Special attention must be given to the cardiotoxicity induced by doxorubicin. Irreversible myocardial toxicity, manifested in its most severe form by life-threatening or fatal congestive heart failure, may occur either during therapy or months to years after termination of therapy. The probability of developing impaired myocardial function, based on a combined index of signs, symptoms and decline in left ventricular ejection fraction (LVEF) is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of doxorubicin, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2 and 6 to 20% at a dose of 500 mg/m2 given in a schedule of a bolus injection once every 3 weeks (data on file at Pharmacia & Upjohn). In a retrospective review by Von Hoff et al, the probability of developing congestive heart failure was reported to be 5/168 (3%) at a cumulative dose of 430 mg/m2 of doxorubicin, 8/110 (7%) at 575 mg/m2 and 3/14 (21%) at 728 mg/m2. The cumulative incidence of CHF was 2.2%. In a prospective study of doxorubicin in combination with cyclophosphamide, fluorouracil and/or vincristine in patients with breast cancer or small cell lung cancer, the cumulative incidence of congestive heart failure was 5 to 6%. The probability of CHF at various cumulative doses of doxorubicin was 1.5% at 300 mg/m2, 4.9% at 400 mg/m2, 7.7% at 450 mg/m2 and 20.5% at 500 mg/m2.
Cardiotoxicity may occur at lower doses in patients with prior mediastinal irradiation, concurrent cyclophosphamide therapy exposure at an early age and advanced age. Data also suggest that pre-existing heart disease is a co-factor for increased risk of doxorubicin cardiotoxicity. In such cases, cardiac toxicity may occur at doses lower than the respective recommended cumulative dose of doxorubicin. Studies have suggested that concomitant administration of doxorubicin and calcium channel entry blockers may increase the risk of doxorubicin cardiotoxicity. The total dose of doxorubicin administered to the individual patient should also take into account previous or concomitant therapy with related compounds such as daunorubicin, idarubicin and mitoxantrone. Cardiomyopathy and/or congestive heart failure may be encountered several months or years after discontinuation of doxorubicin therapy.
The risk of congestive heart failure and other acute manifestations of doxorubicin cardiotoxicity in pediatric patients may be as much or lower than in adults. Pediatric patients appear to be at particular risk for developing delayed cardiac toxicity in that doxorubicin induced cardiomyopathy impairs myocardial growth as pediatric patients mature, subsequently leading to possible development of congestive heart failure during early adulthood. As many as 40% of pediatric patients may have subclinical cardiac dysfunction and 5 to 10% of pediatric patients may develop congestive heart failure on long term follow-up. This late cardiac toxicity may be related to the dose of doxorubicin. The longer the length of follow-up the greater the increase in the detection rate.
Treatment of doxorubicin induced congestive heart failure includes the use of digitalis, diuretics, after load reducers such as angiotensin I converting enzyme (ACE) inhibitors, low salt diet, and bed rest. Such intervention may relieve symptoms and improve the functional status of the patient.
Monitoring Cardiac Function
In adult patients severe cardiac toxicity may occur precipitously without antecedent ECG changes. Cardiomyopathy induced by anthracyclines is usually associated with very characteristic histopathologic changes on an endomyocardial biopsy (EM biopsy), and a decrease of left ventricular ejection fraction (LVEF), as measured by multi-gated radionuclide angiography (MUGA scans) and/or echocardiogram (ECHO), from pretreatment baseline values. However, it has not been demonstrated that monitoring of the ejection fraction will predict when individual patients are approaching their maximally tolerated cumulative dose of doxorubicin. Cardiac function should be carefully monitored during treatment to minimize the risk of cardiac toxicity. A baseline cardiac evaluation with an ECG, LVEF, and/or an echocardiogram (ECHO) is recommended especially in patients with risk factors for increased cardiac toxicity (pre-existing heart disease, mediastinal irradiation, or concurrent cyclophosphamide therapy). Subsequent evaluations should be obtained at a cumulative dose of doxorubicin of at least 400 mg/m2 and periodically thereafter during the course of therapy. Pediatric patients are at increased risk for developing delayed cardiotoxicity following doxorubicin administration and therefore a follow-up cardiac evaluation is recommended periodically to monitor for this delayed cardiotoxicity.
In adults, a 10% decline in LVEF to below the lower limit of normal or an absolute LVEF of 45%, or a 20% decline in LVEF at any level is indicative of deterioration in cardiac function. In pediatric patients, deterioration in cardiac function during or after the completion of therapy with doxorubicin is indicated by a drop in fractional shortening (FS) by an absolute value of ≥10 percentile units or below 29%, and a decline in LVEF of 10 percentile units or an LVEF below 55%. In general, if test results indicate deterioration in cardiac function associated with doxorubicin, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage.
