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Cytarabine (Conventional)

Pronunciation

Pronunciation

(sye TARE a been con VEN sha nal)

Index Terms

  • Ara-C
  • Arabinosylcytosine
  • Conventional Cytarabine
  • Cytarabine
  • Cytarabine Hydrochloride
  • Cytosar-U
  • Cytosine Arabinosine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Generic: 20 mg/mL (25 mL); 100 mg/mL (20 mL)

Solution, Injection [preservative free]:

Generic: 20 mg/mL (5 mL, 50 mL); 100 mg/mL (20 mL)

Solution Reconstituted, Injection:

Generic: 100 mg (1 ea); 500 mg (1 ea); 1 g (1 ea)

Pharmacologic Category

  • Antineoplastic Agent, Antimetabolite
  • Antineoplastic Agent, Antimetabolite (Pyrimidine Analog)

Pharmacology

Inhibits DNA synthesis. Cytarabine gains entry into cells by a carrier process, and then must be converted to its active compound, aracytidine triphosphate. Cytarabine is a pyrimidine analog and is incorporated into DNA; however, the primary action is inhibition of DNA polymerase resulting in decreased DNA synthesis and repair. The degree of cytotoxicity correlates linearly with incorporation into DNA; therefore, incorporation into the DNA is responsible for drug activity and toxicity. Cytarabine is specific for the S phase of the cell cycle (blocks progression from the G1 to the S phase).

Absorption

Not effective when administered orally; less than 20% absorbed orally

Distribution

Vd: 3 ± 11.9 L/kg; total body water; widely and rapidly since it enters the cells readily; crosses blood-brain barrier with CSF levels of 40% to 50% of plasma level

Metabolism

Primarily hepatic; metabolized by deoxycytidine kinase and other nucleotide kinases to aracytidine triphosphate (active); about 86% to 96% of dose is metabolized to inactive uracil arabinoside (ARA-U); intrathecal administration results in little conversion to ARA-U due to the low levels of deaminase in the cerebral spinal fluid

Excretion

Urine (~80%; 90% as metabolite ARA-U) within 24 hours

Time to Peak

IM, SubQ: 20 to 60 minutes

Half-Life Elimination

IV: Initial: 7 to 20 minutes; Terminal: 1 to 3 hours; Intrathecal: 2 to 6 hours

Protein Binding

13%

Use: Labeled Indications

Acute myeloid leukemia: Remission induction (in combination with other chemotherapy medications) in acute myeloid leukemia (AML)

Acute lymphocytic leukemia: Treatment of acute lymphocytic leukemia (ALL)

Chronic myeloid leukemia: Treatment of chronic myeloid leukemia (CML; blast phase)

Meningeal leukemia: Prophylaxis and treatment of meningeal leukemia

Use: Unlabeled

AML consolidation treatment, AML salvage treatment; acute promyelocytic leukemia (APL) consolidation treatment; treatment of primary central nervous system (CNS) lymphoma; treatment of chronic lymphocytic leukemia (CLL); treatment of relapsed or refractory Hodgkin lymphoma; treatment of non-Hodgkin lymphomas (NHL)

Contraindications

Hypersensitivity to cytarabine or any component of the formulation

Dosing: Adult

Note: Doses >1000 mg/m2 are associated with a moderate emetic potential in adults (Basch, 2011; Roila, 2010); antiemetics are recommended to prevent nausea and vomiting.

Acute myeloid leukemia (AML) remission induction: IV: Standard-dose (manufacturer's labeling; in combination with other chemotherapy agents): 100 mg/m2/day continuous infusion for 7 days or 200 mg/m2/day continuous infusion (as 100 mg/m2 over 12 hours every 12 hours) for 7 days

Indication-specific dosing:

AML induction: IV:

7 + 3 regimens (a second induction course may be administered if needed; refer to specific references): 100 mg/m2/day continuous infusion for 7 days (in combination with daunorubicin or idarubicin or mitoxantrone) (Arlin, 1990; Dillman, 1991; Fernandez, 2009; Vogler, 1992; Wiernik, 1992) or (Adults <60 years) 200 mg/m2/day continuous infusion for 7 days (in combination with daunorubicin) (Dillman, 1991)

