Cytarabine

Indications

Cytarabine may be used alone or in combination with other chemotherapeutic agents. It is indicated for induction of remission of leukaemia, particularly for acute myeloid leukaemia, in adults and children. Cytarabine has been used for remission induction in acute lymphocytic leukaemia, chronic myeloid leukaemia and erythroleukaemia; and in the treatment and maintenance therapy of meningeal leukaemia and other meningeal neoplasms. Chiidren with non-Hodgkin's lymphoma have benefitted from a combination drug programme (LSA2L2) that includes cytarabine.

Pharmacology

Cytarabine is an antineoplastic agent. Cytarabine is a synthetic pyrimidine nucleoside, which is converted intracellularly to the nucleotide, cytarabine triphosphate. The exact mechanism of action of cytarabine is not fully understood, but cytarabine triphosphate appears to inhibit DNA synthesis by the inhibition of DNA polymerase. Cytarabine's actions are cell-cycle specific. Cytarabine is also immunosuppressant and has demonstrated antiviral activity in vitro.

Dosage & Administration

Cytarabine Injection 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, subcutaneously, or intrathecally (preservative free preparation only). In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anticancer drugs is 100 mg/m2/day by continuous IV infusion (1 to 7 Days) or 100 mg/m2 IV every 12 hours 1 to 7 Days). The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

Intrathecal Use in Meningeal Leukemia: Cytarabine injection has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area.

Use in Children: Appropriate studies with cytarabine have not been performed in the paediatric population. However, paediatric specific problems that would limit the usefulness of this medication in children are not expected.

Use in the Elderly: Although studies with cytarabine have not been performed in the geriatric population, geriatric specific problems that would limit the usefulness of this medication in the elderly are not expected. Elderly patients are, however, more likely to have age related renal function impairment, which may require reduction of dosage in patients receiving cytarabine.
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Interaction

May reduce efficacy of 5-fluorocytosine, digoxin, gentamicin. May increase risk of neurotoxicity with other cytotoxic agents (intrathecal).

Contraindications

Cytarabine is contraindicated in patients with known hypersensitivity to the drug.

Side Effects

The major adverse effect of cytarabine is haematologic toxicity. Myelosuppression is normally manifested by megaloblastosis, leucopenia, anaemia, reticulocytopenia and thrombocytopenia. Leucopenia follows mainly from granulocyte depression; lymphocytes are minimally affected. The severity of these adverse effects is dependent on the dose of the drug and schedule of administration.

Incidence and severity of haematologic toxicity is minimal after a single intravenous dose of cytarabine, but myelosuppression occurs in almost all patients with daily IV injections or continuous IV infusions of the drug.

Nausea and vomiting may occur in patients on cytarabine therapy, and usually occur more frequently and severely following rapid IV administration as opposed to continuous infusion of the drug.

Viral, bacterial, fungal parasitic or saprophytic infection which can be mild, severe and at times fatal, may be associated with the use of cytarabine when used alone or in combination with other immunosuppressive agents following immunosuppressive doses that affect cellular or humoral immunity.

Neurotoxicity following intrathecal cytarabine has been associated with preservative containing diluents and many clinicians recommend the use of preservative free diluents instead.

A cytarabine syndrome characterised by fever, myalgia, bone pain, malaise, maculopapular rash, conjunctivitis, and occasionally chest pain, has been reported. A "flu-like" syndrome has been reported, which may be treated with corticosteroid therapy if severe. Anaphylactoid reactions have occurred.

It normally occurs at 6 to 12 hours after administration of the drug; corticosteroids have been shown to be of benefit in the treatment and prevention of the syndrome. If treatment of the symptoms of the syndrome is required, administration of corticosteroids should be considered, as well as continuation of cytarabine therapy.

Two patients with adult non lymphocytic leukaemia developed peripheral motor and sensory neuropathies after consolidation with high dose cytarabine, daunorubicin and asparaginase. A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and radiologically pronounced cardiomegaly has been reported following experimental high dose therapy of cytarabine for relapsed leukaemia. This syndrome can have fatal consequences.

Pregnancy & Lactation

Cytarabine is suspected to have caused or may be expected to cause an increased incidence of human fetal malformations or irreversible damages. It may also have adverse pharmacological effects. Cytarabine has been shown to be teratogenic in some animal species and should not be used during pregnancy, especially during the first trimester, not in women likely to become pregnant. It is not known whether cytarabine is excreted in human milk. Women should be advised not to breast feed while being treated with cytarabine, because of the risks to the infant.

Precautions & Warnings

Patient with previous drug-induced bone marrow suppression. Renal or hepatic impairment. Pregnancy and lactation.

Overdose Effects

Severe bone marrow depression, gastrointestinal toxicity and vomiting are among the signs and symptoms expected. Treatment with cytarabine should be ceased and supportive measures instituted. In bone marrow depression, transfusions of blood products may be required and active measures may be necessary to combat infection. Hyperuricaemia is avoided by the addition of allopurinol to treatment schedules and measures such as alkalinisation of . the urine and hydration may also be adopted. Techniques attempting to prevent the occurrence of alopecia have met with varying success. Scalp tourniquets and ice packs have been used to minimize concentrations of antineoplastic agents in the scalp after intravenous injection. Such methods, however, may allow the development of a cancer-cell sanctuary and should not be used in patients with leukaemia or other conditions with circulating malignant cells. The treatment of extravasation is controversial. Warm moist soaks or ice packs have been applied and a corticosteroid may sometimes be instilled into the affected area. Antiemetic therapy should be given in an attempt to prevent or control nausea and vomiting.

Therapeutic Class

Cytotoxic Chemotherapy

Storage Conditions

Store the vial in original carton at 15°C to 30°C. Protect from light. Do not refrigerate. Keep out of the reach of children.