EPIRUBICIN HYDROCHLORIDE

4). Conventional dose When epirubicin hydrochloride is used as a single agent, the recommended dose in adults is 60 – 90 mg/m² body surface area. Epirubicin hydrochloride should be injected intravenously over 3 – 5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient’s haematological status and bone marrow function.

If signs of toxicity, including severe neutropenia/neutropenic fever and thrombocytopenia occur (which could persist at day 21), dose modification or postponement of the subsequent dose may be required. High dose Epirubicin as a single agent for the high dose treatment of lung cancer should be administered according to the following regimens: • Small cell lung cancer (previously untreated): 120 mg/m² epirubicin hydrochloride on day 1, every 3 weeks.

For high-dose treatment, epirubicin may be given as an intravenous bolus over 3 – 5 minutes or as an infusion of up to 30 minutes duration. Breast cancer In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin hydrochloride ranging from 100 mg/m² (as a single dose on day 1) to 120 mg/m² (in two divided doses on days 1 and 8) every 3 – 4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen, are recommended.

Lower doses (60 – 75 mg/m² for conventional treatment and 105 – 120 mg/m² for high-dose treatment) are recommended for patients whose bone marrow function has been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone marrow infiltration.

The total dose per cycle may be divided over 2 – 3 successive days. The following doses of epirubicin hydrochloride are commonly used in monotherapy and combination chemotherapy for various other tumours, as shown: Epirubicin hydrochloride dose (mg/m²)a Cancer indication Monotherapy Combination therapy Advanced ovarian cancer 60 – 90 50 – 100 Gastric cancer 60 – 90 50 SCLC 120 120 Bladder cancer Intravesical administration of 50 mg/50 ml or 80 mg/50 ml (carcinoma-in-situ) Prophylaxis: 50 mg/50 ml weekly for 4 weeks then monthly for 11 months a Doses generally given day 1 or day 1, 2 and 3 at 21-day intervals Combination therapy If epirubicin hydrochloride is used in combination with other cytotoxic products, the dose should be reduced accordingly.

Commonly used doses are shown in the table above. Impaired liver function The major route of elimination of epirubicin is the hepatobiliary system. 4 – 3 mg/100 ml 50 % > 3 mg/100 ml > 4 times upper normal limit 75 % Impaired renal function Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route.

However, dose adjustment may be necessary in patients with serum creatinine > 5 mg/dl. Paediatric population The safety and efficacy of epirubicin in children have not yet been established. Method of administration Epirubicin is for intravenous or intravesical use only.

9 %) infusion after checking that the needle is properly placed in the vein. 4). In case of extravasation, administration should be stopped immediately. Intravesical administration Epirubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ.

It should not be given intravesically for the treatment of invasive tumours that have penetrated the bladder wall. 3). Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

9 %) or water for injection).

If local toxicity is observed:

A dose reduction to 30 mg/50 ml is advised.

Carcinoma-in-situ:

Up to 80 mg/50 ml (depending on individual tolerability of the patient). For prophylaxis: 4 weekly administrations of 50 mg/50 ml followed by 11 monthly instillations at the same dose. 9 % sterile saline 30 mg 15 ml 35 ml 50 ml 50 mg 25 ml 25 ml 50 ml 80 mg 40 ml 10 ml 50 ml The solution should be retained intravesically for 1 – 2 hours.

To avoid undue dilution with urine, the patient should be instructed not to drink any fluids in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.

Tabulated list of adverse reactions The following undesirable effects have been observed and reported during treatment with epirubicin with the following frequencies: More than 10 % of treated patients can expect to develop undesirable effects.

The most common undesirable effects are myelosuppression, gastrointestinal side effects, anorexia, alopecia, infection. System Organ Class Very common ≥ 1/10 Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1 000 to < 1/100 Rare ≥ 1/10 000 to < 1/1 000 Very Rare < 1/10 0 00 Not known (cannot be estimated from the available data) Infections and infestations Infection, conjunctivitis Bacterial cystitis§ Sepsis*, pneumonia* Septic shock, cellulitis Neoplasms benign, malignant and unspecified (incl.

4) Nervous system disorders Dizziness Headache Eye disorders Keratitis Cardiac disorders Ventricul ar tachycardi a, AV block, bundle- branch block, bradycard ia, (see section 4. g. 4) Hypersensiti vity to irradiated skin (radiation recall reaction) §Following intravesical administration *ADR identified post-marketing Description of selected adverse reactions Neoplasms benign, malignant and unspecified (including cysts and polyps) Secondary acute myeloid leukaemia with or without a pre-leukaemic phase, in patients treated with epirubicin in combination with DNA-damaging antineoplastic agents.

These leukaemias have a short (1 – 3 years) latency. Blood and lymphatic system disorders High doses of epirubicin have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse events which are not different from those seen at conventional doses with the exception of reversible severe neutropenia (< 500 neutrophils/mm³ for < 7 days) which occurred in the majority of patients.

Only few patients required hospitalisation and supportive therapy for severe infectious complications at high doses. Skin and subcutaneous tissue disorders Alopecia, normally reversible, appears in 60 – 90 % of treated cases; it is accompanied by lack of beard growth in males.

General disorders and administration site conditions Mucositis may appear 5 – 10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, ulceration and bleeding, mainly along the side of the tongue and the sublingual mucosa.

Local pain and tissue necrosis (following accidental paravenous injection) may occur. Intravesical administration As only a small amount of the active ingredient is reabsorbed after intravesical instillation, severe systemic adverse reactions as well as allergic reactions are rare.

Commonly reported are local reactions like burning sensation and frequent voiding (pollakisuria). 4). These adverse reactions are mostly reversible. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

General Epirubicin 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, mucositis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

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.

e. e. delayed) events. 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 transient, reversible and not a consideration for the discontinuation of epirubicin treatment.

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 medicinal product. 1). Monitoring of cardiac function Cardiac function should be assessed before patients undergo treatment with epirubicin 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 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. Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP) and a reduction of the ejection fraction (LVET).

Electrocardiogram (ECG) changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. g. 5) with an increased risk in the elderly.

Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.

It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive. 6). Cardiotoxicity in combination with trastuzumab 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.

This may be moderate to severe and has been associated with death. 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 trastuzumab and anthracyclines. The reported half-life of trastuzumab is variable.

The substance may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.

If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin therapy, it […]

1 or to other anthracyclines or anthracenediones. 6). 4) • patients with acute systemic infections • unstable angina pectoris • myocardiopathy • acute inflammatory heart diseases • severe inflammation of the mucous membranes in the mouth and/or gastrointestinal tract Intravesical use • urinary tract infections • invasive tumours penetrating the bladder • catheterisation problems • inflammation of the bladder • haematuria • contracted bladder • large volume of residual urine