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Daunoxome (Daunorubicin Citrate) - Warnings and Precautions

 
 



WARNINGS

  1. Cardiac function should be monitored regularly in patients receiving DaunoXome (daunorubicin citrate liposome injection) because of the potential risk for cardiac toxicity and congestive heart failure. Cardiac monitoring is advised especially in those patients who have received prior anthracyclines or who have pre-existing cardiac disease or who have had prior radiotherapy encompassing the heart.
  2. Severe myelosuppression may occur.
  3. DaunoXome should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
  4. Dosage should be reduced in patients with impaired hepatic function. (See DOSAGE AND ADMINISTRATION)
  5. A triad of back pain, flushing, and chest tightness has been reported in 13.8% of the patients (16/116) treated with DaunoXome in the Phase III clinical trial, and in 2.7% of treatment cycles (27/994). This triad generally occurs during the first five minutes of the infusion, subsides with interruption of the infusion, and generally does not recur if the infusion is then resumed at a slower rate.
 

WARNINGS

DaunoXome is intended for administration under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

The primary toxicity of DaunoXome is myelosuppression, especially of the granulocytic series, which may be severe, and associated with fever and may result in infection. Effects on the platelets and erythroid series are much less marked. Careful hematologic monitoring is required and since patients with HIV infection are immunocompromised, patients must be observed carefully for evidence of intercurrent or opportunistic infections.

Special attention must be given to the potential cardiac toxicity of DaunoXome. Although there is no reliable means of predicting congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with a decrease of the left ventricular ejection fraction (LVEF). Cardiac function should be evaluated in each patient by means of a history and physical examination before each course of DaunoXome and determination of LVEF should be performed at total cumulative doses of DaunoXome of 320 mg/m2, and every 160 mg/m2 thereafter.

Patients who have received prior therapy with anthracyclines (doxorubicin > 300 mg/m2 or equivalent), have pre-existing cardiac disease, or have received previous radiotherapy encompassing the heart may be less "cardiac" tolerant to treatment with DaunoXome.  Therefore, monitoring of LVEF at cumulative DaunoXome doses should occur prior to therapy and every 160 mg/m2 of DaunoXome.

In patients with Kaposi's sarcoma, congestive heart failure has been reported in one patient at a cumulative dose of 340 mg/m2 of DaunoXome. In eight Kaposi's sarcoma patients, LVEF decreases were reported at cumulative doses ranging from 200 mg/m2 to 2100 mg/m2 (median dose 320 mg/m2) of DaunoXome. In clinical studies in malignancies other than Kaposi's sarcoma and treated with doses of DaunoXome greater than the recommended dose of 40 mg/m2, congestive heart failure has been reported at a cumulative dose as low as 200 mg/m2 of DaunoXome; seven patients have been reported with LVEF decreases. The proportion of patients at risk for cardiotoxicity is unknown because the denominator is uncertain since there were several instances of missing repeat cardiac evaluations.

A triad of back pain, flushing, and chest tightness has been reported in 13.8% of the patients (16/116) treated with DaunoXome in the randomized clinical trial and in 2.7% of treatment cycles (27/994). This triad generally occurs during the first five minutes of the infusion, subsides with interruption of the infusion, and generally does not recur if the infusion is then resumed at a slower rate. This combination of symptoms appears to be related to the lipid component of DaunoXome, as a similar set of signs and symptoms has been observed with other liposomal products not containing daunorubicin.

Daunorubicin has been associated with local tissue necrosis at the site of drug extravasation. Although no such local tissue necrosis has been observed with DaunoXome, care should be taken to ensure that there is no extravasation of drug when DaunoXome is administered.

Dosage should be reduced in patients with impaired hepatic function. (See DOSAGE AND ADMINISTRATION)

Pregnancy Category D

DaunoXome can cause fetal harm when administered to a pregnant woman. DaunoXome was administered to rats on gestation days 6 through 15 at 0.3, 1.0 or 2.0 mg/kg/day, (about 1/20th, 1/6th, or 1/3rd the recommended human dose on a mg/m2 basis). DaunoXome produced severe maternal toxicity and embryolethality at 2.0 mg/kg/day and was embryotoxic and caused fetal malformations (anophthalmia, microphthalmia, incomplete ossification) at 0.3 mg/kg/day. Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.

There are no studies of DaunoXome in pregnant women. If DaunoXome is used during pregnancy, or if the patient becomes pregnant while taking DaunoXome, the patient must be warned of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant while taking DaunoXome.

PRECAUTIONS

Drug Interactions

In the patient population studied, DaunoXome has been administered to patients receiving a variety of concomitant medications (e.g., antiretroviral agents, antiviral agents, anti-infective agents). Although interactions of DaunoXome (daunorubicin citrate liposome injection) with other drugs have not been observed, no systematic studies of interactions have been conducted.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No carcinogenesis, mutagenesis, or impairment of fertility studies were conducted with DaunoXome.

Carcinogenesis: Carcinogenicity and mutagenicity studies have been conducted with daunorubicin, the active component of DaunoXome. A high incidence of mammary tumors was observed about 120 days after a single intravenous dose of 12.5 mg/kg daunorubicin in rats (about 2 times the human dose on a mg/m2 basis). Mutagenesis: Daunorubicin was mutagenic in in vitro tests (Ames assay, V79 hamster cell assay), and clastogenic in in vitro (CCRF-CEM human lymphoblasts) and in in vivo (SCE assay in mouse bone marrow) tests. Impairment of Fertility: Daunorubicin intravenous doses of 0.25 mg/kg/day (about 8 times the human dose on a mg/m2 basis) in male dogs caused testicular atrophy and total aplasia of spermatocytes in the seminiferous tubules.

Pregnancy

Pregnancy "Category D". See WARNINGS Section.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

Safety and effectiveness in the elderly have not been established.

Special Populations

Safety has not been established in patients with pre-existing hepatic or renal dysfunction.

Page last updated: 2012-05-18

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