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Cytarabine (Conventional)

Medically reviewed by Drugs.com. Last updated on Jul 27, 2019.

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)

Solution, Injection [preservative free]:

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

Pharmacologic Category

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

Pharmacology

Cytarabine 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

Off Label Uses

Acute myeloid leukemia (consolidation)

Data from several randomized clinical trials in patients with acute myeloid leukemia (AML) support the use of cytarabine (in combination with daunorubicin or idarubicin or mitoxantrone [5 + 2 regimens], in combination with daunorubicin and etoposide [5 + 2 + 5 regimen], or as a single agent) [Arlin 1990], [Bishop 1996], [Mayer 1994], [Wiernik 1992].

Acute myeloid leukemia (salvage)

Data from open-label studies in adult patients with relapsed or refractory acute myeloid leukemia (AML) support the use of cytarabine (in combination with cladribine and G-CSF [CLAG regimen] or with cladribine, mitoxantrone, and G-CSF [CLAG-M regimen] or in combination with fludarabine and G-CSF [FLAG regimen] or high dose cytarabine in combination with an anthracycline [HiDAC regimen] or in combination with mitoxantrone and etoposide [MEC regimen]) or in combination with clofarabine and filgrastim in the treatment of refractory or relapsed AML in adults [Amadori 1991], [Archimbaud 1991], [Archimbaud 1995], [Becker 2011], [Herzig 1985], [Montillo 1998], [Wierzbowska 2008], [Wrzesien-Kus 2003].

Acute promyelocytic leukemia (consolidation)

Data from two clinical trials in patients with high-risk acute promyelocytic leukemia (APL) support the use of cytarabine (in combination with idarubicin and tretinoin) [Lo Coco 2010], [Sanz 2010]. Data from two studies in patients with newly diagnosed APL also supports the use of cytarabine (in combination with daunorubicin) during the consolidation phase of treatment [Ades 2006], [Ades 2008].

Acute promyelocytic leukemia (induction)

Data from three clinical trials in patients with acute promyelocytic leukemia (APL) support the use of cytarabine (in combination with tretinoin and daunorubicin) for the treatment of APL [Ades 2006], [Ades 2008], [Powell 2010].

Chronic lymphocytic leukemia (refractory)

Data from a phase II study support the use of cytarabine (in combination with fludarabine, oxaliplatin, and rituximab) in the treatment of fludarabine-refractory chronic lymphocytic leukemia [Tsimberidou 2008].

Hodgkin lymphoma (relapsed or refractory)

Data from multiple trials support the use of cytarabine as a component of combination chemotherapy in the treatment of relapsed or refractory Hodgkin lymphoma (HL). A phase II trial using cytarabine in combination with cisplatin and dexamethasone (DHAP) illustrated the safety and toxicity of this regimen in patients with relapsed/refractory HL [Josting 2002]. A small phase II trial studied cytarabine in combination with etoposide, methylprednisolone, and cisplatin (ESHAP) and found it to be an active regimen in this patient population [Aparicio 1999]. Cytarabine in combination with carmustine, etoposide, and melphalan is an effective salvage regimen (Mini-BEAM) or transplant preparative regimen (BEAM) in patients with relapsed/refractory HL [Chopra 1993], [Colwill 1995], [Martin 2001].

Non-Hodgkin lymphoma

Data from multiple trials support the use of cytarabine as a component of combination chemotherapy in the treatment of non-Hodgkin lymphoma (NHL). The CALGB 9251 regimen utilizes cytarabine as a component of an multi-agent chemotherapy regimen in the treatment of aggressive Burkitt or Burkittlike NHL [Lee 2001], [Rizzieri 2004]. Cytarabine in combination with ifosfamide, mesna, and etoposide (IVAC, alternating with CODOX-M) also is effective in the management of highly aggressive NHL [Magrath 1996], [Mead 2008]. Data from 2 phase II trials support the use of cytarabine in combination with cisplatin and dexamethasone [DHAP regimen [Velasquez 1988]] or in combination with etoposide, methylprednisolone, and cisplatin [ESHAP regimen [Velasquez 1994]] in the treatment of relapsed or refractory NHL. Cytarabine may be used in combination with carmustine, etoposide, and melphalan (BEAM) as a transplant preparative regimen in the management of relapsed/refractory NHL [Linch 2010], [van Imhoff 2005].

