyrimidine antagonist, is an antimetabolite antineoplastic agent.

Conventional Cytarabine

Acute Myeloid Leukemia

Cytarabine is used principally as a component of various chemotherapeutic regimens for remission induction in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL).237 AML includes acute promyelocytic, monocytic, myelomonocytic, megakaryoblastic, and erythroid leukemias.236 Induction regimens are used to rapidly reduce the tumor burden in order to achieve complete remission,231,236 which generally is defined as less than 5% leukemic blast cells in the bone marrow and normalization of peripheral blood counts (including hemoglobin concentration, hematocrit, granulocyte count, and platelet count).231 Cytarabine used alone has produced complete remissions in 25-40% of patients, but combination therapy for induction of remissions is superior to single-agent therapy and is preferred. Although maintenance regimens (with lower doses) previously were administered for prolonged periods (e.g., years) in the treatment of AML, most current treatment regimens in the US no longer employ maintenance therapy236 but instead use intensive consolidation therapy that is administered for a shorter period of time at higher doses and then discontinued since there is no evidence of superior disease-free survival with prolonged maintenance.232,234,236

Remission rates in adult AML are inversely related to age, with expected rates exceeding 65% in those younger than 60 years of age.236 In addition, some evidence suggests that, once attained, duration of remission may be shorter in older patients, and increased morbidity and mortality during induction also appear to be directly related to age.236 Other adverse prognostic factors include leukemic CNS involvement, systemic infection at diagnosis, elevated leukocyte count (exceeding 100,000/ mm³) treatment-induced AML, and a history of myelodysplastic syndrome.236 In addition, leukemias that express the progenitor cell antigen CD34 and/or P-glycoprotein (MDR-1 gene product) have an inferior outcome.236 Cytogenetic analysis, although not readily available, provides the strongest prognostic information for newly diagnosed AML, with abnormalities that indicate a good prognosis including t(8;21), inv(16), and t(15; 17); normal cytogenetics generally indicate average-risk AML.236 Patients with AML that is characterized by deletions of the long arms or monosomies of chromosomes 5 or 7; by translocations or inversions of chromosome 3, t(6;9),t(9;22); or by abnormalities of 11q23 exhibit particularly poor prognoses with chemotherapy.236

Cytarabine and an anthracycline (usually daunorubicin) have been principal components of induction regimens, but various regimens have been used in combination therapy and comparative efficacy is continually being evaluated. Cytarabine has been used with agents such as daunorubicin, doxorubicin, idarubicin, thioguanine, or vincristine. The 2-drug regimen of cytarabine and daunorubicin generally results in a complete response rate of approximately 65% in patients with previously untreated AML.236 The results of randomized trials comparing combined mitoxantrone and cytarabine therapy with combined daunorubicin and cytarabine therapy have shown the two regimens to have similar efficacy and toxicity as induction therapy in patients with previously untreated AML.231,232,233,234,235,236 There is some evidence that dose intensity of cytarabine as a component of induction therapy may affect disease-free survival.236,238,239,240,241 In one study, high-dose rapid cytarabine administration combined with daunorubicin and etoposide produced similar complete response rate but superior disease-free survival compared with conventional-dose continuous-infusion cytarabine combined with these drugs.236,238 In another study in which the second course of induction therapy was administered after hematopoietic recovery or in a planned sequence beginning on day 10 of therapy (i.e., during aplasia), both regimens produced similar remission rates but the timed sequential regimen produced superior disease-free survival regardless of the postremission therapy (e.g., consolidation chemotherapy, allogeneic or autologous bone marrow transplantation).236,239,240,241 Some clinicians have used thioguanine or mercaptopurine in addition to intensive therapy with cytarabine and daunorubicin for remission induction; complete remissions occurred in 60-85% of patients.

Cytarabine has also been used with other antineoplastic agents in regimens of consolidation therapy for AML following induction of a complete remission; however, the role of such therapy in the prolongation of remissions is not firmly established. Cytarabine-containing consolidation chemotherapy regimens that do not employ bone marrow transplantation are associated with treatment-related death rates that usually are less than 10-20% and have produced disease-free survival rates of 20-50%.236,239,242,243 There is some evidence that high-dose cytarabine consolidation regimens provide a clear benefit in survival in patients younger than 60 years of age,236,242 but dose-intensive cytarabine-based chemotherapy can be complicated by severe neurologic and/or pulmonary toxicity and therefore should be administered under the direction of clinicians experienced in the use of such regimens in facilities equipped to manage potential complications.224,236,244,245 Consolidation therapy has ranged in duration from one to 4 or more cycles,236,239,242,243 but the optimal doses, schedules, and duration of consolidation chemotherapy remain to be established.236

Cytarabine also has been used with other antineoplastic agents in the treatment of erythroleukemia.

Cytarabine has been used alone in high-dose† regimens to induce remissions in some patients with refractory acute myeloid leukemia, or with secondary acute myeloid leukemia.

Acute Lymphocytic Leukemia

Cytarabine has been used alone or with other antineoplastic agents for remission induction in acute lymphocytic (lymphoblastic) leukemia (ALL);237 however, combinations containing other antineoplastic agents are more effective. Cytarabine has generally been limited to use with other antineoplastic agents for remission induction in some patients who do not achieve a complete remission with combinations containing other agents or who relapse during maintenance therapy. Cytarabine has also been used occasionally in regimens of consolidation and/or maintenance therapy following induction of a complete remission by combinations containing other agents. Although long-term survivors may eventually experience a recurrence or relapse, a substantial number of children with acute lymphocytic leukemia have achieved long-term complete remissions following induction and maintenance combination therapy.

Cytarabine has been used alone in high-dose regimens to induce remissions in some patients with refractory ALL.

Meningeal Leukemia and Other Meningeal Neoplasms

Cytarabine has been used effectively alone or with other chemotherapeutic agents in the treatment and maintenance therapy of meningeal leukemia and other meningeal neoplasms (e.g., lymphoma). Although therapeutic concentrations of cytarabine in the CSF have apparently been attained during continuous IV or subcutaneous infusions of the drug, cytarabine is usually administered intrathecally to ensure therapeutic concentrations of the drug. Many clinicians consider intrathecal cytarabine and intrathecal methotrexate to have similar efficacy in the treatment of these conditions; however, intrathecal cytarabine produces less systemic toxicity than intrathecal methotrexate. Intrathecal cytarabine may be useful in patients whose CNS disease does not respond to intrathecal methotrexate or in patients with methotrexate-related neurotoxicity. Focal leukemic involvement of the CNS may not respond to intrathecal cytarabine or intrathecal methotrexate and may better be treated with radiation therapy. The value of intrathecal cytarabine in the prophylaxis of meningeal leukemia has not been established.