Low intensity therapy (off-label dosing): Adults ≥65 years: SubQ: 20 mg/m2/day for 14 days out of every 28-day cycle for at least 4 cycles (Fenaux, 2010) or 10 mg/m2 every 12 hours for 21 days; if complete response not achieved, may repeat a second course after 15 days (Tilly, 1990)

AML consolidation (off-label use): IV:

5 + 2 regimens: 100 mg/m2/day continuous infusion for 5 days (in combination with daunorubicin or idarubicin or mitoxantrone) (Arlin, 1990; Wiernik, 1992)

5 + 2 + 5 regimen: 100 mg/m2/day continuous infusion for 5 days (in combination with daunorubicin and etoposide) (Bishop, 1996)

Single-agent: Adults ≤60 years: 3000 mg/m2 over 3 hours every 12 hours on days 1, 3, and 5 (total of 6 doses); repeat every 28 to 35 days for 4 courses (Mayer, 1994)

AML salvage treatment (off-label use): IV:

CLAG regimen: 2000 mg/m2/day over 4 hours for 5 days (in combination with cladribine and G-CSF); may repeat once if needed (Wrzesień -Kuś, 2003)

CLAG-M regimen: 2000 mg/m2/day over 4 hours for 5 days (in combination with cladribine, G-CSF, and mitoxantrone); may repeat once if needed (Wierzbowska, 2008)

FLAG regimen: 2000 mg/m2/day over 4 hours for 5 days (in combination with fludarabine and G-CSF); may repeat once if needed (Montillo, 1998)

GCLAC regimen: Adults 18 to 70 years (Becker, 2011):

Induction: 2,000 mg/m2 over 2 hours once daily for 5 days (in combination with clofarabine and filgrastim; administer 4 hours after initiation of clofarabine); may repeat induction once if needed.

Consolidation: 1,000 mg/m2 over 2 hours once daily for 5 days (in combination with clofarabine and filgrastim; administer 4 hours after initiation of clofarabine) for 1 or 2 cycles

HiDAC (high-dose cytarabine) ± an anthracycline: 3000 mg/m2 over 1 hour every 12 hours for 6 days (total of 12 doses) (Herzig, 1985)

MEC regimen: 1000 mg/m2/day over 6 hours for 6 days (in combination with mitoxantrone and etoposide) (Amadori, 1991) or

Adults <60 years: 500 mg/m2/day continuous infusion days 1, 2, and 3 and days 8, 9, and 10 (in combination with mitoxantrone and etoposide); may administer a second course if needed (Archimbaud, 1991; Archimbaud, 1995)

Acute promyelocytic leukemia (APL) induction (off-label dosing): IV: 200 mg/m2/day continuous infusion for 7 days beginning on day 3 of treatment (in combination with tretinoin and daunorubicin) (Ades, 2006; Ades, 2008; Powell, 2010)

APL consolidation (off-label use): IV:

In combination with idarubicin and tretinoin: High-risk patients (WBC ≥10,000/mm3) (Sanz, 2010): Adults ≤60 years:

First consolidation course: 1000 mg/m2/day for 4 days

Third consolidation course: 150 mg/m2 every 8 hours for 4 days

In combination with idarubicin, tretinoin, and thioguanine: High-risk patients (WBC >10,000/mm3) (Lo Coco, 2010): Adults ≤61 years:

First consolidation course: 1000 mg/m2/day for 4 days

Third consolidation course: 150 mg/m2 every 8 hours for 5 days

In combination with daunorubicin (Ades, 2006; Ades, 2008):

First consolidation course: 200 mg/m2/day for 7 days

Second consolidation course:

Age ≤60 years and low risk (WBC <10,000/mm3): 1000 mg/m2 every 12 hours for 4 days (8 doses)

Age <50 years and high risk (WBC ≥10,000/mm3): 2000 mg/m2 every 12 hours for 5 days (10 doses)

Age 50 to 60 years and high risk (WBC ≥10,000/mm3): 1500 mg/m2 every 12 hours for 5 days (10 doses) (Ades, 2008)

Age >60 years and high risk (WBC ≥10,000/mm3): 1000 mg/m2 every 12 hours for 4 days (8 doses)

Acute lymphocytic leukemia (ALL; off-label dosing):