Primary central nervous system lymphoma

Data from a multicenter open-label randomized phase II study support the use of cytarabine (in combination with methotrexate) in the treatment of primary central nervous system lymphoma [Ferreri 2009].

Contraindications

Hypersensitivity to cytarabine or any component of the formulation

Dosing: Adult

Note: Antiemetics may be recommended to prevent nausea and vomiting; IV doses >1,000 mg/m2 are associated with a moderate emetic potential (Hesketh 2017; Roila 2016).

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: 3,000 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: 2,000 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: 2,000 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: 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)

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: 3,000 mg/m2 over 1 hour every 12 hours for 6 days (total of 12 doses) (Herzig 1985)

MEC regimen: 1,000 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: 1,000 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: 1,000 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): 1,000 mg/m2 every 12 hours for 4 days (8 doses)

Age <50 years and high risk (WBC ≥10,000/mm3): 2,000 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): 1,000 mg/m2 every 12 hours for 4 days (8 doses)

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

Induction regimen, relapsed or refractory: IV: 3,000 mg/m2 over 3 hours daily for 5 days (in combination with idarubicin [day 3]) (Weiss 2002)

Dose-intensive regimen: IV: 3,000 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: 1,000 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: 2,000 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: 2,000 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: 2,000 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): 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)

Adults ≤65 years: Cycles 2 and 4 (IVAC): 2,000 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): 1,000 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: 2,000 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: 1,000 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: 2,000 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: Dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. In pediatric patients, IV dosing may be based on either BSA (mg/m2) or weight (mg/kg); use extra precaution to verify dosing parameters during calculations. Intrathecal dosing is based on the age of the patient. Cytarabine is associated with a low to high emetic potential (depending on dose or regimen); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013; Paw Cho Sing 2019).

Acute lymphocytic leukemia, B-cell (B-ALL):

High risk B-ALL: Limited data available, multiple regimens reported:

Larsen 2016: Consolidation and delayed intensification I and II: Children and Adolescents: IV, SubQ: 75 mg/m2 over 1 to 30 minutes or subcutaneous once daily for 4 days every 7 days for 2 courses; specific days depends on protocol phase.

Steinherz 1993: NYII Protocol: Consolidation: Children and Adolescents: IV: 3,000 mg/m2 over 3 hours for 4 doses on Days 28, 29, 35, and 36; experts at some centers have suggested fewer doses (eg, 2 doses).

Isolated CNS; relapse: Limited data available; multiple regimens reported: Infants, Children, and Adolescents: IV: 300 mg/m2/dose; frequency dependent upon protocol.

Ribeiro 1995, Rivera 1996: Children and Adolescents ≤14 years: Induction: Administer on Days 8, 22, 36; for Maintenance administer every 5 weeks for 52 weeks in combination with teniposide.

Winick 1993: Continuation therapy: Infants, Children, and Adolescents: Administer on day 1 and 4 of week 7, 14, 21, 28, 35, 42, 49, and 56 in conjunction with teniposide.

Acute myeloid leukemia (AML):

Remission induction:

Manufacturer's labeling: Infants, Children, and Adolescents: IV: Standard dose: 100 mg/m2/day continuous infusion for 7 days or 200 mg/m2/day continuous infusion (as 100 mg/m2/dose over 12 hours every 12 hours) for 7 days.

Alternate dosing: Limited data available:

ADE regimen (Gamis 2014): Note: Some aspects of protocol dosing based on previous reports (Cooper 2012; Gibson 2011; Guest 2014; Woods 1990).

Induction 1 ADE (10 + 3 + 5) and Induction 2 ADE (8 + 3 + 5):

Infants and Children with BSA <0.6 m2: IV: 3.3 mg/kg over 1 to 30 minutes every 12 hours for 10 days (induction 1) or 8 days (induction 2) in combination with daunorubicin and etoposide.

Children and Adolescents with BSA ≥0.6 m2: IV: 100 mg/m2 over 1 to 30 minutes every 12 hours for 10 days (induction 1) or 8 days (induction 2) in combination with daunorubicin and etoposide.