Chronic Myelogenous Leukemia

IV cytarabine is used with other antineoplastic agents (e.g., daunorubicin) in the treatment of patients with chronic myelogenous leukemia (CML) who are in the accelerated or blastic phase of the disease; however, the prognosis for patients receiving standard therapy remains poor and other therapies are continually being evaluated.237,253,254

Cytarabine also is used in combination with interferon alfa for the treatment of the chronic phase of CML.237,253 Concomitant administration of cytarabine with interferon alfa-2b has been associated with increased survival in patients with CML.246,247 Results of a randomized controlled study in previously untreated patients with CML demonstrate a longer survival in patients receiving interferon alfa-2b (5 million units/m² given subcutaneously daily) in combination with cytarabine (20 mg/m² daily for 10 days given subcutaneously 2 weeks after initiation of interferon alfa-2b therapy and monthly thereafter) versus those receiving interferon alfa-2b without cytarabine; patients from both groups also received hydroxyurea 50 mg/kg daily until a complete hematologic remission was achieved.246 After 3 years, median survival rate of about 86 or 79%, respectively, reportedly was observed in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine while overall hematologic response rate was 66 or 55% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively.246,247 Major cytogenetic response rate after 12 months was 41 or 24% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively.246,247 Longer survival was observed in patients with cytogenetic response.246 Some patients underwent allogeneic or autologous bone marrow transplantation, and the 2-year survival rate after allogeneic bone marrow transplantation was 56 or 59% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively, while 2-year survival rate after autologous bone marrow transplantation was 61 or 68% in patients receiving combined interferon alfa-2b therapy with cytarabine or interferon alfa-2b without cytarabine, respectively.246 Patients who did not have complete hematologic or major cytogenetic responses within 6 or 12 months, respectively, were allowed to cross over to combined treatment with interferon alfa-2b and cytarabine.246,248,249 Among patients who received initial therapy with interferon alfa-2b without cytarabine, but then crossed over to receive combined treatment with interferon alfa-2b and cytarabine, complete and partial responses of 2 and 6%, respectively, were observed.246,249

Other Uses

Cytarabine has been used with other antineoplastic agents in regimens of maintenance therapy in the treatment of non-Hodgkin's lymphomas in children. Cytarabine has also been used with other antineoplastic agents for remission induction and/or maintenance therapy in adults with non-Hodgkin's lymphomas†, principally advanced diffuse histiocytic lymphoma. It has been suggested, but is not clearly established, that cytarabine decreases the incidence of CNS relapse in patients with advanced diffuse histiocytic lymphoma because the drug crosses the blood-brain barrier. However, the best combination or sequential therapy in the treatment of advanced diffuse histiocytic lymphoma has not been established and comparative efficacy is continually being evaluated. Cytarabine has also been used alone in high-dose† regimens with some success for the treatment of refractory non-Hodgkin's lymphomas.

Liposomal Cytarabine

Lymphomatous Meningitis

Liposomal cytarabine is used for the intrathecal treatment of lymphomatous meningitis.255 This indication is based on a controlled study showing an increased complete response rate for liposomal cytarabine compared with conventional (unencapsulated) cytarabine in patients with lymphomatous meningitis.255 There are no controlled trials that demonstrate a clinical benefit (e.g., amelioration of disease-related symptoms, increased time to disease progression, prolonged survival) for the use of intrathecal therapy with liposomal cytarabine for lymphomatous meningitis.255

In a multicenter randomized trial, 99 patients with neoplastic meningitis caused by solid tumors, lymphoma (33 patients), or leukemia, received either liposomal cytarabine or conventional (unencapsulated) cytarabine.255 The patients with lymphoma received either liposomal cytarabine 50 mg intrathecally once every 2 weeks or conventional (unencapsulated) cytarabine 50 mg intrathecally twice weekly.255 According to the study protocol, patients were to receive concurrent treatment with dexamethasone to minimize symptoms associated with chemical arachnoiditis, a known toxicity associated with intrathecal therapy with cytarabine and methotrexate.255 Patients with disease that did not achieve a complete response at 4 weeks discontinued treatment with the study drug.255

Among the 33 patients with lymphoma in the randomized trial, complete response rates were 41% (7/17) in those receiving liposomal cytarabine and 6% (1/16) in those receiving conventional cytarabine.255 For 4 of the 7 patients with a complete response to liposomal cytarabine, the study protocol was violated when response was determined by the reading of an unblinded pathologist rather than by central pathology review of the data.255 The median overall survival was 99.5 days in those receiving liposomal cytarabine and 63 days in those receiving conventional cytarabine; the majority of patients in the study died from progressive systemic disease and not neoplastic meningitis.255

Seizures occurred more frequently in patients receiving liposomal cytarabine (24%) than in those receiving conventional cytarabine (6%).255

Reconstitution and Administration

Cytarabine as a single-entity preparation is not interchangeable with the fixed liposomal combination of daunorubicin and cytarabine (daunorubicin/cytarabine liposomal; Vyxeos^®).256 To avoid dosing errors, clinicians should confirm the correct drug name, formulation, and dose prior to preparation and administration.256

Conventional Cytarabine

Conventional (unencapsulated) cytarabine may be administered IV by rapid injection or continuous infusion, or by subcutaneous or intrathecal injection.201

For IV, intrathecal, or subcutaneous injection or IV infusion, commercially available conventional (unencapsulated) cytarabine injection may be diluted with a compatible IV solution (e.g., water for injection, 5% dextrose injection, 0.9% sodium chloride injection).250 Only the preservative-free preparation of conventional (unencapsulated) cytarabine injection is suitable for intrathecal administration;250 conventional (unencapsulated) cytarabine injection containing benzyl alcohol should be used only for IV or subcutaneous administration.251 (See Chemistry and Stability: Stability.) Alternatively, conventional (unencapsulated) cytarabine sterile powder can be used for IV or subcutaneous administration by reconstituting it with bacteriostatic water for injection containing 0.945% benzyl alcohol.201 The sterile powder is usually reconstituted by adding 5 mL of diluent to the vial labeled as containing 100 mg, 10 mL of diluent to the vial labeled as containing 500 mg, 10 mL of diluent to the vial labeled as containing 1 g, or 20 mL of diluent to the vial labeled as containing 2 g of the drug.201 The resultant solutions contain 20, 50, 100, or 100 mg of cytarabine per mL, respectively.201 The desired dose of the reconstituted solution may be given IV rapidly or may be further diluted with 5% dextrose or 0.9% sodium chloride injection for IV infusion. Because of the potential toxicity of large amounts of benzyl alcohol, the manufacturers warn that diluents containing this preservative should not be used to reconstitute cytarabine if high-dose† regimens of the drug are employed.201

The manufacturers state that diluents containing benzyl alcohol should not be used when conventional (unencapsulated) cytarabine is administered intrathecally.201 Cytarabine that has been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates. (See Cautions: Pediatric Precautions.) Many clinicians recommend that conventional (unencapsulated) cytarabine sterile powder be reconstituted with preservative-free 0.9% sodium chloride injection, Elliott's B solution or other isotonic buffered diluents which do not contain a preservative (e.g., lactated Ringer's injection), or the patient's spinal fluid. Cytarabine is usually administered in 5-15 mL of solution, after an equivalent volume of CSF is removed.

