ARASID 100 - ARASID 500 - ARASID

A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia.

Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA.

Its actions are specific for the

S phase of the cell cycle.

It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472).

For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia.

Cytarabine is indicated in combination with daunorubicin for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia.

Anti-metabolites masquerade as purine or pyrimidine.

• which become the building blocks of DNA.

They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division.

Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate).

This metabolite then damages

DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA.

The latter mechanism is probably the most important.

Cytotoxicity is highly specific for the

S phase of the cell cycle.

Less than 20% of the Oral administered dose is absorbed from the gastrointestinal tract.

The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U.

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Cytarabine syndrome may develop.

• it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise.

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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 leucocyte 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 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 diluent 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.

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.

Cytarabine can cause fetal harm when administered to a pregnant woman.

Cytarabine causes abnormal cerebellar development in the neonatal hamster and is teratogenic to the rat fetus.

There are no adequate and well-controlled studies in pregnant women.

Women of childbearing potential should be advised to avoid becoming pregnant.

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

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 intravenous infusion only.

Intrathecal use of cytarabine injection requires the use of single-dose, unpreserved solutions only.

Cytarabine injection is not active orally.

The schedule and method of administration varies with the program of therapy to be used.

While cytarabine injection may be given by intravenous infusion or injection, or subcutaneously or intrathecally, THE PURPOSE OF THE PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF INTRAVENOUS INFUSIONS.

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 injection dose in combination with other anti-cancer drugs is 100 mg/m 2 /day by continuous intravenous infusion (Days to 7) or 100 mg/m 2 intravenously every 12 hours (Days to 7).

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

Cytarabine injection has been used intrathecally in acute leukemia in doses ranging from 5 mg/m to 75 mg/m 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/m 2 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.

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.

Cytarabine injection given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic system is indicated.

Modification 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 injection.

When cytarabine injection 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 injection is left to the discretion of the treating physician.

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

Chemical stability studies were performed by a stability indicating HPLC assay on cytarabine injection in infusion solutions.

These studies showed that when cytarabine injection was diluted with Water for Injection, 5% Dextrose Injection or Sodium Chloride Injection, in both glass and plastic infusion bags, 97 to 100% of the cytarabine was present after 8 days storage at room temperature.

This chemical stability information in no way indicates that it would be acceptable practice to infuse a cytarabine injection admixture well after the preparation time.

Good professional practice suggests that administration of an admixture should be as soon after preparation as feasible.

Parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Procedures for proper handling and disposal of anti-cancer drugs should be considered.

Several guidelines on this subject have been published. 1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Direction for Dispensing From Pharmacy Bulk Package The 50 mL Pharmacy Bulk Package is for use in the Pharmacy Admixtures Service only.

A single entry through the bottle closure should be made with a sterile dispensing set or transfer device.

Transfer individual doses to appropriate intravenous infusion solutions.

Use of a syringe with needle is not recommended.

Multiple entries will increase the potential of microbial and particulate contamination.

The above process should be carried out under a laminar flow hood using aseptic technique.

Care should be exercised to protect personnel from aerosolized drug See DOSAGE AND ADMINISTRATION, REFERENCES.

Discard any unused portion within 4 hours after initial closure entry.

Cytarabine Injection is available in a Pharmacy Bulk Package supplied as follows: NDC Cytarabine Injection (20 mg per mL) Package Factor 71288.

• 168 -50 1,000 mg per 50 mL Pharmacy Bulk Bottle 1 bottle per carton Storage Conditions Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Protect from light.

Retain in carton until time of use.

The container closure is not made with natural rubber latex.

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F).

Protect from light.

Retain in carton until time of use.

The container closure is not made with natural rubber latex.

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 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.

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.