General precautions: Doxorubicin should only be administered under the supervision of a physician experienced in the use of chemotherapy. It is recommended that the patient be hospitalised during at least the first phase of treatment since close observation and laboratory monitoring is necessary. Prior to treatment with doxorubicin, cardiac and hepatic function and haematology baseline tests should be carried out.
Nausea, vomiting and mucositis are often extremely severe and should be treated appropriately. Doxorubicin should not be administered intramuscularly or subcutaneously.
Extravasation: Extravasation results in a severe and progressive tissue necrosis. Extravasation is signified by pain and/or a burning sensation at the site of intravenous administration of doxorubicin. If extravasation occurs, the injection should be terminated immediately and restarted in another vein. Ice packs should be applied to the site of extravasation. Flooding with normal saline, local infiltration with corticosteroids, or sodium hydrogen-carbonate solution (8.4%), and application of dimethylsulfoxide have been reported with varying success. Local application of hydrocortisone cream 1% may be beneficial. The advice of the plastic surgery consultant should be asked for, and wide excision of the involved area should be considered.
Cardiotoxicity: There is an established risk of development of anthracycline induced cumulative dose dependent cardiomyopathy, therefore cumulative dose of 450-550mg/m2 should not be exceeded. At doses above this the risk of development of cardiac failure increases considerably. Reduction of the cumulative dose is the most important means of avoiding doxorubicin cardiotoxicity. The cardiotoxicity of doxorubicin may manifest as tachycardia, ECG changes or cardiac failure which may occur suddenly up to several months/years after discontinuation of treatment without preceding ECG changes. The risk of developing heart failure in cancer patients treated with doxorubicin persists throughout life. Cardiac failure due to doxorubicin may be unresponsive to conventional treatment.
The risk of cardiotoxicity increases in patients previously treated with mediastinal or pericardial irradiation, in patients treated with other or previous anthracyclines and/or anthracenediones, in patients with a history of cardiac disease, in elderly patients (age ≥ 70 years) as well as in children below 15 years. Cardiotoxicity may occur at doses lower than the recommended cumulative limit. The total cumulative dose of doxorubicin to an individual patient should therefore take into account any previous or concomitant treatment with other potentially cardiotoxic drugs or therapy such as high dose IV cyclophosphamide, mitomycin C or dacarbazine, other anthracyclines such as daunorubicin, or mediastinal or pericardial irradiation.
Acute severe arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.
ECG changes may occur including a reduction in the voltage of the QRS wave, and a prolongation of the systolic time interval, and the ejection fraction may be reduced.
Extreme care should be taken in patients with existing heart disease, such as a recent myocardial infarction, heart failure, cardiomyopathy, pericarditis or dysrhythmias, or in patients who have received other cardiotoxic agents such as cyclophosphamide (see Interactions).
Monitoring of the cardiac function: Cardiac function should be assessed prior to the start of treatment and should be carefully monitored throughout treatment and assessed after the doxorubicin therapy. An ECG before and after each treatment is recommended. Changes in ECG such as depression or negative T-wave, decrease in the ST-segment or arrhythmias are usually signs of an acute but transient (reversible) toxic effect and are not considered indications for suspension of doxorubicin therapy. However a persistent reduction in the amplitude of QRS-wave and a prolongation of the systolic interval are considered more indicative of anthracycline induced cardiotoxicity.
When the voltage of the QRS wave decreases by 30% or at a fractional shortening of 5% it is recommended that treatment be stopped.
The optimum method of prediction of cardiomyopathy is detection of a reduction of the left ventricular ejection fraction (LVEF), determined by ultrasound or a heart scintigraphy. LVEF investigation should be performed prior to treatment and repeated after each cumulative dose of 100mg/m2 and at any clinical signs of cardiac failure. As a rule an absolute decrease of > 10% or a decrease below 50% in patients with normal initial LVEF-values is a sign of impairment of cardiac function. Continued treatment with doxorubicin in such patients must be carefully evaluated.
Myelosuppression: The high incidence of bone marrow depression requires careful haematological monitoring. There is a significant risk of neutropenia, thrombocytopenia and anaemia occurring less frequently. The nadir is reached between 10-14 days after administration. Blood values usually return to normal within 21 days after administration. Doxorubicin therapy should not be started or continued when polynuclear granulocyte counts are below 2000/mm3. In the treatment of acute leukaemias this limit may be set lower, depending on the circumstances. Severe myelosuppression may result in haemorrhage or superinfection and is an indication for the reduction or suspension of doxorubicin treatment.
Because of the potential for immunosuppression, measures should be taken to prevent secondary infection.
Hyperuricaemia: As with other cancer chemotherapeutic agents, there is a risk of hyperuricaemia resulting in acute gout or urate nephropathy following tumor lysis with regimens containing doxorubicin.
Hepatic impairment: Since doxorubicin is excreted mainly via the liver, reduced hepatic function or failure may delay elimination and increase overall toxicity. Therefore it is recommended that hepatic function tests (SGOT, SGPT, alkaline phosphatase and bilirubin) be carried out prior to and during the treatment.
The blood uric acid level should be monitored; sufficient fluid intake should be ascertained (with a daily minimum of 3 l/m2). If necessary, a xanthine-oxidase inhibitor (allopurinol) may be administered.
Men as well as women should take effective contraceptive measures during and for at least three months after doxorubicin therapy.
Discoloration of urine: Patients should be warned that doxorubicin may impart a red colour to the urine, particularly in the first specimen following administration, but that this is no cause for alarm.
Intravesical route: The intravesical route of administration should not be attempted in patients with, invasive tumours that have penetrated the bladder wall, urinary tract infections, inflammatory conditions of the bladder.
Effects on ability to drive and use machines: Patients who suffer from any effects that may impair driving performance (drowsiness, nausea or vomiting) should avoid driving and operating machinery.