7 + 3 regimen (Woods 1990):

Infants and Children <3 years: IV: 3.3 mg/kg/day continuous infusion for 7 days; minimum of 2 courses (in combination with daunorubicin).

Children ≥3 years and Adolescents: IV: 100 mg/m2/day continuous infusion for 7 days; minimum of 2 courses (in combination with daunorubicin).

Intensification: Limited data available (Gamis 2014): Note: Some aspects of protocol dosing based on previous reports (Cooper 2012; Gibson 2011; Guest 2014; Woods 1990).

Intensification 1: AE therapy.

Infants and Children with BSA <0.6 m2: IV: 33 mg/kg over 1 hour every 12 hours for 5 days (in combination with etoposide).

Children and Adolescents with BSA ≥0.6 m2: IV: 1,000 mg/m2 over 1 hour every 12 hours for 5 days (in combination with etoposide).

Intensification 2 (for patients not undergoing stem cell transplant): MA therapy:

Infants and Children with BSA <0.6 m2: IV: 33 mg/kg over 1 hour every 12 hours for 4 days (in combination with mitoxantrone).

Children and Adolescents with ≥0.6 m2: IV: 1,000 mg/m2 over 1 hour every 12 hours for 4 days (in combination with mitoxantrone).

Intensification 3 (for patients not undergoing stem cell transplant):

Infants and Children with BSA <0.6 m2: IV: 99 mg/kg every 12 hours on days 1, 2, 8 and 9 in combination with E. coli L-asparaginase; Note: Some centers have substituted Erwinia asparaginase due to E. coli L-Asparaginase no longer being available.

Children and Adolescents with BSA ≥0.6 m2: IV: 3,000 mg/m2 every 12 hours on Days 1, 2, 8, and 9 in combination with E. coli L-asparaginase; Note: Some centers have substituted Erwinia asparaginase due to E. coli L-Asparaginase no longer being available.

Consolidation or refractory disease: Capizzi II regimen (high-dose cytarabine [fixed]): Children ≥6 years and Adolescents: IV: 3,000 mg/m2 over 3 hours every 12 hours for 4 doses, followed by E. coli L-Asparaginase (some centers have substituted Erwinia asparaginase due to E. coli L-Asparaginase no longer being available) 6 hours after the last dose of cytarabine (Capizzi 1984).

Salvage treatment for refractory/recurrent disease: Limited data available:

Clofarabine/cytarabine regimen: Children and Adolescents: IV: 1,000 mg/m2 over 2 hours once daily for 5 days (in combination with clofarabine; administer cytarabine 4 hours after initiation of clofarabine) for up to 2 induction cycles (Cooper 2014).

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

MEC regimen:

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

Adolescents ≥15 years: IV: 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).

Non-Hodgkin lymphomas: Limited data available:

Intermediate-risk B-cell NHL (Group B): Consolidation: R-CYM 1 and 2 regimen (Goldman 2013; Patte 2007): Children and Adolescents: IV: 100 mg/m2/day as a continuous infusion over 24 hours on Days 2 through 6 (5 days; total dose: 500 mg/m2 as a 120-hour infusion) (in combination with rituximab and methotrexate).

High-risk B-cell NHL (Group C): Consolidation: R-CYVE 1 and 2 regimen (Cairo 2007; Patte 2001): Infants ≥6 months, Children, and Adolescents: IV: 50 mg/m2 infused over 12 hours (2000 to 0800) for 5 doses (Days 1 to 5); follow each 12-hour infusion dose with 3,000 mg/m2 infused over 3 hours which starts at the end of the 12-hour infusion (0800 - 1100) x 5 doses (days 2 to 6) in combination with etoposide.

B-lineage lymphoblastic lymphoma (B-LLy) (Termuhlen 2013):

Consolidation phase: Children and Adolescents: IV, SubQ: 75 mg/m2 once daily for 4 days every 7 days for 4 courses (Days 0 to 3, 7 to 10, 14 to 17, 21 to 24).

Delayed intensification: Children and Adolescents: IV, SubQ: 75 mg/m2 once daily for 4 days every 7 days for 2 courses (Days 35 to 38 and 42 to 45).