Induction regimen, relapsed or refractory: IV: 3000 mg/m2 over 3 hours daily for 5 days (in combination with idarubicin [day 3]) (Weiss, 2002)

Dose-intensive regimen: IV: 3000 mg/m2 over 2 hours every 12 hours days 2 and 3 (4 doses/cycle) of even numbered cycles (in combination with methotrexate; alternates with Hyper-CVAD) (Kantarjian, 2000)

CALGB 8811 regimen (Larson, 1995): SubQ

Early intensification phase: 75 mg/m2/dose days 1 to 4 and 8 to 11 (4-week cycle; repeat once)

Late intensification phase: 75 mg/m2/dose days 29 to 32 and 36 to 39

Linker protocol: Adults <50 years: IV: 300 mg/m2/day days 1, 4, 8, and 11 of even numbered consolidation cycles (in combination with teniposide) (Linker, 1991)

Chronic lymphocytic leukemia (CLL; off-label use): OFAR regimen: IV: 1000 mg/m2/dose over 2 hours days 2 and 3 every 4 weeks for up to 6 cycles (in combination with oxaliplatin, fludarabine, and rituximab) (Tsimberidou, 2008)

Primary central nervous system (CNS) lymphoma (off-label use): IV: 2000 mg/m2 over 1 hour every 12 hours days 2 and 3 (total of 4 doses) every 3 weeks (in combination with methotrexate and followed by whole brain irradiation) for a total of 4 courses (Ferreri, 2009)

Hodgkin lymphoma, relapsed or refractory (off-label use): IV:

DHAP regimen: 2000 mg/m2 over 3 hours every 12 hours day 2 (total of 2 doses/cycle) for 2 cycles (in combination with dexamethasone and cisplatin) (Josting, 2002)

ESHAP regimen: 2000 mg/m2 day 5 (in combination with etoposide, methylprednisolone, and cisplatin) every 3 to 4 weeks for 3 or 6 cycles (Aparicio, 1999)

Mini-BEAM regimen: 100 mg/m2 every 12 hours days 2 to 5 (total of 8 doses) every 4 to 6 weeks (in combination with carmustine, etoposide, and melphalan) (Colwill, 1995; Martin, 2001)

BEAM regimen (transplant preparative regimen): 200 mg/m2 twice daily for 4 days beginning 5 days prior to transplant (in combination with carmustine, etoposide, and melphalan) (Chopra, 1993)

Non-Hodgkin lymphomas (off-label use): IV:

CALGB 9251 regimen: Cycles 2, 4, and 6: 150 mg/m2/day continuous infusion days 4 and 5 (Lee, 2001; Rizzieri, 2004)

CODOX-M/IVAC regimen:

Adults ≤60 years: Cycles 2 and 4 (IVAC): 2000 mg/m2 every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna, and etoposide; IVAC alternates with CODOX-M) (Magrath, 1996)

Adults ≤65 years: Cycles 2 and 4 (IVAC): 2000 mg/m2 over 3 hours every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna, and etoposide; IVAC alternates with CODOX-M) (Mead, 2008)

Adults >65 years: Cycles 2 and 4 (IVAC): 1000 mg/m2 over 3 hours every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna, and etoposide; IVAC alternates with CODOX-M) (Mead, 2008)

DHAP regimen:

Adults ≤70 years: 2000 mg/m2 over 3 hours every 12 hours day 2 (total of 2 doses/cycle) every 3 to 4 weeks for 6 to 10 cycles (in combination with dexamethasone and cisplatin) (Velasquez, 1988)

Adults >70 years: 1000 mg/m2 over 3 hours every 12 hours day 2 (total of 2 doses/cycle) every 3 to 4 weeks for 6 to 10 cycles (in combination with dexamethasone and cisplatin) (Velasquez, 1988)

ESHAP regimen: 2000 mg/m2 over 2 hours day 5 every 3 to 4 weeks for 6 to 8 cycles (in combination with etoposide, methylprednisolone, and cisplatin) (Velasquez, 1994)

BEAM regimen (transplant preparative regimen): 200 mg/m2 twice daily for 3 days beginning 4 days prior to transplant (in combination with carmustine, etoposide, and melphalan) (Linch, 2010) or 100 mg/m2 over 1 hour every 12 hours for 4 days beginning 5 days prior to transplant (in combination with carmustine, etoposide, and melphalan) (van Imhoff, 2005)

Meningeal leukemia: Intrathecal: Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer, 1983; Kerr, 2001). Dosing provided in the manufacturer's labeling is BSA-based (usual dose 30 mg/m2 every 4 days; range: 5 to 75 mg/m2 once daily for 4 days or once every 4 days until CNS findings normalize, followed by 1 additional treatment).