Conventional (unencapsulated) cytarabine injection that is commercially available in pharmacy bulk packages is not intended for direct IV infusion; individual doses can be withdrawn and used undiluted or further diluted in a compatible IV solution.252 The manufacturer states that pharmacy bulk packages are not intended for preparation of doses intended for intrathecal administration.252

Liposomal Cytarabine

Cytarabine liposome injection is administered intrathecally only .255

For intrathecal administration, commercially available cytarabine liposome injection is suitable; no reconstitution or dilution of the injection is required.255 Dilution of the cytarabine liposome injection is not recommended.255 Particles of liposomal cytarabine have a greater density than the diluent and may settle with time.255 Vials of cytarabine liposome injection should be allowed to warm to room temperature and then the vials should be gently agitated or inverted to re-suspend the particles immediately prior to withdrawal of the injection from the vial.255 Aggressive agitation of the vials should be avoided.255 Cytarabine liposome injection is a potentially toxic compound that should be handled with caution; the use of gloves is recommended.255 If liposomal cytarabine suspension contacts the skin, wash immediately with soap and water; if it contacts mucous membranes, flush thoroughly with water.255

Cytarabine liposome injection should be withdrawn from the vial immediately before administration.255 The single-use vial does not contain any preservative; cytarabine liposome injection must be used within 4 hours of withdrawal from the vial.255 Unused portions of the injection should be discarded properly, and unused portions of the drug should not be saved for later administration.255 Cytarabine liposome injection should not be mixed with any other medications.255

In-line filters should not be used when administering cytarabine liposome injection.255 Liposomal cytarabine should be administered directly into the CSF via an intraventricular reservoir or by direct injection into the lumbar sac.255 Liposomal cytarabine should be injected slowly over a period of 1-5 minutes.255 Following administration of the drug by lumbar puncture, the patient should be instructed to lie flat for 1 hour.255 Following administration of the drug, patients should be observed by the clinician for immediate toxic reactions.255

Dosage

Dosage of conventional (unencapsulated) cytarabine must be based on the clinical and hematologic response and tolerance of the patient to obtain optimum therapeutic results with minimum adverse effects. Although higher total doses of cytarabine can be given by rapid IV injection compared with continuous IV infusion with similar hematologic toxicity, the most effective dosage schedule and method of administration have not been established.201 Clinicians should consult published protocols for the dosage of cytarabine and other chemotherapeutic agents and the method and sequence of administration.

IV Dosage

Acute Myeloid Leukemia

In combination chemotherapy, the usual dosage of conventional (unencapsulated) cytarabine for induction therapy in acute myeloid leukemia is 2-6 mg/kg daily or 100-200 mg/m² daily by continuous IV infusion or in 2 or 3 divided doses by rapid IV injection or IV infusion, for 5-10 days in a course of therapy or daily until a remission is attained.

Non-Hodgkin's Lymphomas

For the treatment of refractory non-Hodgkin's lymphomas, conventional (unencapsulated) cytarabine has been administered by IV infusion in a dosage of 3 g/m² every 12 hours for up to 12 doses†; IV infusions generally were made over 1-3 hours.

Intrathecal Dosage

Meningeal Leukemia and Other Meningeal Neoplasms

In the treatment and maintenance therapy of meningeal leukemia and other meningeal neoplasms, conventional (unencapsulated) cytarabine has been given by intrathecal injection in doses of 5-75 mg/m² or 30-100 mg once every 2-7 days to once daily for 4 or 5 days. The dosage schedule is usually determined by the type and severity of CNS manifestations and the patient's response to prior therapy.201 A frequently used intrathecal cytarabine dosage has been 30 mg/m² once every 4 days until CSF findings are normal, followed by one additional dose.201 If systemic toxicity occurs with intrathecal cytarabine, modification of other therapy may be necessary.201

Lymphomatous Meningitis

Intrathecal therapy with liposomal cytarabine can cause serious toxicity, such as chemical arachnoiditis (see Cautions: Adverse Effects Associated With Intrathecal Administration: Liposomal Cytarabine) or neurotoxicity.255 All patients receiving liposomal cytarabine should receive dexamethasone concurrently to lessen the manifestations of chemical arachnoiditis, and patients should be monitored carefully throughout therapy for drug-related neurotoxicity.255 Therapy with oral or IV dexamethasone 4 mg twice daily for 5 days should be initiated on the day of intrathecal administration of liposomal cytarabine in each 14-day treatment cycle.255

For the treatment of lymphomatous meningitis, induction therapy with liposomal cytarabine 50 mg is administered intrathecally (by intraventricular delivery or lumbar puncture) once every 14 days for 2 doses (weeks 1 and 3).255 Consolidation therapy with liposomal cytarabine 50 mg is administered intrathecally (by intraventricular delivery or lumbar puncture) once every 14 days for 3 doses (weeks 5, 7 and 9) followed by one additional dose at week 13.255 Maintenance therapy with liposomal cytarabine 50 mg is administered intrathecally (by intraventricular delivery or lumbar puncture) once every 28 days for 4 doses (weeks 17, 21, 25, and 29).255

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Hematologic Toxicity

Conventional Cytarabine: Suspension or modification of therapy should be considered if the polymorphonuclear granulocyte count falls below 1000/mm³ or the platelet count falls below 50,000/mm³;201 however, during remission induction therapy in acute leukemia, the drug is usually administered in a short course and therapy is not discontinued or adjusted based on peripheral blood counts. If therapy has been discontinued, definite signs of bone marrow recovery appear, and granulocyte and platelet counts are at least 1000/mm³ and 50,000/mm³, respectively, cytarabine therapy should be resumed if indicated.201 If therapy is withheld until peripheral counts of blood elements return to normal, cytarabine may not be effective.201 Treatment of severe hematologic toxicity may consist of supportive therapy, antibiotics for complicating infections, and blood product transfusions.

Neurotoxicity

Conventional Cytarabine: Patients receiving high-dose cytarabine should be monitored carefully for signs of neuropathy; dosage schedule adjustment may be required to avoid irreversible neurotoxicity.201

Liposomal Cytarabine: Patients receiving intrathecal therapy with liposomal cytarabine should be monitored continuously for the development of neurotoxicity.255 If the patient develops neurotoxicity, subsequent doses of liposomal cytarabine should be reduced to 25 mg.255 If toxicity persists, therapy with liposomal cytarabine should be discontinued.255

Dosage in Renal and Hepatic Impairment

Reduction of cytarabine dosage in patients with impaired renal function does not appear to be necessary. The manufacturers state that cytarabine should be used with caution and in reduced dosage in patients with poor hepatic function, but some clinicians believe that dosage adjustment is not necessary in patients with impaired hepatic function.

