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General: Epirubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy.
Diagnostic and treatment facilities should be readily available management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of epirubicin.
Epirubicin is not active when given orally and should not be injected intramuscularly or intrathecally.
Careful baseline monitoring of various laboratory parameters and cardiac function should precede initial treatment with epirubicin.
Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with epirubicin.
While treatment with high doses of epirubicin (e.g., ≥90 mg/m2 every 3 to 4 weeks) causes adverse events generally similar to those seen at standard doses (<90 mg/m2 every 3 to 4 weeks), the severity of the neutropenia and stomatitis/mucosal inflammation may be increased. Treatment with high doses of epirubicin does require special attention for possible clinical complications due to profound myelosuppression.
Cardiac Function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.
Early (i.e. Acute) Events: Early cardiotoxicity of epirubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a consideration for the discontinuation of epirubicin treatment.
Late (i.e. Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin or within 2 to 3 months after treatment termination, but later events (several months to years after completion of treatment) have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution.
Above this level the risk of irreversible congestive heart failure increases greatly.
Heart failure may appear several weeks after discontinuing therapy with epirubicin and may be unresponsive to specific medical treatment. In establishing the maximal cumulative dose of epirubicin, consideration should be given to any concomitant therapy with potentially cardiotoxic drugs.
Cardiac function should be assessed before patients undergo treatment with epirubicin and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m2 epirubicin should be exceeded only with extreme caution.
An ECG is recommended before and after each treatment cycle. Alterations in the ECG tracing, such as flattening or inversion of the Twave, depression of the S-T segment, or the onset of arrhythmias, generally transient and reversible, need not necessarily be taken as indications to discontinue treatment. With cumulative doses <900 mg/m2, there is evidence that cardiac toxicity rarely occurs. In case of cardiac insufficiency, treatment with epirubicin should be discontinued.
Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving epirubicin treatment is highly important and it is advisable to assess cardiac function by non-invasive techniques. Electrocardiogram (ECG) changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors, particularly prior anthracycline or anthracenedione use. However cardiotoxicity with epirubicin may occur at lower cumulative doses whether or not risk factors are present. It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g. trastuzumab) with an increased risk in the elderly.
Trastuzumab and anthracyclines such as epirubicin should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of traztuzumab and anthracyclines.
Because the reported half-life of trastuzumab is approximately 28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as epirubicin after stopping trastuzumab may possibly be at increased risk of cardiotoxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin are used, the patient's cardiac function should be monitored carefully.
If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin therapy, it should be treated with the standard medications for this purpose.
Haematologic Toxicity: As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematological profiles should be assessed before and during each cycle of therapy with epirubicin. Red blood cell, differential white blood cell (WBC), neutrophil and platelet counts should be carefully monitored both before and during each cycle of therapy. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include pyrexia, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.
Secondary Leukaemia: Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemia's can have a 1- to 3-year latency period.
Gastrointestinal: Epirubicin is emetigenic. Mucosal inflammation/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.
Liver Function: The major route of elimination of epirubicin is the hepatobiliary system. Before starting therapy with epirubicin, and during treatment, liver function should be evaluated (SGOT, SGT, alkaline phosphatase, bilirubin, AST). Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients. Patients with severe hepatic impairment should not receive epirubicin.
Renal Function: Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/mL.
Epirubicin may impart a red colour to the urine for one or two days after administration.
Effects at Site of Injection: Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site.
Extravasation: Extravasation of epirubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein. Should signs or symptoms of extravasation occur during intravenous administration of epirubicin, the drug infusion should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool using hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.
Other: As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin.
Tumour Lysis Syndrome: Epirubicin may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumour-lysis syndrome.
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections (see section 4.5). Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Reproductive system: Epirubicin can cause genotoxicity. Men and women treated with epirubicin should adopt appropriate contraceptives. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate.
Additional warnings and precautions for other routes of administration: Intravesical route: Administration of epirubicin may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumours).
Intra-arterial route: Intra-arterial administration of epirubicin (transcatheter arterial embolization for the localized or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of epirubicin) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.