Off-label uses or doses for intrathecal therapy: Intrathecal:

CNS prophylaxis (ALL): 100 mg weekly for 8 doses, then every 2 weeks for 8 doses, then monthly for 6 doses (high-risk patients) or 100 mg on day 7 or 8 with each chemotherapy cycle for 4 doses (low risk patients) or 16 doses (high-risk patients) (Cortes, 1995)

or as part of intrathecal triple therapy (TIT): 40 mg days 0 and 14 during induction, days 1, 4, 8, and 11 during CNS therapy phase, every 18 weeks during intensification and maintenance phases (Storring, 2009)

CNS prophylaxis (APL, as part of TIT): 50 mg per dose; administer 1 dose prior to consolidation and 2 doses during each of 2 consolidation phases (total of 5 doses) (Ades, 2006; Ades, 2008)

CNS leukemia treatment (ALL, as part of TIT): 40 mg twice weekly until CSF cleared (Storring, 2009)

CNS lymphoma treatment: 50 mg twice a week for 4 weeks, then weekly for 4-8 weeks, then every other week for 4 weeks, then every 4 weeks for 4 doses (Glantz, 1999)

Leptomeningeal metastases treatment: 25 to 100 mg twice weekly for 4 weeks, then once weekly for 4 weeks, then a maintenance regimen of once a month (Chamberlain, 2010) or 40 to 60 mg per dose (DeAngelis, 2005)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Doses >200 mg/m2 are associated with a moderate emetic potential and 3000 mg/m2 is associated with a high emetic potential (Dupuis, 2011); antiemetics are recommended to prevent nausea and vomiting.

Acute myeloid leukemia (AML) remission induction: IV: Standard-dose (manufacturer's labeling labeling; in combination with other chemotherapy agents): 100 mg/m2/day continuous infusion for 7 days or 200 mg/m2/day continuous infusion (as 100 mg/m2 over 12 hours every 12 hours) for 7 days

Indication-specific dosing:

AML induction: 7 + 3 regimen: IV:

Children <3 years (off-label dosing): 3.3 mg/kg/day continuous infusion for 7 days; minimum of 2 courses (in combination with daunorubicin) (Woods, 1990)

Children ≥3 years: 100 mg/m2/day continuous infusion for 7 days; minimum of 2 courses (in combination with daunorubicin) (Woods, 1990)

AML consolidation (off-label use): 5 + 2 + 5 regimen: IV: Adolescents ≥15 years: 100 mg/m2/day continuous infusion for 5 days for 2 consolidation courses (in combination with daunorubicin and etoposide) (Bishop, 1996)

AML salvage treatment (off-label use):

Clofarabine/Cytarabine regimen: Induction: IV: Children ≥1 year and Adolescents: 1,000 mg/m2/day over 2 hours for 5 days (in combination with clofarabine; cytarabine is administered 4 hours after initiation of clofarabine) for up to 2 induction cycles (Cooper, 2014)

FLAG regimen: IV: Children ≥11 years: 2,000 mg/m2/day over 4 hours for 5 days (in combination with fludarabine and G-CSF); may repeat once if needed (Montillo, 1998)

MEC regimen: IV:

Children ≥5 years: 1,000 mg/m2/day over 6 hours for 6 days (in combination with etoposide and mitoxantrone) (Amadori, 1991)

Adolescents ≥15 years: 500 mg/m2/day continuous infusion days 1, 2, and 3 and days 8, 9, and 10 (in combination with mitoxantrone and etoposide); may administer a second course if needed (Archimbaud, 1991; Archimbaud, 1995)