For patients receiving liposomal cytarabine for lymphomatous meningitis, adverse effects are reported as the rate per cycle occurring in at least 10% of patients in the randomized study comparing intrathecal administration of liposomal cytarabine with intrathecal administration of conventional cytarabine or methotrexate.255

Hematologic Effects and Infectious Complications

Conventional Cytarabine

The major adverse effect of conventional (unencapsulated) cytarabine is hematologic toxicity; the severity depends on the dose of the drug and schedule of administration.201 Myelosuppression is manifested by megaloblastosis, reticulocytopenia, leukopenia, thrombocytopenia, and anemia.201 Leukopenia results mainly from granulocyte depression; lymphocytes are minimally affected. The incidence and severity of hematologic toxicity is minimal after a single IV dose of cytarabine, but myelosuppression, anemia, and thrombocytopenia occur in almost all patients with daily IV injections or continuous IV infusions of the drug. Myelosuppression after subcutaneous injection is similar to that which occurs after IV injection. Following 5-day constant IV infusions or rapid IV injections of cytarabine 50-600 mg/m², the leukocyte count decreases in a biphasic manner.201 There is an initial decrease beginning in the first 24 hours after the drug is administered, with a nadir at 7-9 days.201 This nadir is followed by a brief rise in the leukocyte count with a peak at about 12 days.201 The second leukocyte count nadir, which is greater than the first, occurs at 15-24 days and is followed by a rapid rise to above baseline levels in the next 10 days.201 The platelet count begins to decrease by 5 days after beginning cytarabine therapy with the nadir at 12-15 days; platelet levels rise rapidly to above baseline levels in the next 10 days.201

Liposomal Cytarabine

Adverse hematologic or lymphatic effects occurred in 19% of treatment cycles, and were severe in 11% of treatment cycles, in patients receiving liposomal cytarabine for lymphomatous meningitis, including neutropenia in 9% (severe in 8%), thrombocytopenia in 8% (severe in 5%), and anemia in 1% (severe in 1%), of treatment cycles.255 Transient elevations in CSF protein and white blood cell counts have been observed in patients following intrathecal therapy with methotrexate or (conventional or liposomal) cytarabine.255

Nervous System Effects

Conventional Cytarabine

Severe, sometimes fatal, neurologic toxicity has occurred in patients receiving high-dose regimens of conventional (unencapsulated) cytarabine.201 (See Cautions: Adverse Effects Associated With High-Dose Regimens.) Neuritis, neural toxicity, headache, and dizziness have been reported in patients receiving cytarabine.201

Liposomal Cytarabine

Adverse neurologic effects occurred in 45% of treatment cycles, and were severe in 18% of treatment cycles, in patients receiving liposomal cytarabine for lymphomatous meningitis, including confusion in 14% (severe in 4%), somnolence in 12% (severe in 4%), and abnormal gait in 4% (severe in 1%) of treatment cycles.255

Headache, associated with chemical arachnoiditis, occurred in 28% of treatment cycles, and was severe in 5% of treatment cycles, in patients receiving liposomal cytarabine for lymphomatous meningitis.255 In the controlled lymphoma study, seizures occurred in 24% of patients receiving liposomal cytarabine.255 Infectious meningitis may be associated with intrathecal drug therapy.255 Hydrocephalus, possibly precipitated by arachnoiditis, also has been reported.255

Intrathecal administration of cytarabine may cause myelopathy or other neurologic toxicity and, rarely, can lead to a permanent neurologic deficit.255 Administration of intrathecal cytarabine in combination with other chemotherapeutic agents or with cranial/spinal irradiation may increase the risk of neurotoxicity.255 Blockage to CSF flow may increase free cytarabine concentrations in the CSF and increase the risk of neurotoxicity.255 Following intrathecal administration of liposomal cytarabine, CNS toxicity, including persistent extreme somnolence, hemiplegia, visual disturbances including blindness, deafness, and cranial nerve palsies have been reported.255 Manifestations of peripheral neuropathy, such as pain, numbness, paresthesia, weakness, and impaired bowel and bladder control, also have been observed in patients receiving liposomal cytarabine.255

GI Effects

Conventional Cytarabine

Severe, sometimes fatal, GI toxicity has occurred in patients receiving high-dose regimens of conventional (unencapsulated) cytarabine.201 (See Cautions: Adverse Effects Associated With High-Dose Regimens.)

Nausea and vomiting may occur in patients receiving conventional cytarabine and generally occur more frequently and are more severe following rapid IV administration than with continuous IV infusion of the drug.201 After intrathecal administration of cytarabine, the most common adverse effects are nausea, vomiting, and fever.255 Antiemetics may be effective in treating nausea and vomiting.

Other adverse GI effects include diarrhea, anorexia, and oral and anal inflammation or ulceration; less frequently, abdominal pain, sore throat, esophagitis, esophageal ulceration, bowel necrosis, and GI hemorrhage may occur.201 In one study, conventional cytarabine reportedly induced severe intestinal toxicity when used in several sequential chemotherapeutic regimens. Toxic effects on GI mucosa included cellular atypia, immaturity, and necrosis, and were associated with diarrhea, ileus, abdominal pain, hematemesis, melena, hypokalemia, hypocalcemia, protein-losing enteropathy, transient weight gain, and intestinal infections.

Liposomal Cytarabine

Adverse GI effects occurred in 27% of treatment cycles, and were severe in 7% of treatment cycles, in patients receiving liposomal cytarabine for lymphomatous meningitis, including nausea and vomiting associated with chemical arachnoiditis in 11 and 12%, respectively, and constipation in 7%, of treatment cycles.255

Respiratory Effects

Severe, sometimes fatal, pulmonary toxicity has occurred in patients receiving high-dose regimens of conventional (unencapsulated) cytarabine.201 (See Cautions: Adverse Effects Associated With High-Dose Regimens.) Pneumonia and shortness of breath have been reported in patients receiving conventional cytarabine.201

Hepatic Effects

Hepatic dysfunction is a frequent adverse effect of cytarabine therapy.201 Jaundice and elevations in serum bilirubin, transaminases, and alkaline phosphatase have occurred in patients receiving cytarabine alone or with other antineoplastic agents. Veno-occlusive hepatic disease also reportedly developed in 2 men and 4 children who were receiving chemotherapy for acute myelogenous leukemia; all patients had received prior cytarabine therapy but were receiving thioguanine alone or with other agents when they became symptomatic.

Adverse Effects Associated with Intrathecal Administration

Conventional Cytarabine

Intrathecal administration of conventional (unencapsulated) cytarabine infrequently causes systemic toxicity, but the patient's hematologic status must be carefully monitored. Dosage adjustment of concurrently administered antineoplastic agents may be necessary.

The most frequent adverse effects of intrathecally administered conventional cytarabine are nausea, vomiting, fever, and transient headaches; these effects generally are mild and self-limiting. Meningism, paresthesia, paraplegia, spastic paraparesis, and seizures have been reported rarely.

