Dose limiting toxicities of therapy are myelosuppression and cardiotoxicity. Other reactions reported are:

Cardiotoxicity - (See WARNINGS.)

Cutaneous - Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds and dermal crease, primarily in pediatric patients, and onycholysis have been reported in a few cases. Recall of skin reaction due to prior radiotherapy has occurred with doxorubicin administration.

Gastrointestinal - Acute nausea and vomiting occurs frequently and may be severe. This may be alleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur 5 to 10 days after administration. The effect may be severe leading to ulceration and represents a site of origin for severe infections. The dosage regimen consisting of administration of doxorubicin on three successive days results in greater incidence and severity of mucositis. Ulceration and necrosis of the colon, especially the cecum, may occur leading to bleeding or severe infections which can be fatal. This reaction has been reported in patients with acute non-lymphocytic leukemia treated with a 3-day course of doxorubicin combined with cytarabine. Anorexia and diarrhea have been occasionally reported.

Vascular - Phlebosclerosis has been reported especially when small veins are used or a single vein is used for repeated administration. Facial flushing may occur if the injection is given too rapidly.

Local - Severe cellulitis, vesication and tissue necrosis will occur if extravasation of doxorubicin occurs during administration. Erythematous streaking along the vein proximal to the site of injection had been reported (see DOSAGE AND ADMINISTRATION).

Hematologic - The occurrence of secondary acute myeloid leukemia with or without a preleukemic phase has been reported in patients concurrently treated with doxorubicin in association with DNA-damaging antineoplastic agents. Such cases could have a short (1-3 years) latency period. An analysis of 1474 breast cancer patients who received adjuvant doxorubicin treatment in clinical trials, showed a 10-year estimated risk of developing treatment-related leukemia at 2.5% (95% confidence interval [CI], 1.0% to 5.1%) for the 810 patients receiving radiotherapy plus chemotherapy and 0.5% (95% CI, 0.1% to 2.4%) for the 664 patients receiving chemotherapy alone. The overall risk was 1.5 % (95% CI, 0.7%-2.9%) at 10 years for the entire patient population. Pediatric patients are also at risk of developing secondary acute myeloid leukemia.

Hypersensitivity - Fever, chills and urticaria have been reported occasionally. Anaphylaxis may occur. A case of apparent cross sensitivity to lincomycin has been reported.

Other - Conjunctivitis and lacrimation occur rarely.

Literature contains the following drug interactions with doxorubicin in humans: cyclosporine (Sandimmune) may induce coma and/or seizures, phenobarbital increases the elimination of doxorubicin, phenytoin levels may be decreased by doxorubicin, streptozocin (Zanosar) may inhibit the hepatic metabolism, and administration of live vaccines to immunosuppressed patients, including those undergoing cytotoxic chemotherapy, may be hazardous.

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.

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