Acute life-threatening arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.
There is a high incidence of bone marrow depression, primarily of leukocytes, requiring careful hematologic monitoring. With the recommended dose schedule, leukopenia is usually transient, reaching its nadir 10 to 14 days after treatment with recovery usually occurring by the 21st day. White blood counts as low as 1000/mm3 are to be expected during treatment with appropriate doses of doxorubicin. Red blood cell and platelet levels should also be monitored since they may also be depressed. Hematologic toxicity may require dose reduction or suspension or delay of doxorubicin therapy. Persistent severe myelosuppression may result in superinfection or hemorrhage.
Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported. Radiation induced toxicity to the myocardium, mucosae, skin and liver have been reported to be increased by the administration of doxorubicin. Pediatric patients receiving concomitant doxorubicin and actinomycin-D have manifested acute “recall” pneumonitis at variable times after local radiation therapy.
Since metabolism and excretion of doxorubicin occurs predominantly by the hepatobiliary route, toxicity to recommended doses of doxorubicin can be enhanced by hepatic impairment; therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional laboratory tests such as SGOT, SGPT, alkaline phosphatase and bilirubin. (See DOSAGE AND ADMINISTRATION.)
Necrotizing colitis manifested by typhlitis (cecal inflammation), bloody stools and severe and sometimes fatal infections have been associated with a combination of doxorubicin given by I.V. push daily for 3 days and cytarabine given by continuous infusion daily for 7 or more days.
On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle (see DOSAGE AND ADMINISTRATION). If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein.
Pregnancy Category D
Safe use of doxorubicin in pregnancy has not been established. Doxorubicin is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits. There are no adequate and well-controlled studies in pregnant women. If doxorubicin is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.
Doxorubicin is not an anti-microbial agent.
Information for Patients
RUBEX (doxorubicin hydrochloride for injection, USP) imparts a red coloration to the urine for 1 to 2 days after administration, and patients should be advised to expect this during active therapy.
Paclitaxel: Two published studies report that initial administration of paclitaxel infused over 24 hours followed by doxorubicin administered over 48 hours resulted in a significant decrease in doxorubicin clearance with more profound neutropenic and stomatitis episodes than the reverse sequence of administration.
Progesterone: In a published study, progesterone was given intravenously to patients with advanced malignancies (ECOG PS <2) at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m2) via bolus. Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed.
Verapamil: A study of the effects of verapamil on the acute toxicity of doxorubicin in mice revealed higher initial peak concentrations of doxorubicin in the heart with a higher incidence and severity of degenerative changes in cardiac tissue resulting in a shorter survival.
Cyclosporine: The addition of cyclosporine to doxorubicin may result in increases in AUC for both doxorubicin and doxorubicinol possibly due to a decrease in clearance of parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to doxorubicin results in more profound and prolonged hematologic toxicity than doxorubicin alone. Coma and/or seizures have also been described.
Literature reports have also described the following drug interactions: phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar®) may inhibit hepatic metabolism of doxorubicin, and administration of live vaccines to immunosuppressed patients including those undergoing cytotoxic chemotherapy may be hazardous.
Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests, and radionuclide left ventricular ejection fraction (see WARNINGS).
Like other cytotoxic drugs, doxorubicin may induce “tumor lysis syndrome” and hyperuricemia in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Formal long-term carcinogenicity studies have not been conducted with doxorubicin. Doxorubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models (including bacterial systems, mammalian cells in culture, and female Sprague-Dawley rats).
The possible adverse effect on fertility in males and females in humans or experimental animals have not been adequately evaluated. Testicular atrophy was observed in rats and dogs.
A variant of chemotherapy-related acute non-lymphocytic leukemia has been reported to occur infrequently a few years after multiple drug treatment of some neoplasms, which sometimes included doxorubicin. The exact role of doxorubicin has not been elucidated.
Pediatric patients treated with doxorubicin or other topoisomerase II inhibitors are at a risk for developing acute myelogenous leukemia and other neoplasms. The extent of increased risk associated with doxorubicin has not been precisely quantified.
Pregnancy Category D
Because of the potential for serious adverse reactions in nursing infants from doxorubicin, mothers should be advised to discontinue nursing during doxorubicin therapy.
Pediatric patients are at increased risk for developing delayed cardiotoxicity. Follow-up cardiac evaluations are recommended periodically to monitor for the delayed cardiotoxicity (see WARNINGS).
Doxorubicin, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure. It may also contribute to gonadal impairment, which is usually temporary.