Neurotoxicity following intrathecal injection of conventional cytarabine has been associated with diluents containing preservatives, and many clinicians recommend that preserved diluents not be used. The manufacturers state that diluents containing benzyl alcohol should not be used if the drug is administered intrathecally.201 (See Dosage and Administration: Reconstitution and Administration.) Blindness occurred in 2 leukemic patients in remission who had received systemic combination chemotherapy, prophylactic CNS irradiation, and intrathecal conventional cytarabine.201 Necrotizing leukoencephalopathy also occurred in 5 children who had received intrathecal conventional cytarabine, methotrexate, and hydrocortisone sodium succinate and CNS irradiation.201

The manufacturer states that administration of cytarabine both IV and intrathecally within a period of a few days may be associated with an increased risk of neurotoxicity (i.e., spinal cord toxicity).201

Progressive ascending paralysis, resulting in death in one patient, occurred in 2 children 4-6 months after receiving intrathecal and IV conventional cytarabine at usual doses in combination with other drugs and CNS irradiation.200,201

Liposomal Cytarabine

Chemical arachnoiditis, a syndrome manifested mainly by nausea, vomiting, headache, and fever, is a common adverse effect of intrathecal therapy with liposomal cytarabine and appears to be more common with this formulation than with the conventional (unencapsulated) formulation.255 Toxic effects may occur following a single dose or cumulative doses of liposomal cytarabine.255 Although toxicity is most likely to occur within 5 days of administration of the drug, adverse effects can occur at any time during therapy, and patients receiving intrathecal therapy with liposomal cytarabine should be monitored continuously.255 If it is not treated, chemical arachnoiditis may be fatal.255 Concurrent administration of dexamethasone may reduce the incidence and severity of chemical arachnoiditis associated with intrathecal administration of liposomal cytarabine.255

Arachnoiditis is a common adverse effect of neoplastic meningitis, and it may be difficult to distinguish the disease-related syndrome from drug-related, or chemical, arachnoiditis.255 In clinical studies of liposomal cytarabine, chemical arachnoiditis was defined as the occurrence of neck rigidity, neck pain, or meningism, or any two of the following manifestations: nausea, vomiting, headache, fever, back pain, or CSF pleocytosis; the grade of severity of chemical arachnoiditis was based on the most severe manifestation.255 More than 90% of the cases of chemical arachnoiditis occurred within 48 hours of the intrathecal administration of liposomal cytarabine.255 The duration of manifestations was 1-5 days.255

Concurrent administration of dexamethasone may reduce the incidence and severity of chemical arachnoiditis associated with intrathecal administration of liposomal cytarabine.255 In an early study of liposomal cytarabine, chemical arachnoiditis was observed in 100% of treatment cycles in patients who did not receive prophylactic treatment with dexamethasone, and in 33% of treatment cycles in patients who did receive prophylactic treatment with dexamethasone.255 In the randomized study, a greater number of episodes of chemical arachnoiditis, including grade 3 or 4 chemical arachnoiditis, occurred in patients receiving liposomal cytarabine compared with those receiving conventional cytarabine for lymphomatous meningitis.255

Deaths have occurred in patients receiving intrathecal liposomal cytarabine during clinical studies.255 One patient developed encephalopathy and died 36 hours after an intraventricular dose of liposomal cytarabine 125 mg.255 This patient was receiving concurrent whole-brain irradiation and had previously received cyclophosphamide, doxorubicin, and fluorouracil, as well as intraventricular methotrexate.255 Another patient developed focal seizures and progressed to status epilepticus after receiving liposomal cytarabine 50 mg by the intraventricular route.255 This patient died approximately 8 weeks following the last dose of the drug.255 A patient with extensive lymphoma involving the nasopharynx, brain, and meninges with multiple neurologic deficits died of apparent disease progression 4 days after his second dose of liposomal cytarabine.255

Metabolic Effects

Conventional Cytarabine

As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in patients receiving cytarabine, and serum uric acid concentrations should be monitored. Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization of the urine, and/or administration of allopurinol.

Liposomal Cytarabine

Adverse metabolic or nutritional effects occurred in 16% of treatment cycles in patients receiving liposomal cytarabine for lymphomatous meningitis, including peripheral edema in 7% of treatment cycles.255

Dermatologic and Sensitivity Reactions

Anaphylactic reactions have been reported following IV administration of conventional cytarabine.255 Anaphylaxis with acute cardiopulmonary arrest that required resuscitation occurred in one patient immediately after IV administration of conventional (unencapsulated) cytarabine.201

Allergic edema, pruritus, and urticaria have been reported with conventional (unencapsulated) cytarabine. Alopecia, freckling, rash (occasionally associated with conjunctivitis), and skin ulceration also have been reported. A corticosteroid-responsive syndrome that includes maculopapular rash may occur. (See Cautions: Other Adverse Effects.)

Genitourinary Effects

Conventional Cytarabine

Urinary retention has been reported in patients receiving cytarabine.201

Liposomal Cytarabine

Adverse genitourinary effects occurred in 11% of treatment cycles, and were severe in 3% of treatment cycles, in patients receiving liposomal cytarabine for lymphomatous meningitis.255 Urinary incontinence occurred in 3% of treatment cycles.255

Local Effects

Reactions at the injection site including pain, inflammation, thrombophlebitis, or cellulitis have been reported in patients receiving conventional (unencapsulated) cytarabine.201 Rarely, pain and inflammation have occurred at sites of subcutaneous injection.201

Other Adverse Effects

Conventional Cytarabine

Other reported adverse effects of cytarabine include fever, sepsis, conjunctivitis (may occur with rash), chest pain, pericarditis, pancreatitis, renal dysfunction.201 A cytarabine syndrome manifested as fever, myalgia, bone pain, maculopapular rash, conjunctivitis, malaise, and occasionally chest pain, has been reported.201 The syndrome usually occurs 6-12 hours after administration of the drug; corticosteroids are beneficial in the treatment and prevention of the syndrome.201 If symptoms of the syndrome require treatment, administration of corticosteroids should be considered as well as continuation of cytarabine therapy.201

Liposomal Cytarabine

Asthenia, adverse effects of the special senses, and pain were reported in 19, 16, and 11% of treatment cycles, and were severe in 5, 1, and 3% of treatment cycles, respectively, in patients receiving liposomal cytarabine for lymphomatous meningitis.255 Fever and back pain, associated with chemical arachnoiditis, occurred in 11 and 7% of treatment cycles, and were severe in 4 and 0% of treatment cycles, respectively, in patients receiving liposomal cytarabine for lymphomatous meningitis.255

