Daunorubicin Hydrochloride (Page 2 of 4)

WARNINGS

Bone Marrow

Daunorubicin hydrochloride is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with daunorubicin hydrochloride should not be started in patients with pre-existing drug-induced bone marrow suppression unless the benefit from such treatment warrants the risk. Persistent, severe myelosuppression may result in superinfection or hemorrhage.

Cardiac Effects

Special attention must be given to the potential cardiac toxicity of daunorubicin hydrochloride, particularly in infants and children. Pre-existing heart disease and previous therapy with doxorubicin are co-factors of increased risk of daunorubicin-induced cardiac toxicity and the benefit-to-risk ratio of daunorubicin hydrochloride therapy in such patients should be weighed before starting daunorubicin hydrochloride. In adults, at total cumulative doses less than 550 mg/m2 , acute congestive heart failure is seldom encountered. However, rare instances of pericarditis-myocarditis, not dose-related, have been reported.

In adults, at cumulative doses exceeding 550 mg/m2 , there is an increased incidence of drug-induced congestive heart failure. Based on prior clinical experience with doxorubicin, this limit appears lower, namely 400 mg/m2 , in patients who received radiation therapy that encompassed the heart.

In infants and children, there appears to be a greater susceptibility to anthracycline-induced cardiotoxicity compared to that in adults, which is more clearly dose-related. Anthracycline therapy (including daunorubicin) in pediatric patients has been reported to produce impaired left ventricular systolic performance, reduced contractility, congestive heart failure or death. These conditions may occur months to years following cessation of chemotherapy. This appears to be dose-dependent and aggravated by thoracic irradiation. Long-term periodic evaluation of cardiac function in such patients should, thus, be performed. In both children and adults, the total dose of daunorubicin hydrochloride administered should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents or related compounds such as doxorubicin.

There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of the cardiac toxic effect of daunorubicin hydrochloride. However, certain changes in the electrocardiogram and a decrease in the systolic ejection fraction from pre-treatment baseline may help to recognize those patients at greatest risk to develop congestive heart failure. On the basis of the electrocardiogram, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated with a significant risk of drug-induced cardiomyopathy. Therefore, an electrocardiogram and/or determination of systolic ejection fraction should be performed before each course of daunorubicin hydrochloride. In the event that one or the other of these predictive parameters should occur, the benefit of continued therapy must be weighed against the risk of producing cardiac damage.

Early clinical diagnosis of drug-induced congestive heart failure appears to be essential for successful treatment.

Evaluation of Hepatic and Renal Function

Significant hepatic or renal impairment can enhance the toxicity of the recommended doses of daunorubicin hydrochloride; therefore, prior to administration, evaluation of hepatic function and renal function using conventional clinical laboratory tests is recommended (see DOSAGE AND ADMINISTRATION section).

Pregnancy

Daunorubicin hydrochloride may cause fetal harm when administered to a pregnant woman. An increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, or rachischisis) and abortions was reported in rabbits at doses of 0.05 mg/kg/day or approximately 1/100th of the highest recommended human dose on a body surface area basis. Rats showed an increased incidence of esophageal, cardiovascular and urogenital abnormalities as well as rib fusions at doses of 4 mg/kg/day or approximately 1/2 the human dose on a body surface area basis. Decreases in fetal birth weight and post-delivery growth rate were observed in mice. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Secondary Leukemias

There have been reports of secondary leukemias in patients exposed to topoisomerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy.

Extravasation at Injection Site

Extravasation of daunorubicin hydrochloride at the site of intravenous administration can cause severe local tissue necrosis. (See ADVERSE REACTIONS section)

PRECAUTIONS

General

Therapy with daunorubicin hydrochloride requires close patient observation and frequent complete blood-count determinations. Cardiac, renal, and hepatic function should be evaluated prior to each course of treatment.

Appropriate measures must be taken to control any systemic infection before beginning therapy with daunorubicin hydrochloride.

Daunorubicin hydrochloride may transiently impart a red coloration to the urine after administration, and patients should be advised to expect this.

Laboratory Tests

Daunorubicin hydrochloride may induce hyperuricemia secondary to rapid lysis of leukemic cells. As a precaution, allopurinol administration is usually begun prior to initiating antileukemic therapy. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Daunorubicin hydrochloride, when injected subcutaneously into mice, causes fibrosarcomas to develop at the injection site. When administered to mice thrice weekly intraperitoneally, no carcinogenic effect was noted after 18 months of observation. In male rats administered daunorubicin thrice weekly for 6 months, at 1/70th the recommended human dose on a body surface area basis, peritoneal sarcomas were found at 18 months. A single IV dose of daunorubicin administered to rats at 1.6 fold the recommended human dose on a body surface area basis caused mammary adenocarcinomas to appear at 1 year. Daunorubicin was mutagenic in vitro (Ames assay, V79 hamster cell assay), and clastogenic in vitro (CCRFCEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests.

In male dogs at a daily dose of 0.25 mg/kg administered intravenously, testicular atrophy was noted at autopsy. Histologic examination revealed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis.

Pregnancy Category D

(See WARNINGS section)

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 daunorubicin, mothers should be advised to discontinue nursing during daunorubicin therapy.

Elderly

See CLINICAL PHARMACOLOGY, Special Populations, Geriatric Patients section.

Pediatric Use

See CLINICAL PHARMACOLOGY, Special Populations, Pediatric Patients section and WARNINGS, Cardiac Effects section.

Drug Interactions

Use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Daunorubicin hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride. Cyclophosphamide used concurrently with daunorubicin hydrochloride may also result in increased cardiotoxicity.

Dosage reduction of daunorubicin hydrochloride 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.

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