Acute lymphocytic leukemia (ALL; off-label dosing): POG 8602/PVA regimen, intensification phase: IV: Children ≥1 year: 1,000 mg/m2 continuous infusion over 24 hours day 1 (beginning 12 hours after start of methotrexate) every 3 weeks or every 12 weeks for 6 cycles (Land, 1994)

Non-Hodgkin lymphomas (off-label use):

CODOX-M/IVAC regimen: IV: Children ≥3 years: Cycles 2 and 4 (IVAC): 2,000 mg/m2 every 12 hours days 1 and 2 (total of 4 doses/cycle) (IVAC is combination with ifosfamide, mesna and etoposide; IVAC alternates with CODOX-M) (Magrath, 1996)

High-dose cytarabine: IV: Children >1 year and Adolescents: 3,000 mg/m2 over 3 hours every 12 hours on days 2 and 3 (secondary phase; total of 4 doses) in combination with methotrexate and intrathecal methotrexate/cytarabine (Bowman, 1996)

Meningeal leukemia: Intrathecal: Note: Optimal intrathecal chemotherapy dosing should be based on age rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer, 1983; Kerr, 2001). Dosing provided in the manufacturer's labeling is BSA-based (usual dose 30 mg/m2 every 4 days; range: 5 to 75 mg/m2 once daily for 4 days or once every 4 days until CNS findings normalize, followed by 1 additional treatment).

Age-based intrathecal dosing (off-label; Woods, 1990): Intrathecal:

CNS prophylaxis:

<1 year: 20 mg per dose

1 to 1.99 years: 30 mg per dose

2 to 2.99 years: 50 mg per dose

≥3 years: 70 mg per dose

ALL CNS prophylaxis, age-specific doses from literature:

Administer on day 0 of induction therapy (Gaynon, 1993):

1 to <2 years: 30 mg per dose

2 to <3 years: 50 mg per dose

≥3 years: 70 mg per dose

Administer as part of triple intrathecal therapy (TIT) on days 1 and 15 of induction therapy; days 1, 15, 50, and 64 (standard risk patients) or days 1, 15, 29, and 43 (high-risk patients) during consolidation therapy; day 1 of reinduction therapy, and during maintenance therapy (very high-risk patients receive on days 1, 22, 45, and 59 of induction, days 8, 22, 36, and 50 of consolidation therapy, days 8 and 38 of reinduction therapy, and during maintenance) (Lin, 2007):

<1 year: 18 mg per dose

1 to 2 years: 24 mg per dose

2 to 3 years: 30 mg per dose

≥3 years: 36 mg per dose

Administer on day 0 of induction therapy, then as part of TIT on days 7, 14, and 21 during consolidation therapy; as part of TIT on days 0, 28, and 35 for 2 cycles of delayed intensification therapy, and then maintenance treatment as part of TIT on day 0 every 12 weeks for 38 months (boys) or 26 months (girls) from initial induction treatment (Matloub, 2006):

1 to <2 years: 16 mg per dose

2 to <3 years: 20 mg per dose

≥3 years: 24 to 30 mg per dose

Administer on day 15 of induction therapy, days 1 and 15 of reinduction phase; and day 1 of cycle 2 of maintenance 1A phase (Pieters, 2007):

<1 year: 15 mg per dose

≥1 year: 20 mg per dose

Treatment, CNS leukemia (ALL): Intrathecal: Administer as part of TIT weekly until CSF remission, then every 4 weeks throughout continuation treatment (Lin, 2007):

<1 year: 18 mg per dose

1 to 2 years: 24 mg per dose

2 to 3 years: 30 mg per dose

≥3 years: 36 mg per dose

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended:

Aronoff, 2007 (cytarabine 100 to 200 mg/m2): Children and Adults: No adjustment necessary

Kintzel, 1995 (high-dose cytarabine 1 to 3 g/m2):

CrCl 46 to 60 mL/minute: Administer 60% of dose

CrCl 31 to 45 mL/minute: Administer 50% of dose

CrCl <30 mL/minute: Consider use of alternative drug

Smith, 1997 (high-dose cytarabine; ≥2 g/m2/dose):

Serum creatinine 1.5 to 1.9 mg/dL or increase (from baseline) of 0.5 to 1.2 mg/dL: Reduce dose to 1 g/m2/dose