Adverse Effects Associated with High-Dose Regimens

Severe and sometimes fatal CNS, GI, and pulmonary toxicity, which differs from that seen with usual dosages, has been associated with high-dose† cytarabine regimens for refractory or secondary acute leukemia or refractory non-Hodgkin's lymphomas.201 Adverse effects associated with these regimens include cerebral and cerebellar dysfunction (e.g., somnolence, coma, personality changes), which are usually reversible; hemorrhagic conjunctivitis and reversible corneal toxicity (e.g., keratitis), which may be minimized or prevented by prophylaxis with ophthalmic corticosteroid preparations; one case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH); severe GI ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; bowel necrosis; necrotizing colitis; sepsis and liver abscess; liver damage with increased hyperbilirubinemia; pericarditis with tamponade; and pulmonary edema.201 Reversible, acute aseptic meningitis, combined with cerebellar dysfunction, has been reported in at least one patient.205 Rarely, severe rash leading to desquamation has occurred.201 Complete alopecia occurs more commonly with high-dose regimens than with usual dosage regimens of the drug.201 A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly and which was sometimes fatal, has been reported in patients with refractory acute leukemia receiving high-dose therapy.201 Cases of cardiomyopathy with subsequent death also have been reported in patients receiving high-dose cytarabine in combination with cyclophosphamide in preparation for bone marrow transplantation; this cardiac toxicity may be schedule dependent.201

Peripheral motor and sensory neuropathies also have occurred occasionally in patients receiving high-dose cytarabine therapy.201,202,203,204 Neuropathies have involved the lower and/or upper extremities, and have been manifested as muscle weakness, gait disturbances, walking difficulties, handwriting difficulties, paresthesia, numbness, hypoalgesia, hypoesthesia, and myalgia.202,203,204 Patients receiving high-dose cytarabine should be observed for signs of neuropathy;201,202,203,204 dosage schedule adjustment may be necessary to avoid irreversible neurologic toxicity.201,202 According to the manufacturer, patients with renal or hepatic impairment may be at increased risk of CNS toxicity associated with high-dose cytarabine therapy.201

Diffuse interstitial pneumonitis, possibly related to cytarabine therapy, has been reported occasionally in patients receiving relatively high doses (e.g., 1 g/m²) of cytarabine alone or in combination with other antineoplastic agents.201,213,214,215,216,217,218,219,220,221 Pancreatitis also has occurred in patients receiving high-dose cytarabine therapy.201,212,218 Cases of acute pancreatitis have been reported in patients receiving cytarabine who were previously treated with asparaginase.201

There is some evidence to suggest that the incidence of cerebellar dysfunction (e.g., ataxia, dysarthria, dysdiadochokinesia, dysmetria, tremor, nystagmus) associated with high-dose† (1-3 g/m² given by IV infusion over 1 hour twice daily for 2-6 days) regimens of cytarabine may be increased when drug manufactured by Quad (no longer commercially available in the US) is used compared with that when cytarabine manufactured by Upjohn is used.222,223,224 A causal relationship of this apparent increased incidence of cerebellar dysfunction associated with the Quad preparation has not been established, but results of a retrospective analysis conducted by FDA of a limited number of case histories (25 received Quad's product and 34 received Upjohn's product) revealed that cerebellar dysfunction occurred in 32% of patients receiving the high-dose regimen with cytarabine manufactured by Quad compared with 9% in those receiving the Upjohn preparation.222,223 While both preparations meet USP compendial standards, there are small differences in impurities and potency of the sterile powders manufactured by these companies; however, the clinical importance of these differences has not been established, but it is possible that such differences are of no consequence with usual regimens but may be important at very high dosages.222,223,224 Quad recommends that any remaining cytarabine manufactured by them be used only at the labeled dosages, and that their preparation not be used for high-dose regimens.222,223,224

Precautions and Contraindications

Cytarabine is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.201 Liposomal cytarabine must be used only by clinicians experienced in intrathecal therapy with cytotoxic agents.255 Adequate diagnostic and treatment facilities are required for the management of complications associated with cytarabine therapy.201,255

Hematologic Toxicity

Conventional Cytarabine

Treatment with conventional (unencapsulated) cytarabine should be initiated only with extreme caution in patients with preexisting drug-induced bone marrow suppression.201 Patients who receive myelosuppressive drugs experience an increased frequency of infections (e.g., viral, bacterial, fungal, parasitic, or saprophytic) as well as possible hemorrhagic complications.201 Because these complications are potentially fatal,201 the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs.

The patient's hematologic status must be carefully monitored during conventional cytarabine therapy.201 Leukocyte and platelet counts should be performed frequently during therapy.201 Leukocyte and platelet counts should be determined daily during remission induction therapy of acute leukemia.201 Frequent bone marrow examinations should be performed after blast cells have disappeared from the peripheral blood.201 Patients should receive conventional cytarabine therapy only in facilities where seriously, and possibly fatal, complications of bone marrow suppression can be adequately managed (e.g., infection secondary to granulocytopenia or other impaired body defenses, hemorrhage secondary to thrombocytopenia).201

Liposomal Cytarabine

Although systemic exposure to free cytarabine is expected to be minimal following intrathecal administration of liposomal cytarabine, the possibility of hematologic toxicity, including leukopenia, thrombocytopenia, and anemia, cannot be ruled out.255 Patients should be monitored carefully for hematologic toxicity during therapy with liposomal cytarabine.255

Renal or Hepatic Toxicity

Periodic determinations of renal function should be performed in patients receiving cytarabine.201 Periodic determinations of hepatic function also should be performed in patients receiving cytarabine, and the drug should be used with caution and in reduced dosage in patients with poor hepatic function.201

Neurotoxicity

Conventional Cytarabine

Patients receiving high-dose† cytarabine therapy should be monitored closely for signs of neurotoxicity (e.g., peripheral neuropathy, cerebellar dysfunction).201,202,203,204 (See Cautions: Adverse Effects Associated with High-Dose Regimens.)

Liposomal Cytarabine

Patients receiving intrathecal therapy with liposomal cytarabine should be monitored continuously for the development of neurotoxicity.255 If neurotoxicity occurs, dosage reduction or discontinuance of therapy is required.255 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy: Neurotoxicity in Dosage and Administration: Dosage.)

Toxicity Associated with Intrathecal Administration of Liposomal Cytarabine

Patients should be informed about the expected adverse effects of intrathecal therapy with liposomal cytarabine, including headache, nausea, vomiting, and fever.255 Patients should be informed about early signs and symptoms of neurotoxicity.255 The importance of concurrent dexamethasone administration should be emphasized when each cycle of therapy with liposomal cytarabine is initiated.255 Patients should be instructed to notify the clinician if signs or symptoms of neurotoxicity develop, or if oral dexamethasone is not well tolerated.255

Other Toxicity

Serum uric acid concentrations should be monitored in patients receiving conventional cytarabine; rapid lysis of neoplastic cells can lead to hyperuricemia.201

Lack of Interchangeability with the Fixed Liposomal Combination of Daunorubicin and Cytarabine

The pharmacokinetic properties, formulation, and dosage of cytarabine as a single-entity preparation differ from those of the fixed liposomal combination of daunorubicin and cytarabine (Vyxeos^®); these preparations are not interchangeable.256

Contraindications

Conventional cytarabine is contraindicated in patients with known hypersensitivity to the drug.201 Liposomal cytarabine is contraindicated in patients who are hypersensitive to cytarabine or any component of the formulation, and in patients with active meningeal infection.255

Pediatric Precautions

Benzyl alcohol is associated with a fatal “gasping syndrome” in premature infants.201 Conventional (unencapsulated) cytarabine that has been reconstituted with bacteriostatic water for injection containing benzyl alcohol should not be used in neonates. Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.

