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General: Epirubicin hydrochloride should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy.
Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with epirubicin hydrochloride.
While treatment with high doses of epirubicin hydrochloride (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/mucositis may be increased. Treatment with high doses of epirubicin hydrochloride 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 hydrochloride 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 hydrochloride treatment.
Late (i.e. delayed) events: Delayed cardiotoxicity usually develops late in the course of therapy with epirubicin hydrochloride 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 medicinal product.
The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin hydrochloride in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution (see Pharmacology: Pharmacodynamics under Actions).
Cardiac function should be assessed before patients undergo treatment with epirubicin hydrochloride and must be monitored throughout therapy to minimise 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 hydrochloride 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 hydrochloride should be exceeded only with extreme caution.
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 medicinal products with the ability to suppress cardiac contractility or cardiotoxic medicinal products (e.g. trastuzumab) (see Interactions) with an increased risk in the elderly.
Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzumab therapy alone or in combination with anthracyclines such as epirubicin hydrochloride. This may be moderate to severe and has been associated with death. Trastuzumab and anthracyclines such as epirubicin hydrochloride 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 trastuzumab and anthracyclines.
Because the 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 hydrochloride after stopping trastuzumab may possibly be at an increased risk of cardio toxicity. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin hydrochloride are used, the patient's cardiac function should be monitored carefully.
If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin hydrochloride therapy, it should be treated with the standard medications for this purpose.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present.
It is probable that the toxicity of epirubicin hydrochloride and other anthracyclines or anthracenediones is additive.
Haematologic toxicity: As with other cytotoxic agents, epirubicin hydrochloride may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin hydrochloride haematologic toxicity and is the most common acute dose-limiting toxicity of this medicinal product. 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 fever, 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 hydrochloride. Secondary leukaemia is more common when such medicinal products are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic medicinal products, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period (see Pharmacology: Pharmacodynamics under Actions).
Gastrointestinal: Epirubicin hydrochloride is emetogenic. Mucositis/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 hydrochloride is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin hydrochloride. Patients with elevated bilirubin or AST may experience slower clearance of medicinal product with an increase in overall toxicity. Lower doses are recommended in these patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Patients with severe hepatic impairment should not receive epirubicin hydrochloride (see Contraindications).
Renal function: Serum creatinine should be assessed before and during therapy. Dose adjustment is necessary in patients with serum creatinine >5 mg/dl (see Dosage & 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 (see Dosage & Administration).
Extravasation: Extravasation of epirubicin hydrochloride during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of epirubicin hydrochloride, 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 (please 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 hydrochloride.
Tumour-lysis syndrome: Epirubicin hydrochloride 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 minimise 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 hydrochloride, may result in serious or fatal infections (see Interactions).
Vaccination with a live vaccine should be avoided in patients receiving epirubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Reproductive system: Epirubicin hydrochloride can cause genotoxicity. Men and women treated with epirubicin hydrochloride should adopt appropriate contraceptives. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.
Additional warnings and precautions for other routes of administration: lntravesical route: Administration of epirubicin hydrochloride 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 catheterisation problems (e.g., urethral obstruction due to massive intravesical tumours).
Intra-arterial route: Intra-arterial administration of epirubicin hydrochloride (transcatheter arterial embolisation for the localised 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 hydrochloride) localised or regional events which include gastroduodenal ulcers (probably due to reflux of the medicinal products 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.
The safe use of product in latex-sensitive individuals has not been studied.
Effects on ability to drive and use machines: There have been no reports of particular adverse events relating to effects on ability to drive and to use machines.
