Daunorubicin in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.
Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. It forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA- topoisomerase II complex, preventing the religation portion of the ligation- religation reaction that topoisomerase II catalyzes. Single strand and double-strand DNA breaks result. It may also inhibit polymerase activity, affect the regulation of gene expression, and produce free radical damage to DNA. It possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.
Distribution: Daunorubicin is rapidly and widely distributed in tissues, with the highest levels in the spleen, kidneys, liver, lungs and heart. The drug binds to many cellular components, particularly nucleic acids. There is no evidence that it crosses the blood-brain barrier, but the drug apparently crosses the placenta.
Metabolism and Elimination: Daunorubicin is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of Daunorubicin. Further metabolism via reduction cleavage of the glycosidic bond, 4-O demethylation, and conjugation with both sulfate and glucuronide have been demonstrated. Simple glycosidic cleavage of Daunorubicin or Daunorubicinol is not a significant metabolic pathway in man. Twenty-five percent of an administered dose of Daunorubicin is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.
Intravenous- Acute leukaemias: Adult: 30-45 mg/m2 BSA daily on days 1-3 of the induction course and days 1 and 2 for the subsequent courses. Admin as a solution in 0.9% sodium chloride into a fast-running infusion of sodium chloride or glucose. May repeat course 3-6 wk later. Max (total cumulative dose): 550 mg/m2 in patients without risk factors for cardiotoxicity and 400 mg/m2 in patients who have received chest radiotherapy. Child: For acute lymphoblastic leukaemia: 25 mg/m2 BSA once wkly in combination with other regimens. <2 yr old or BSA <0.5 m2: 1 mg/kg once wkly. Max (total cumulative dose): 300 mg/m2 and in children <2 yr: 10 mg/kg. AIDS-related Kaposi's sarcoma: Adult: As the liposomal formulation: Initially, 40 mg/m2 once every 2 wk, diluted in glucose 5% to a concentration of 0.2-1 mg/ml and given over 30-60 minutes. May continue for as long as disease control can be maintained.
The use of Daunorubicin in a patient who has previously received Doxorubicin increases the risk of cardiotoxicity. Daunorubicin should not be used in patients who have previously received the recommended maximum cumulative doses of Doxorubicin or Daunorubicin. Cyclophosphamide used concurrently with Daunorubicin may also result in increased cardiotoxicity. Dosage reduction of Daunorubicin may be required when used concurrently with other myelosuppressive agents. Hepatotoxic medications, such as high-dose Methotrexate, may impair liver function and increase the risk of toxicity.
Heart failure. Pregnancy, lactation. Regular blood count and ECG monitoring; elderly, children. Hepatic or renal impairment may increase risk of toxicity. Pre-existing cardiac disease and previous treatment with doxorubicin. Myocardial toxicity leading to potentially fatal congestive heart failure may occur during therapy or mth to yr after therapy cessation. Incidence of myocardial toxicity increases after total cumulative dose exceeds 400-550 mg/m2in adults, 300 mg/m2 in children >2 yr, or 10 mg/kg in children <2 yr. Risk of severe myelosuppression leading to infection or haemorrhage.
GI disturbances; stomatitis; alopoecia and dermatological reactions. Extravasation of daunorubicin may cause severe local tissue necrosis damaging surrounding muscles, tendons and nerves. IV infusion, back pain, flushing and chest tightness.
Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).
Store unopened vials in the refrigerator, 2°-8°C. Contains no preservatives. Discard unused portions. Protect from light. If Daunorubicin contacts the skin or mucosae, the area should be washed thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered.
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