Safety and efficacy of liposomal cytarabine in children have not been established.255

Mutagenicity and Carcinogenicity

Cytarabine is mutagenic and potentially carcinogenic.201,255 Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of liposomal cytarabine, but its active ingredient is cytarabine.255 Cytarabine was mutagenic in in vitro tests.255 Cytarabine was clastogenic, exhibiting chromosomal aberrations and sister chromatid exchange, in in vitro tests in human leukocytes and in in vivo tests in rodent bone marrow; clastogenicity also was demonstrated using the mouse micronucleus assay.255 In in vitro tests, cytarabine caused the transformation of hamster embryo cells and rat H43 cells.255 Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities and chromosomal aberrations were observed in mice given cytarabine intraperitoneally.255

Pregnancy, Fertility, and Lactation

Pregnancy

Cytarabine can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.201 Because systemic exposure to cytarabine is negligible during intrathecal therapy with liposomal cytarabine, the risk of fetal toxicity is thought to be low.255 However, there are no formal studies assessing the reproductive toxicity of liposomal cytarabine.255

Congenital abnormalities have been reported, particularly when the fetus has been exposed to systemic therapy with cytarabine during the first trimester.201 There is a definite, but considerably reduced risk to the fetus when therapy is initiated during the second or third trimester.201 At least 3 cases of major limb malformations have been reported in infants of mothers who received IV cytarabine, alone or in combination with other agents, during the first trimester.255 One infant had extremity and ear deformities, and another infant had upper and lower distal limb defects.201 A few women have received cytarabine with other antineoplastic agents during the second and third trimesters (20th-28th week of gestation) and delivered apparently normal infants. However, in one patient a trisomy C chromosomal abnormality was found in the chorionic tissue following a therapeutic abortion at 24 weeks of gestation after 4 weeks of therapy with cytarabine and thioguanine; the fetus appeared to have no congenital abnormalities.

In animal studies, cytarabine has been shown to cause abnormal cerebellar development in the neonatal hamster.201 Cytarabine has been shown to be teratogenic in mice and rats.201,255 Abnormalities including cleft palate, phocomelia, deformed appendages, and skeletal abnormalities have been observed in the offspring of mice given cytarabine doses of at least 2 mg/kg daily (about 0.2 times the recommended human dose on a mg/m² basis) administered intraperitoneally during the period of organogenesis.255 Deformed appendages have been observed in the offspring of rats given cytarabine 20 mg/kg (about 4 times the recommended human dose on a mg/m² basis) as a single intraperitoneal dose on day 12 of gestation.255 Reduced prenatal and postnatal brain size and permanent impairment of learning ability were observed in rats given single intraperitoneal doses of cytarabine 50 mg/kg (about 10 times the recommended human dose on a mg/m² basis) on day 14 of gestation.255

Cytarabine was embryotoxic in mice when given during the period of organogenesis.255 Decreased fetal weight was observed in mice given cytarabine 0.5 mg/kg daily (about 0.05 times the recommended human dose on a mg/m² basis), and increased early and late resorptions and decreased live litter sizes were observed in mice given cytarabine 8 mg/kg daily (approximately equal to the recommended human dose on a mg/m² basis).255

There are no adequate and well-controlled studies to date using conventional or liposomal cytarabine in pregnant women.201,255 Cytarabine should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.201,255 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.201,255 Women receiving systemic therapy with cytarabine, particularly during the first trimester, should be counseled on the advisability of continuing the pregnancy.201 The manufacturers suggest that infants delivered by women who received cytarabine therapy during pregnancy receive follow-up monitoring.201 Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug.201,255

Fertility

There are no adequate studies on the effects of cytarabine on fertility.255 Because systemic exposure to free cytarabine is expected to be minimal following intrathecal administration of liposomal cytarabine, the risk of impaired fertility is thought to be low.255

Lactation

It is not known whether cytarabine is distributed into human milk.201,255 Because of the potential for serious adverse reactions to conventional cytarabine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.201 Systemic exposure to free cytarabine following intrathecal administration of liposomal cytarabine is negligible, so the risk of the drug being distributed into human milk is thought to be low.255 However, because many drugs are distributed into human milk and because of the potential for serious adverse reactions in nursing infants, the use of liposomal cytarabine is not recommended in nursing women.255

Formal studies of drug interactions have not been conducted for liposomal cytarabine.255

Cardiac Glycosides

GI absorption of oral digoxin tablets may be substantially reduced in patients receiving combination chemotherapy regimens (including regimens containing cytarabine),201,207,208 possibly as a result of temporary damage to intestinal mucosa caused by the cytotoxic agents.207,208 Plasma concentrations of digoxin should be carefully monitored in patients receiving such combination chemotherapy regimens.201,207 Use of digoxin oral elixir210 or liquid-filled capsules208 may minimize the potential interaction, since the drug is rapidly and extensively absorbed from these dosage forms.208,210 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.201,207,209

Anti-infective Agents

One in vitro study indicates that cytarabine may antagonize the activity of gentamicin against Klebsiella pneumoniae .201,211 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.201,211

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.201

Antineoplastic Agents

The incidence of toxicity may be increased when liposomal cytarabine is used concurrently with systemic chemotherapy in patients with neoplastic meningitis.255 Increased neurotoxicity has been observed in patients receiving concomitant intrathecal administration of conventional cytarabine and other cytotoxic agents.255

Radiation Toxicity

The incidence of toxicity may be increased when cytarabine is used concurrently with radiation therapy in patients with neoplastic meningitis.255

Laboratory Test Interferences

Because particles of liposomal cytarabine are similar in size and appearance to white blood cells, CSF examinations must be interpreted carefully following administration of the drug.

Acute Toxicity

Limited information is available on the acute toxicity of conventional (unencapsulated) cytarabine.201 IV doses of cytarabine 4.5 g/m² administered over 1 hour every 12 hours for 12 doses caused excessive toxicity, including irreversible CNS toxicity and death.201 Single doses of cytarabine up to 3 g/m² IV have been administered by rapid IV infusion without apparent toxicity.201 There is no known antidote for overdosage of conventional (unencapsulated) cytarabine.201

Limited information is available on the acute toxicity of liposomal cytarabine.255 Overdosage of liposomal cytarabine may be associated with severe chemical arachnoiditis, including encephalopathy.255 In an uncontrolled study, single doses of liposomal cytarabine up to 125 mg were administered without dexamethasone prophylaxis.255 One patient died of encephalopathy 36 hours after receiving an intraventricular dose of liposomal cytarabine 125 mg.255 This patient also was receiving concomitant whole brain irradiation and had previously received intraventricular methotrexate.255 There is no known antidote for overdosage of liposomal cytarabine by intrathecal administration or free (unencapsulated) cytarabine released from the drug.255 In a case of overdosage of free cytarabine administered intrathecally, exchange of CSF with isotonic saline solution was performed; this method may be considered in case of overdosage with liposomal cytarabine.255 Treatment of toxicity is mainly supportive and should be directed at maintaining vital functions.255

Pharmacology

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.