Serum creatinine ≥2 mg/dL or increase (from baseline) of >1.2 mg/dL: Reduce dose to 0.1 g/m2/day as a continuous infusion

Hemodialysis: In 4 hour dialysis sessions (with high flow polysulfone membrane) 6 hours after cytarabine 1 g/m2 over 2 hours, 63% of the metabolite ARA-U was extracted from plasma (based on a single adult case report) (Radeski, 2011)

Dosing: Hepatic Impairment

Dose may need to be adjusted in patients with liver failure since cytarabine is partially detoxified in the liver. There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended:

Floyd, 2006: Transaminases (any elevation): Administer 50% of dose; may increase subsequent doses in the absence of toxicities

Koren, 1992 (dose level not specified): Bilirubin >2 mg/dL: Administer 50% of dose; may increase subsequent doses in the absence of toxicities

Dosing: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012).

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity: Utilize actual body weight (full weight) for calculation of body surface area in cytarabine dosing for hematopoietic stem cell transplant conditioning regimens in pediatrics and adults (Bubalo, 2014).

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Note: Solutions containing bacteriostatic agents may be used for SubQ and standard-dose (100 to 200 mg/m2) IV cytarabine preparations, but should not be used for the preparation of either intrathecal doses or high-dose IV therapies.

IV:

Powder for reconstitution: Reconstitute with bacteriostatic water for injection (for standard-dose).

For IV infusion: Further dilute in 250 to 1000 mL 0.9% NaCl or D5W.

Intrathecal: Powder for reconstitution: Reconstitute with preservative free sodium chloride 0.9%; may further dilute to preferred final volume (volume generally based on institution or practitioner preference; may be up to 12 mL) with Elliott's B solution, sodium chloride 0.9% or lactated Ringer’s. Intrathecal medications should not be prepared during the preparation of any other agents.

Triple intrathecal therapy (TIT): Cytarabine 30 to 50 mg with hydrocortisone sodium succinate 15 to 25 mg and methotrexate 12 mg are reported to be compatible together in a syringe (Cheung, 1984) and cytarabine 18 to 36 mg with hydrocortisone 12 to 24 mg and methotrexate 6 to 12 mg, prepared to a final volume of 6 to 12 mL, is reported compatible as well (Lin, 2008).

Intrathecal preparations should be administered as soon as possible after preparation because intrathecal preparations are preservative free.

Administration

IV: Infuse standard dose therapy for AML (100 to 200 mg/m2/day) as a continuous infusion. Infuse high-dose therapy (off-label) over 1 to 3 hours (usually). Other rates have been used, refer to specific reference.

In adults, doses >1000 mg/m2 are associated with a moderate emetic potential (Basch, 2011; Roila, 2010). In pediatrics, doses >200 mg/m2 are associated with a moderate emetic potential and 3000 mg/m2 is associated with a high emetic potential (Dupuis, 2011); antiemetics are recommended to prevent nausea and vomiting.

Intrathecal: Intrathecal doses should be administered as soon as possible after preparation.

May also be administered SubQ.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Compatibility

Stable in D5LR, D51/4NS, D5NS, D10NS, D5W, LR, NS.

Y-site administration: Incompatible with allopurinol, caspofungin, gallium nitrate, ganciclovir.

Storage

Store intact vials of powder for reconstitution at 20°C to 25°C (68°F to 77°F); store intact vials of solution at 15°C to 30°C (59°F to 86°F).

IV:

Powder for reconstitution: Reconstituted solutions should be stored at room temperature and used within 48 hours.

For IV infusion: Solutions for IV infusion diluted in D5W or NS are stable for 8 days at room temperature, although the manufacturer recommends administration as soon as possible after preparation.

Intrathecal: Administer as soon as possible after preparation. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flucytosine: Cytarabine (Conventional) may diminish the therapeutic effect of Flucytosine. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Frequency not always defined. CNS, gastrointestinal, ophthalmic, and pulmonary toxicities are more common with high-dose regimens.

