Cytarabine Injection

Cytarabine in combination with other approved anticancer drugs is indicated for remission induction in acute non-lymphocytic leukemia of adults and children. It has also been found useful in the treatment of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia.

Intrathecal administration of Cytarabine Injection (preservative-free only) is indicated for the prophylaxis and treatment of meningeal leukemia.

Cytarabine is not active orally. The schedule and method of administration varies with the program of therapy to be used. Cytarabine Injection may be given by intravenous infusion or injection or subcutaneously. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug's rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m²/day by continuous intravenous infusion (Days 1-7) or 100 mg/m² intravenous every 12 hours (Days 1-7).

The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

Intrathecal Use in Meningeal Leukemia: DO NOT USE CYTARABINE INJECTION (which contains benzyl alcohol) INTRATHECALLY.

The following dosage information regarding intrathecal use is included for informational purposes only.

Cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m² to 75 mg/m² of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m² every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modifications of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine.

When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious lifethreatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician.

Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may be better treated with radiotherapy.

Cytarabine is contraindicated in those patients who are hypersensitive to the drug.

Cytarabine Injection is available as follows:

STORAGE CONDITIONS

Protect from light. Retain in carton until time of use.

Cytarabine Injection, an antineoplastic agent, is a sterile preserved solution for intravenous or subcutaneous administration and is available in 20 mg/mL (500 mg/25 mL) multiple-dose vial. Each mL contains: 20 mg Cytarabine, USP and the following inactive ingredients: benzyl alcohol 0.9% and Water for Injection q.s. The pH is adjusted with hydrochloric acid and/or sodium hydroxide to a target pH of 7.6.

Cytarabine is chemically 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone. The structural formula is:

Cytarabine is an odorless, white to off-white, crystalline powder which is freely soluble in water and slightly soluble in alcohol and in chloroform.

NOT FOR INTRATHECAL USE - CONTAINS BENZYL ALCOHOL

FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY

Rx only

Store at 20°C to 25°C (68°F to 77°F) [USP Controlled Room Temperature].

Only physicians experienced in cancer chemotherapy should use Cytarabine Injection.

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.

( see boxed WARNING )

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leukocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses and hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine.

Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some of the experimental cytarabine dose schedules. These reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia, bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. If experimental high dose therapy is used, do not use a Cytarabine Injection containing benzyl alcohol.

Cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal.

Benzyl alcohol is contained in this product. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.

Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients.

DO NOT USE CYTARABINE INJECTION (which contains benzyl alcohol) INTRATHECALLY.

There is no antidote for cytarabine overdosage. Doses of 4.5 g/m² by intravenous infusion over 1 hour every 12 hours for 12 doses has caused an unacceptable increase in irreversible CNS toxicity and death.

Single doses as high as 3 g/m² have been administered by rapid intravenous infusion without apparent toxicity.

• 1.
  Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publications No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.
• 2.
  AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA, 1985; 2.53 (11): 1590-1592.
• 3.
  National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
• 4.
  Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428.
• 5.
  Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center CA-A Cancer Journal of Clinicians, 1983; (Sept/Oct) 258-263.
• 6.
  American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp. Pharm, 1990; 47:1033-1049.
• 7.
  Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work Practice Guidelines), Am J. Health- Syst Pharm, 1996; 53: 1669-1685.

Distributed by Hospira, Inc. Lake Forest, IL 60045 USA

GUJ-DRUGS/G/28/1267

LAB-1174-3.0

Revised: 12/2022

See WARNINGS. A review of the literature has shown 32 reported cases where cytarabine was given during pregnancy, either alone or in combination with other cytotoxic agents.

Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis.

Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure.

There were seven infants with various problems in the neonatal period including pancytopenia; transient depression of WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased IgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis.

Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue.

Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on cytarabine should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

See INDICATIONS AND USAGE .

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

See General Precautions .

Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative.

An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for reevaluation of antibacterial therapy.

Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine. This may be due to potential competitive inhibition of its uptake.

Not applicable.

Patients receiving cytarabine must be monitored closely. Frequent platelet and leukocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm³. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control.

When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours post injection. This problem tends to be less severe when the drug is infused.

The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor.

Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

Like other cytotoxic drugs, cytarabine may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem.

Acute pancreatitis has been reported to occur in a patient receiving cytarabine by continuous infusion and in patients being treated with cytarabine who have had prior treatment with L-asparaginase.

Not applicable.

25 mL Vial

NDC 61703-304-36

Sterile

Rx only

Cytarabine Injection

500 mg/25 mL

(20 mg/mL)

For Intravenous or Subcutaneous Use Only

Not for Intrathecal Use

Multiple-Dose Vial

Cytotoxic Agent

VIAL

Hospira

1 x 25 mL Vial

NDC 61703-304-36

Sterile

Rx only

Cytarabine

Injection

500 mg/25 mL

(20 mg/mL)

For Intravenous

or Subcutaneous Use Only

Not for Intrathecal Use

Multiple-Dose Vial

Cytotoxic Agent

Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported.

NOT FOR INTRATHECAL USE - CONTAINS BENZYL ALCOHOL

FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY

Rx only

Store at 20°C to 25°C (68°F to 77°F) [USP Controlled Room Temperature].