Pharmacokinetics

The effects of gender, race, or renal or hepatic impairment on the pharmacokinetics of liposomal cytarabine have not been studied.255

Absorption

Less than 20% of a dose of conventional (unencapsulated) cytarabine is absorbed from the GI tract, and the drug is not effective when administered orally. Following subcutaneous or IM† injection of radiolabeled cytarabine (as the conventional formulation), peak plasma concentrations of radioactivity occur within 20-60 minutes and are considerably lower than those attained after IV administration. Continuous IV infusions of conventional cytarabine produce relatively constant plasma concentrations of the drug in 8-24 hours.

Cytarabine liposome injection is a sustained-release formulation of the drug that is designed for intrathecal administration.255 According to preliminary analysis of pharmacokinetic data, peak concentrations of free cytarabine occur within 5 hours in both the ventricle and the lumbar sac following intrathecal administration of liposomal cytarabine into the lumbar sac or an intraventricular reservoir.255

Distribution

Conventional (unencapsulated) cytarabine is rapidly and widely distributed into tissues and fluids, including liver, plasma, and peripheral granulocytes. Following rapid IV injection of conventional 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 infusion 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 conventional cytarabine diffuses into the systemic circulation but is rapidly metabolized and usually only low plasma concentrations of unchanged drug occur.

Following intrathecal administration of 50 or 75 mg of liposomal cytarabine, systemic exposure to cytarabine is negligible.255 Cytarabine apparently crosses the placenta. It is not known if cytarabine or ara-U is distributed into milk.

Elimination

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.

Following intrathecal administration of 12.5-75 mg of liposomal cytarabine, CSF concentrations of the drug decline in a biphasic manner with a terminal phase half-life of 100-263 hours.255

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-β-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.201,255 The clearance rate of cytarabine in CSF is similar to the CSF bulk flow rate of 0.24 mL/minute.255 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.

Cytarabine and ara-U are excreted in urine. After rapid IV, IM† , subcutaneous, or intrathecal injection or continuous IV infusion of cytarabine, about 70-80% of the dose is excreted in urine within 24 hours. Approximately 90% of the urinary drug excretion occurs as ara-U and about 10% as unchanged cytarabine.

Chemistry and Stability

Chemistry

Cytarabine is a synthetic pyrimidine nucleoside. Cytarabine differs from the physiological nucleosides, cytidine and deoxycytidine, in that the sugar moiety is arabinose instead of ribose or deoxyribose. Cytarabine is a pyrimidine antagonist antimetabolite. The drug occurs as an odorless, white to off-white, crystalline powder, is very slightly soluble in alcohol and has a solubility of 100 mg/mL in water. Cytarabine has a pK_a of 4.35. Hydrochloric acid and/or sodium hydroxide may be added to the commercially available lyophilized product to adjust the pH. Commercially available cytarabine injection 100 mg/5 mL (20 mg/mL) occurs as a sterile, isotonic solution of the drug in 0.68% sodium chloride; hydrochloric acid and/or sodium hydroxide may be added to adjust the pH to 7.4;250 this preparation also is available in a pharmacy bulk package that is restricted to use in the preparation of admixtures for IV infusion.252 Each mL of the cytarabine injection contains approximately 0.12 mEq of sodium.250 Commercially available cytarabine injection 2 g/20 mL occurs as a sterile solution in water for injection; hydrochloric acid and/or sodium hydroxide may be added to adjust the pH to 7.7.250 Commercially available cytarabine injection 500 mg/25 mL (20 mg/mL) contains benzyl alcohol as a preservative and hydrochloric acid and/or sodium hydroxide may be added to adjust the pH to 7.6.251

Commercially available cytarabine liposome injection is a sterile, preservative-free injectable suspension of cytarabine encapsulated in multivesicular lipid-based particles.255 The injection is a sterile, nonpyrogenic, white to off-white suspension of cytarabine in 0.9% sodium chloride in water for injection that has a pH of 5.5-8.5.255 Each mL of the cytarabine liposome injection contains 10 mg of cytarabine encapsulated in lipid-based particles.255

Stability

Conventional Cytarabine

Conventional (unencapsulated) cytarabine sterile powder should be stored at 25°C but may be exposed to temperatures of 15-30°C.201 Commercially available conventional cytarabine injection should be stored at controlled room temperature (15-30°C);250,251,252 the injection should be stored in the manufacturer's carton until time of use and should be protected from light.250

Following reconstitution of the sterile powder with bacteriostatic water for injection containing 0.945% benzyl alcohol, solutions containing 20, 50, or 100 mg of cytarabine per mL have a pH of about 5 and are stable for 48 hours at 20-25°C; solutions that develop a slight haze should not be used.201 The manufacturer states that following dilution of the reconstituted solution with water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, solutions containing 0.5 mg of cytarabine per mL are stable for at least 8 days at room temperature.201 In a study of solutions for intrathecal injection, those containing 5 mg of cytarabine per mL in Elliott's B solution (an investigational electrolyte solution containing sodium bicarbonate as a buffer), 0.9% sodium chloride injection, or lactated Ringer's injection were stable for 7 days at room temperature. However, when cytarabine is reconstituted with a diluent that does not contain a preservative or when reconstituted solutions of the drug are diluted in compatible IV solutions, the possibility of contamination should be considered. Although commercially available cytarabine injection is stable for 8 days at room temperature when diluted with sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection,250 the manufacturer states that good professional practice suggests that these admixtures be used as soon after preparation as possible; in addition, any unused portions should be discarded.251 The manufacturer also recommends that any unused portion of cytarabine injection in pharmacy bulk packages be discarded within 4 hours after initial entry through the closure into the container.252

Solutions of cytarabine have been reported to be incompatible with various drugs, but the incompatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Liposomal Cytarabine

Cytarabine liposome injection should be stored at 2-8°C; freezing should be avoided and the vial should be protected from aggressive agitation.255 Cytarabine liposome injection contains no preservative and should be used within 4 hours of withdrawal from the vial; unused portions should be discarded.255 When stored according to manufacturer recommendations, cytarabine liposome injection may be used up to the expiration date printed on the label.255 Cytarabine liposome injection should not be mixed with any other medications.255

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Only references cited for selected revisions after 1984 are available electronically.

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