Cardiovascular: Angina pectoris, chest pain, hepatic veno-occlusive disease (also called hepatic sinusoidal obstruction syndrome), local thrombophlebitis, pericarditis

Central nervous system: Aseptic meningitis, cerebral dysfunction, dizziness, headache, neuritis, neurotoxicity, paralysis (intrathecal and IV combination therapy), reversible posterior leukoencephalopathy syndrome

Dermatologic: Acute generalized exanthematous pustulosis, alopecia, dermal ulcer, ephelis, pruritus, skin rash, urticaria

Endocrine & metabolic: Hyperuricemia

Gastrointestinal: Abdominal pain, anal fissure, anal inflammation, anorexia, diarrhea, esophageal ulcer, esophagitis, increased serum amylase, increased serum lipase, intestinal necrosis, mucositis, nausea, pancreatitis, sore throat, toxic megacolon, vomiting

Genitourinary: Urinary retention

Hematologic & oncologic: Anemia, bone marrow depression, hemorrhage, leukopenia, megaloblastosis, neutropenia (onset: 1 to 7 days; nadir [biphasic]: 7 to 9 days and at 15 to 24 days; recovery [biphasic]: 9 to 12 days and at 24 to 34 days), reticulocytopenia, thrombocytopenia (onset: 5 days; nadir: 12 to 15 days; recovery 15 to 25 days)

Hepatic: Hepatic insufficiency, increased serum transaminases (acute), jaundice

Hypersensitivity: Allergic edema, anaphylaxis

Infection: Sepsis

Local: Cellulitis at injection site, inflammation at injection site (SC injection), pain at injection site (SC injection)

Neuromuscular & skeletal: Rhabdomyolysis

Ophthalmic: Conjunctivitis

Renal: Renal insufficiency

Respiratory: Acute respiratory distress, dyspnea, interstitial pneumonitis

Miscellaneous: Drug toxicity (cytarabine syndrome; chest pain, conjunctivitis, fever, maculopapular rash, malaise, myalgia, ostealgia), fever

Adverse events associated with high-dose cytarabine

Cardiovascular: Cardiomegaly, cardiomyopathy (in combination with cyclophosphamide)

Central nervous system: Neurotoxicity (patients with renal impairment: ≤55%), coma, drowsiness, neurocerebellar toxicity, peripheral neuropathy (motor and sensory), personality changes

Dermatologic: Alopecia (complete), desquamation, skin rash (severe)

Gastrointestinal: Gastrointestinal ulcer, necrotizing enterocolitis, pancreatitis, peritonitis, pneumatosis cystoides intestinalis

Hepatic: Hepatic abscess, hepatic injury, hyperbilirubinemia

Infection: Sepsis

Ophthalmic: Corneal toxicity, hemorrhagic conjunctivitis

Respiratory: Acute respiratory distress, pulmonary edema

Adverse events associated with intrathecal cytarabine administration

Central nervous system: Aphonia, leukoencephalopathy (necrotizing; with concurrent cranial irradiation, intrathecal methotrexate, and intrathecal hydrocortisone), nerve palsy (accessory nerve), neurotoxicity, paraplegia

Gastrointestinal: Dysphagia, nausea, vomiting

Ophthalmic: Blindness (with concurrent systemic chemotherapy and cranial irradiation), diplopia

Respiratory: Cough, hoarseness

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Experienced physician:

Only physicians experienced in cancer chemotherapy should use cytarabine.

Drug toxicities:

For induction therapy, patients should be treated in a facility with laboratory and supportive resources sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity. The main toxic effect of cytarabine is bone marrow suppression with leukopenia, thrombocytopenia, and anemia. Less serious toxicity includes nausea, vomiting, diarrhea and abdominal pain, oral ulceration, and hepatic dysfunction.

The physician must judge possible benefit to the patient against known toxic effects of this drug in considering the advisability of therapy with cytarabine. Before making this judgment or beginning treatment, the physician should be familiar with the following text.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [U.S. Boxed Warning]: Myelosuppression (leukopenia, thrombocytopenia and anemia) is the major toxicity of cytarabine. Use with caution in patients with prior drug-induced bone marrow suppression. Monitor blood counts frequently; once blasts are no longer apparent in the peripheral blood, bone marrow should be monitored frequently. Monitor for signs of infection or neutropenic fever due to neutropenia or bleeding due to thrombocytopenia.

• Cytarabine syndrome: Cytarabine (ARA-C) syndrome is characterized by fever, myalgia, bone pain, chest pain (occasionally), maculopapular rash, conjunctivitis, and malaise; generally occurs 6 to 12 hours following administration. May be managed with corticosteroids.

