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Doxorubicin is a toxic drug with a low therapeutic index. Patients should be hospitalized during the initial phase of doxorubicin treatment. Determinations of hepatic, hematopoietic [e.g., blood counts, serum levels of total bilirubin, aspartate aminotransferase (AST) and creatinine], and cardiac function should be performed prior to and at regular intervals during doxorubicin therapy. Before doxorubicin treatment, patients should recover from acute toxicities from prior cytotoxic treatment (e.g., stomatitis, neutropenia, thrombocytopenia, and generalized infections). Patients should be carefully monitored during treatment for possible complications due to myelosuppression and cardiotoxicity. Doxorubicin may potentiate toxicities of other antineoplastic drugs.
Cardiovascular: Cardiotoxicity is a known risk of anthracycline treatment. It may be manifested by early (acute) or late (delayed) effects.
Early (Acute) Events: Early cardiotoxicity of Doxorubicin consists mainly of ECG abnormalities such as non-specific ST-T wave changes, prolongation of the QT interval, and arrhythmias (e.g, sinus tachycardia, ventricular, supraventricular, and junctional tachycardia). Conduction disturbances (including atrioventricular and bundle-branch block) have been reported rarely and are usually associated with late-onset anthracycline-induced cardiotoxicity. Although acute cardiotoxicity is transient, rarely, pericarditis-myocarditis syndrome (e.g., pericardial effusion and/or decreased myocardial contractility) and possible cardiac failure may occur. These effects do not usually predict development of delayed cardiotoxicity and are generally not a consideration for doxorubicin treatment discontinuation.
Late (Delayed) Events: Delayed cardiotoxicity usually develops late in the course of Doxorubicin therapy or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, were also seen in clinical studies. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of CHF such as dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
Cardiac function should be assessed before patients undergo treatment with doxorubicin and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. Regular monitoring of LVEF through multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO) is recommended to reduce the risk of cardiac impairment.
Chronic cardiotoxicity, such as heart failure, may occur as total cumulative dosage of doxorubicin hydrochloride approaches or exceeds 550 mg/m2. Cardiotoxicity may occur at a lower total cumulative dosage (e.g., 400 mg/m2) in patients who have received radiotherapy to the mediastinal/pericardial region, concomitant therapy with other potentially cardiotoxic agents (e.g., cyclophosphamide), doxorubicin exposure at an early age, and advanced age. Time of onset of chronic cardiotoxicity may vary but usually is manifested within 1 year of anthracycline therapy. Thereafter, the risk of developing CHF increases rapidly, and it is recommended not to exceed a maximum cumulative dose of 550 mg/m2.
Children, adolescents and females are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Periodic follow-up of cardiac functions is recommended for monitoring.
Hematologic Toxicity: Marked myelosuppression is evident with most cytotoxic drugs, including doxorubicin. Leukocyte, erythrocyte, and platelet counts should be performed prior to and at frequent intervals during therapy. Dose-dependent, reversible leukopenia and/or granulocytopenia are the predominant manifestations of hematologic toxicity and are the most common acute dose-limiting toxicity of doxorubicin, the severity of which depends on the dose and the bone marrow's regenerative capacity. Leukocyte counts as low as 1000/mm3 should be anticipated during therapy with appropriate doses of doxorubicin, although severe myelosuppression may occur. Thrombocytopenia and anemia may also occur. Maximum leukopenia, thrombocytopenia, and anemia generally occur during the second week (nadir 10 to 14 days) following administration of the drug and generally return to normal by day 21. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death. Once manifestations of hematologic toxicities occur, dose reduction or suspension or delay of doxorubicin therapy may be required.
Secondary Leukemia: (see Warnings).
Effects at Site of Injection: Injection into a small vessel or from repeated injections into the same vein may result in phlebosclerosis. Proper dosage and administration procedures should be followed to reduce the risk of phlebitis/thrombophlebitis at the injection site (see Dosage & Administration).
Extravasation: Extravasation of doxorubicin during IV injection may give rise to severe tissue lesions (vesication, severe cellulitis) and necrosis. Once extravasation signs or symptoms occur, drug injection or infusion should be terminated immediately (see Dosage & Administration).
Hepatic Impairment: Hepatic function should be evaluated prior to doxorubicin therapy since its toxicity may be increased by hepatic impairment due to its extensive metabolism by the liver. Evaluation of hepatic function can be done using laboratory tests such as AST, alanine transaminase (ALT), alkaline phosphatase, and bilirubin (see Dosage & Administration). Patients with severe hepatic impairment should not receive doxorubicin (see Contraindications).
Vaccine Use: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin may result in serious or fatal infections (see Interactions).
Gastrointestinal: Doxorubicin is emetogenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of doxorubicin, particularly when given in conjunction with other emetogenic drugs.
Others: Doxorubicin may potentiate toxicities of other antineoplastic drugs. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis, enhanced hepatotoxicity of 6-mercaptopurine and increased radiation-induced toxicities were reported in studies.
As with other cytotoxic drugs, thrombophlebitis and thromboembolic pneumonia, including pulmonary embolism (in some cases fatal), were observed with Doxorubicin in certain clinical trials.
Advice for Patients: Doxorubicin often imparts a red color to the urine 1 to 2 days after administration, and patients should be advised to expect this effect during therapy.
Patients should be informed of the expected adverse effects of doxorubicin. Patients should also understand associated risks of Doxorubicin treatment such as irreversible myocardial damage and treatment-related leukemia.
Laboratory Tests: Initial treatment with doxorubicin requires observation of the patient and periodic monitoring of complete blood counts, hepatic function tests and LVEF. Abnormalities in hepatic function tests may occur. Like other cytotoxic drugs, doxorubicin may induce "tumor-lysis syndrome" and hyperuricemia in patients with rapidly growing tumors. Blood uric acid levels, potassium, calcium, phosphate, and creatinine should be evaluated after initial treatment. Hydration and urine alkalinization to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.
Dental Work: Patients should not undergo dental work during treatment with doxorubicin.
Carcinogenicity, Mutagenicity and Impairment of Fertility: Doxorubicin has been shown to be mutagenic and carcinogenic in experimental models. Secondary AML or MDS have been reported in patients treated with doxorubicin-containing regimens (see Warnings). However, the extent of increased risk of developing secondary malignancies associated with the use of doxorubicin has not been fully established.
Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubes, and hypospermia. Doxorubicin may potentially induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia were evidenced in men treated with doxorubicin, mainly in combination therapies. This effect may be permanent. However, sperm counts have been reported to return to normal levels in some instances. Men undergoing doxorubicin treatment should use effective contraceptive methods.
In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhea. Ovulation and menstruation may return after termination of therapy, although premature menopause can occur. Recovery of menses is related to age at treatment.
Use in Children: Children are at a greater risk for developing secondary leukemia (including AML) and delayed cardiotoxicity. Doxorubicin-induced cardiomyopathy impairs myocardial growth as children mature and CHF may possibly develop during early adulthood. Periodic long-term cardiac function monitoring is recommended to reduce the risk of delayed cardiotoxicity. Doxorubicin, as a part of intensive chemotherapy in children, may contribute to prepubertal growth failure. Pediatric patients treated with Doxorubicin or other topoisomerase II inhibitors are at a risk for developing secondary leukemia, including acute myelogenous leukemia, and other neoplasms.
Use in Elderly: No overall differences in safety and effectiveness were observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The decision to use doxorubicin in the treatment of older patients should be based upon a consideration of overall performance status and concurrent illnesses, in addition to the age of the individual patient.
