Cytarabine

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Cytarabine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Black Box Warning

Black Box Warning:
See full prescribing information for complete Boxed Warning.
ConditionName:

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.

Overview

Cytarabine is an antineoplastic agent that is FDA approved for the treatment of acute non-lymphocytic leukemia of adults and children, acute lymphocytic leukemia and the blast phase of chronic myelocytic leukemia. Intrathecal administration of cytarabine injection is indicated for the prophylaxis and treatment of meningeal leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include thrombophlebitis, rash, hyperuricemia, anal inflammation, diarrhea, loss of apetite, nauseas, stomatitis, mouth ulceration, vomiting, decreased reticulocyte count, megaloblastic anemia, decreased liver function and fever.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Acute Non-Lymphocytic Leukemia

  • Induction: 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/m2 IV every 12 hours (Days 1-7).

Meningeal Leukemia

  • Dosage: 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cytarabine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cytarabine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Cytarabine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cytarabine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cytarabine in pediatric patients.

Contraindications

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

Warnings

Black Box Warning:
See full prescribing information for complete Boxed Warning.
ConditionName:

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.
  • 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.

Adverse Reactions

Clinical Trials Experience

Hematological Effects

Infections

Viral, bacterial, fungal, parasitic or saprophytic infections, in any location in the body may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal.

Cytabarine Syndrome

Cardiovascular effects

Dermatological effects

Endocrine/metabolic Effects

Gastrointestinal Effects

  • Gastrointestinal tract finding: nausea and vomiting are common agh high-dosis[9]. GI bleeding has also been reported[8].
  • Pancreatitis
    • Case report of a 36-year old male in therapy for 7 days with 200mg / m2 surface area / day [11].
    • Case report of 2/30 Patients receiving cytarabine for leukemia and lymphoma in high doses (6.9 g IV every 12 hours for 11 doses and 5.25 g every 12 hours for 6 days)[12].
  • Parotiditis:
    • Case report: 2/30 patients developed parotiditis with cytarabine 200 milligrams/square meter/day in continuous infusion for 7 days [13].
  • Pseudomembranous enterocolitis
    • Case report: 2 patients who developed Pseudomembranous Enterocolitis and as a consequence, needed subtotal colectomy[14].

Hepatic Effects

Immunological Effects

Musculoeskeletal Effects

Neurologic Effects

Ophthalmic Effects

Urinary Tract Effects

Respiratory Effects

Other

Postmarketing Experience

There is limited information regarding Cytarabine Postmarketing Experience in the drug label.

Drug Interactions

  • 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • 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 the 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 Injection 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.


Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cytarabine in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Cytarabine during labor and delivery.

Nursing Mothers

  • 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.

Pediatric Use

There is no FDA guidance on the use of Cytarabine in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Cytarabine in geriatric settings.

Gender

There is no FDA guidance on the use of Cytarabine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Cytarabine with respect to specific racial populations.

Renal Impairment

  • 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.

Hepatic Impairment

There is no FDA guidance on the use of Cytarabine in patients with hepatic impairment.

Females of Reproductive Potential and Males

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

Immunocompromised Patients

There is no FDA guidance one the use of Cytarabine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for IV infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only.
  • When cytarabine is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal cytarabine is left to the discretion of the treating physician.

Monitoring

  • Patients receiving Cytarabine Injection 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 Injection.
  • Like other cytotoxic drugs, Cytarabine Injection 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.

IV Compatibility

If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses.

Overdosage

  • There is no antidote for cytarabine over dosage. 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.

Pharmacology

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Cytarabine chemical structure.png
Cytarabine
Systematic (IUPAC) name
4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one
Identifiers
CAS number 147-94-4
ATC code L01BC01
PubChem 6253
DrugBank DB00987
Chemical data
Formula C9H13N3O5 
Mol. mass 243.217 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 20% oral
Protein binding 13%
Metabolism Liver
Half life biphasic: 10 min, 1-3 hr
Excretion Renal
Therapeutic considerations
Pregnancy cat.

D(AU) D(US)

Legal status

Prescription only

Routes Injectable (intravenous injection or infusion, intrathecal, or subcutaneously)

Mechanism of Action

  • Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. Extensive chromosomal damage, including chromatid breaks have been produced by cytarabine and malignant transformation of rodent cells in culture has been reported. Deoxycytidine prevents or delays (but does not reverse) the cytotoxic activity.

Structure

Cytarabine is chemically 4-amino-l- β-Darabinofuranosyl- 2(lH)-pyrimidinone.

Cytarabine chemical structure.png

Pharmacodynamics

There is limited information regarding Cytarabine Pharmacodynamics in the drug label.

Pharmacokinetics

  • Cytarabine is rapidly metabolized and is not effective orally; less than 20 percent of the orally administered dose is absorbed from the gastrointestinal tract.
  • Following rapid intravenous injection of cytarabine, labeled with tritium, the disappearance from plasma is biphasic. There is an initial distributive phase with a half-life of about 10 minutes, followed by a second elimination phase with a half-life of about 1 to 3 hours. After the distributive phase, more than 80 percent of plasma radioactivity can be accounted for by the inactive metabolite 1-β-D-arabinofuranosyluracil (ara-U). Within 24 hours about 80 percent of the administered radioactivity can be recovered in the urine, approximately 90 percent of which is excreted as ara-U.
  • Relatively constant plasma levels can be achieved by continuous intravenous infusion.
  • After subcutaneous or intramuscular administration of cytarabine labeled with tritium, peak-plasma levels of radioactivity are achieved about 20 to 60 minutes after injection and are considerably lower than those after intravenous administration.
  • Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single intravenous injection. However, in one patient in whom cerebrospinal fluid levels are examined after 2 hours of constant intravenous infusion, levels approached 40 percent of the steady state plasma level. With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a first order half-life of about 2 hours. Because cerebrospinal fluid levels of deaminase are low, little conversion to ara-U was observed.

Nonclinical Toxicology

There is limited information regarding Cytarabine Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Cytarabine Clinical Studies in the drug label.

How Supplied

Cytarabine Injection, PHARMACY BULK PACKAGE. Sterile, Isotonic Solution. Preservative, Free. NDC No. 0069-0154-01.Cytarabine Injection 1000 mg in a 50 mL, (20 mg/mL) flip-top vial (brown cap), packaged individually.

Storage

Store between, 20° - 25°C (68° - 77°F). [See USP Controlled Room Temperature].

Images

Drug Images

Package and Label Display Panel

Patient Counseling Information

There is limited information regarding Cytarabine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Cytarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

There is limited information regarding Cytarabine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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