• Gastrointestinal toxicities: [U.S. Boxed Warning]: Toxicities (less serious) include nausea, vomiting, diarrhea, abdominal pain, oral ulcerations and hepatic dysfunction. In adults, doses >1000 mg/m2 are associated with a moderate emetic potential (Basch, 2011; Roila, 2010). In pediatrics, doses >200 mg/m2 are associated with a moderate emetic potential and 3000 mg/m2 is associated with a high emetic potential (Dupuis, 2011); antiemetics are recommended to prevent nausea and vomiting.

• Hypersensitivity: Anaphylaxis resulting in acute cardiopulmonary arrest has been reported (rare).

• Pancreatitis: There have been reports of acute pancreatitis in patients receiving continuous infusion cytarabine and in patients receiving cytarabine who were previously treated with L-asparaginase.

• Sudden respiratory distress syndrome: Sudden respiratory distress, rapidly progressing to pulmonary edema and cardiomegaly, has been reported with high-dose cytarabine. May present as severe dyspnea with a rapid onset and refractory hypoxia with diffuse pulmonary infiltrates, leading to respiratory failure; may be fatal (Morgan, 2011).

• Tumor lysis syndrome: Tumor lysis syndrome and subsequent hyperuricemia may occur; consider antihyperuricemic therapy and hydrate accordingly.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; may be at higher risk for CNS toxicities and dosage adjustments may be required.

• Renal impairment: Use with caution in patients with impaired renal function (high dose cytarabine); may be at higher risk for CNS toxicities and dosage adjustments may be required.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. There have been case reports of fatal cardiomyopathy when high-dose cytarabine was used in combination with cyclophosphamide as a preparation regimen for transplantation.

Special populations:

• Pediatric: Delayed progressive ascending paralysis has been reported in two children who received combination chemotherapy with IV and intrathecal cytarabine at conventional doses for the treatment of acute myeloid leukemia (was fatal in one patient).

Dosage form specific issues:

• Benzyl alcohol: Some products may contain benzyl alcohol; do not use products containing benzyl alcohol or products reconstituted with bacteriostatic diluent intrathecally or for high-dose cytarabine regimens. Benzyl alcohol is associated with gasping syndrome in premature infants.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Due to the potential toxicities, induction treatment with cytarabine should be in a facility with sufficient laboratory and supportive resources.

• High-dose treatment: High-dose regimens have been associated with GI, CNS, pulmonary, ocular (reversible corneal toxicity and hemorrhagic conjunctivitis; prophylaxis with ophthalmic corticosteroids is recommended) toxicities, and cardiomyopathy. Neurotoxicity associated with high-dose treatment may present as acute cerebellar toxicity (with or without cerebral impairment), personality changes, or may be severe with seizure and/or coma; may be delayed, occurring up to 3 to 8 days after treatment has begun; possibly irreversible. Risk factors for neurotoxicity include cumulative cytarabine dose, prior CNS disease and renal impairment (incidence may be up to 55% in patients with renal impairment); high-dose therapy (>18 g/m2 per cycle) and age >50 years also increase the risk for cerebellar toxicity (Herzig, 1987).

• Intrathecal safety: When used for intrathecal administration, should not be prepared during the preparation of any other agents. After preparation, store intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications also intended for administration into the central nervous system (Jacobson, 2009).

Monitoring Parameters

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

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were demonstrated in animal reproduction studies. Limb and ear defects have been noted in case reports of cytarabine exposure during the first trimester of pregnancy. The following have also been noted in the neonate: Pancytopenia, WBC depression, electrolyte abnormalities, prematurity, low birth weight, decreased hematocrit or platelets. Risk to the fetus is decreased if treatment can be avoided during the first trimester; however, women of childbearing potential should be advised of the potential risks.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience lack of appetite, alopecia, or mouth sores. Have patient report immediately to prescriber signs of infection, shortness of breath, severe abdominal pain, severe nausea, vomiting, severe diarrhea, bruising, bleeding, loss of strength and energy, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of a pancreas problem (pancreatitis, severe abdominal pain, severe back pain, severe nausea, vomiting), or signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feel sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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