Only physicians experienced in cancer chemotherapy should use Cytarabine Injection.

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.

( see boxed WARNING )

Cytarabine is a potent bone marrow suppressant. Therapy should be started cautiously in patients with pre-existing drug-induced bone marrow suppression. Patients receiving this drug must be under close medical supervision and, during induction therapy, should have leukocyte and platelet counts performed daily. Bone marrow examinations should be performed frequently after blasts have disappeared from the peripheral blood.

Facilities should be available for management of complications, possibly fatal, of bone marrow suppression (infection resulting from granulocytopenia and other impaired body defenses and hemorrhage secondary to thrombocytopenia). One case of anaphylaxis that resulted in acute cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine.

Severe and at times fatal CNS, GI and pulmonary toxicity (different from that seen with conventional therapy regimens of cytarabine) has been reported following some of the experimental cytarabine dose schedules. These reactions include reversible corneal toxicity, and hemorrhagic conjunctivitis, which may be prevented or diminished by prophylaxis with a local corticosteroid eye drop; cerebral and cerebellar dysfunction including personality changes, somnolence and coma, usually reversible; severe gastrointestinal ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; sepsis and liver abscess; pulmonary edema, liver damage with increased hyperbilirubinemia, bowel necrosis; and necrotizing colitis. Rarely, severe skin rash, leading to desquamation has been reported. Complete alopecia is more commonly seen with experimental high dose therapy than with standard cytarabine treatment programs. If experimental high dose therapy is used, do not use a Cytarabine Injection containing benzyl alcohol.

Cases of cardiomyopathy with subsequent death has been reported following experimental high dose therapy with cytarabine in combination with cyclophosphamide when used for bone marrow transplant preparation.

A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia from one institution in 16/72 patients. The outcome of this syndrome can be fatal.

Benzyl alcohol is contained in this product. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.

Two patients with childhood acute myelogenous leukemia who received intrathecal and intravenous cytarabine at conventional doses (in addition to a number of other concomitantly administered drugs) developed delayed progressive ascending paralysis resulting in death in one of the two patients.

DO NOT USE CYTARABINE INJECTION (which contains benzyl alcohol) INTRATHECALLY.

There is no antidote for cytarabine overdosage. Doses of 4.5 g/m² by intravenous infusion over 1 hour every 12 hours for 12 doses has caused an unacceptable increase in irreversible CNS toxicity and death.

Single doses as high as 3 g/m² have been administered by rapid intravenous infusion without apparent toxicity.

• 1.
  Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publications No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.
• 2.
  AMA Council Report, Guidelines for Handling Parenteral Antineoplastics, JAMA, 1985; 2.53 (11): 1590-1592.
• 3.
  National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
• 4.
  Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428.
• 5.
  Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center CA-A Cancer Journal of Clinicians, 1983; (Sept/Oct) 258-263.
• 6.
  American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp. Pharm, 1990; 47:1033-1049.
• 7.
  Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work Practice Guidelines), Am J. Health- Syst Pharm, 1996; 53: 1669-1685.

Distributed by Hospira, Inc. Lake Forest, IL 60045 USA

GUJ-DRUGS/G/28/1267

LAB-1174-3.0

Revised: 12/2022

Cytarabine Injection, an antineoplastic agent, is a sterile preserved solution for intravenous or subcutaneous administration and is available in 20 mg/mL (500 mg/25 mL) multiple-dose vial. Each mL contains: 20 mg Cytarabine, USP and the following inactive ingredients: benzyl alcohol 0.9% and Water for Injection q.s. The pH is adjusted with hydrochloric acid and/or sodium hydroxide to a target pH of 7.6.

Cytarabine is chemically 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone. The structural formula is:

Cytarabine is an odorless, white to off-white, crystalline powder which is freely soluble in water and slightly soluble in alcohol and in chloroform.

Cytarabine Injection is available as follows:

STORAGE CONDITIONS

Protect from light. Retain in carton until time of use.

See WARNINGS. A review of the literature has shown 32 reported cases where cytarabine was given during pregnancy, either alone or in combination with other cytotoxic agents.

Eighteen normal infants were delivered. Four of these had first trimester exposure. Five infants were premature or of low birth weight. Twelve of the 18 normal infants were followed up at ages ranging from six weeks to seven years, and showed no abnormalities. One apparently normal infant died at 90 days of gastroenteritis.

Two cases of congenital abnormalities have been reported, one with upper and lower distal limb defects, and the other with extremity and ear deformities. Both of these cases had first trimester exposure.

There were seven infants with various problems in the neonatal period including pancytopenia; transient depression of WBC, hematocrit or platelets; electrolyte abnormalities; transient eosinophilia; and one case of increased IgM levels and hyperpyrexia possibly due to sepsis. Six of the seven infants were also premature. The child with pancytopenia died at 21 days of sepsis.

Therapeutic abortions were done in five cases. Four fetuses were grossly normal, but one had an enlarged spleen and another showed Trisomy C chromosome abnormality in the chorionic tissue.