Meningeal leukemia: Infants, Children, and Adolescents: Note: Optimal intrathecal chemotherapy dosing should be based on age (see following information) rather than on body surface area (BSA); CSF volume correlates with age and not to BSA (Bleyer 1983; Kerr 2001).

Manufacturer's labeling (based on BSA): Intrathecal: 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 one additional treatment.

Alternate dosing: Age-based intrathecal dosing: Intrathecal:

CNS prophylaxis (AML) (Woods 1990):

<1 years: 20 mg per dose.

1 to <2 years: 30 mg per dose.

2 to <3 years: 50 mg per dose.

≥3 years: 70 mg per dose.

CNS prophylaxis (ALL): Dosing regimens variable, age-specific regimens reported from literature:

Gaynon 1993: Administer on day 0 of induction therapy: Children and Adolescents:

<2 years: 30 mg per dose.

2 to <3 years: 50 mg per dose.

≥3 years: 70 mg per dose.

Pieters 2007: Administer on day 15 of induction therapy, days 1 and 15 of reinduction phase; and day 1 of cycle 2 of maintenance 1A phase: Infants and young Children (≤12 months at enrollment):

<1 year: 15 mg per dose.

≥1 years: 20 mg per dose.

Lin 2008: 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): Infants, Children, and Adolescents:

<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.

Treatment, CNS leukemia (ALL), Very high-risk: Administer as part of triple intrathecal therapy (TIT) weekly until CSF remission, then every 4 weeks throughout continuation treatment (Lin 2008): Infants, Children, and Adolescents:

<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: Obesity

American Society of Clinical Oncology (ASCO) Guidelines for appropriate chemotherapy dosing in obese adults with cancer (excludes leukemias):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 (Bubalo 2014).

Reconstitution

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. Do not use the bulk package to prepare intrathecal doses.

IV:

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

For IV infusion: Further dilute in 250 to 1,000 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.

Antiemetics may be recommended to prevent nausea and vomiting; in adults, IV doses >1,000 mg/m2 are associated with a moderate emetic potential (Hesketh 2017; Roila 2016).

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

May also be administered SubQ.

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). Protect from light. Pharmacy bulk vials should be used within 4 hours of initial entry.

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 retained 94% to 100% of potency after 8 days when stored 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. 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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

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. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). 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, 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, 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, megaloblastic anemia, 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, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), increased serum transaminases (acute), jaundice

Hypersensitivity: Allergic edema, anaphylaxis

Infection: Sepsis

Local: Cellulitis at injection site, inflammation at injection site (SC injection), local inflammation (anus), 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: [US 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.

• GI toxicities: [US Boxed Warning]: Toxicities (less serious) include nausea, vomiting, diarrhea, abdominal pain, oral ulcerations and hepatic dysfunction. Antiemetics may be recommended to prevent nausea and vomiting. In adults, IV doses >1,000 mg/m2 are associated with a moderate emetic potential (Hesketh 2017; Roila 2016); in pediatrics, a 75 mg/m2 IV dose is associated with a moderate emetic potential and IV doses ≥3,000 mg/m2 are associated with a high emetic potential (Paw Cho Sing 2019).

• 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.

Other warnings/precautions:

• Experienced physician: [US 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. Monitor for signs/symptoms of bleeding, infection, neutropenic fever, and/or tumor lysis syndrome.

Pregnancy Considerations

Based on the mechanism of action and findings from animal reproduction studies, fetal harm may occur if cytarabine is administered during pregnancy. 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, females of reproductive potential should avoid becoming pregnant during treatment and be advised of the potential risks.

Patient Education

What is this drug used for?

• It is used to treat leukemia.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Lack of appetite

• Hair loss

• Muscle pain

• Bone pain

• Mouth irritation

• Mouth sores

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.

• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.

• Infection

• Mood changes

• Confusion

• Neck rigidity

• Sensitivity to light

• Severe muscle weakness

• Numbness or tingling feeling

• Severe fatigue

• Chest pain

• Vision changes

• Eye pain

• Severe eye irritation

• Application site pain or irritation

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Severe abdominal pain

• Severe nausea

• Vomiting

• Severe diarrhea

• Severe loss of strength and energy

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Bowel problems like black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea.

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.

• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish.

• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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