Because of the potential for abnormalities with cytotoxic therapy, particularly during the first trimester, a patient who is or who may become pregnant while on cytarabine should be apprised of the potential risk to the fetus and the advisability of pregnancy continuation. There is a definite, but considerably reduced risk if therapy is initiated during the second or third trimester. Although normal infants have been delivered to patients treated in all three trimesters of pregnancy, follow-up of such infants would be advisable.

See INDICATIONS AND USAGE .

Cytarabine is contraindicated in those patients who are hypersensitive to the drug.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cytarabine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

See General Precautions .

Reversible decreases in steady-state plasma digoxin concentrations and renal glycoside excretion were observed in patients receiving beta-acetyldigoxin and chemotherapy regimens containing cyclophosphamide, vincristine and prednisone with or without cytarabine or procarbazine. Steady-state plasma digitoxin concentrations did not appear to change. Therefore, monitoring of plasma digoxin levels may be indicated in patients receiving similar combination chemotherapy regimens. The utilization of digitoxin for such patients may be considered as an alternative.

An in vitro interaction study between gentamicin and cytarabine showed a cytarabine related antagonism for the susceptibility of K. pneumoniae strains. This study suggests that in patients on cytarabine being treated with gentamicin for a K. pneumoniae infection, the lack of a prompt therapeutic response may indicate the need for reevaluation of antibacterial therapy.

Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy during therapy with cytarabine. This may be due to potential competitive inhibition of its uptake.

Cytarabine in combination with other approved anticancer drugs is indicated for remission induction in acute non-lymphocytic leukemia of adults and children. It has also been found useful in the treatment of acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia.

Intrathecal administration of Cytarabine Injection (preservative-free only) is indicated for the prophylaxis and treatment of meningeal leukemia.

Not applicable.

Patients receiving cytarabine must be monitored closely. Frequent platelet and leukocyte counts and bone marrow examinations are mandatory. Consider suspending or modifying therapy when drug-induced marrow depression has resulted in a platelet count under 50,000 or a polymorphonuclear granulocyte count under 1000/mm³. Counts of formed elements in the peripheral blood may continue to fall after the drug is stopped and reach lowest values after drug-free intervals of 12 to 24 days. When indicated, restart therapy when definite signs of marrow recovery appear (on successive bone marrow studies). Patients whose drug is withheld until "normal" peripheral blood values are attained may escape from control.

When large intravenous doses are given quickly, patients are frequently nauseated and may vomit for several hours post injection. This problem tends to be less severe when the drug is infused.

The human liver apparently detoxifies a substantial fraction of an administered dose. In particular, patients with renal or hepatic function impairment may have a higher likelihood of CNS toxicity after high-dose cytarabine treatment. Use the drug with caution and possibly at reduced dose in patients whose liver or kidney function is poor.

Periodic checks of bone marrow, liver and kidney functions should be performed in patients receiving cytarabine.

Like other cytotoxic drugs, cytarabine may induce hyperuricemia secondary to rapid lysis of neoplastic cells. The clinician should monitor the patient's blood uric acid level and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem.

Acute pancreatitis has been reported to occur in a patient receiving cytarabine by continuous infusion and in patients being treated with cytarabine who have had prior treatment with L-asparaginase.

Cytarabine is not active orally. The schedule and method of administration varies with the program of therapy to be used. Cytarabine Injection may be given by intravenous infusion or injection or subcutaneously. Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites. In most instances, however, the drug has been well tolerated.

Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion. This phenomenon is related to the drug's rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection. Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anti-cancer drugs is 100 mg/m²/day by continuous intravenous infusion (Days 1-7) or 100 mg/m² intravenous every 12 hours (Days 1-7).

The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

Intrathecal Use in Meningeal Leukemia: DO NOT USE CYTARABINE INJECTION (which contains benzyl alcohol) INTRATHECALLY.

The following dosage information regarding intrathecal use is included for informational purposes only.

Cytarabine has been used intrathecally in acute leukemia in doses ranging from 5 mg/m² to 75 mg/m² of body surface area. The frequency of administration varied from once a day for 4 days to once every 4 days. The most frequently used dose was 30 mg/m² every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment. The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated. Modifications of other anti-leukemia therapy may be necessary. Major toxicity is rare. The most frequently reported reactions after intrathecal administration were nausea, vomiting and fever; these reactions are mild and self-limiting. Paraplegia has been reported. Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation. Isolated neurotoxicity has been reported. Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal cytarabine.

When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious lifethreatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician.

Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may be better treated with radiotherapy.

Not applicable.

25 mL Vial

NDC 61703-304-36

Sterile

Rx only

Cytarabine Injection

500 mg/25 mL

(20 mg/mL)

For Intravenous or Subcutaneous Use Only

Not for Intrathecal Use

Multiple-Dose Vial

Cytotoxic Agent

VIAL

Hospira

1 x 25 mL Vial

NDC 61703-304-36

Sterile

Rx only

Cytarabine

Injection

500 mg/25 mL

(20 mg/mL)

For Intravenous

or Subcutaneous Use Only

Not for Intrathecal Use

Multiple-Dose Vial

Cytotoxic Agent

Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported.