EPIRUBICIN HYDROCHLORIDE

Epirubicin is for intravenous or intravesical use only. Epirubicin is not active when given orally and should not be injected intramuscularly or intrathecally. Intravenous administration (IV) It is advisable to give the drug via the tubing of a freely-running IV saline infusion after checking that the needle is well placed in the vein.

This method minimises the risk of drug extravasation and makes sure that the vein is flushed with saline after the administration of the drug. Extravasation of Epirubicin from the vein during injection may give rise to severe tissue lesions, even necrosis.

Venous sclerosis may result from injection into small vessels or repeated injections into the same vein. Conventional dose When epirubicin hydrochloride is used as a single agent, the recommended dosage in adults is 60-90 mg/m2 body area; the medicine should be injected intravenously over 3-5 minutes and, depending on the patient’s haematomedullary status, the dose should be repeated at 21-day intervals.

High dose Epirubicin hydrochloride as a single agent for the treatment of lung cancer at high doses should be administered according to the following regimens: Lung cancer - Small cell lung cancer (previously untreated): 120 mg/m2 day 1, every 3 weeks.

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.

V. bolus over 3-5 minutes or as an infusion up to 30 minutes. 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. When the drug is used in combination with other antitumour agents, the doses need to be adequately reduced. Since the major route of elimination of Epirubicin hydrochloride is the hepatobiliary system, the dosage should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity.

4 - 3 mg/100 ml) requires a 50% reduction of dose, while severe impairment (bilirubin > 3mg/100 ml) necessitates a dose reduction of 75%. Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route.

Intravesical administration Epirubicin can be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate.

Epirubicin has also been successfully used intravesical as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences. While many regimens have been used, the following may be helpful as a guide: for therapy, 8 x weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg/50ml is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg/50 ml. For prophylaxis, 4 x weekly administrations of 50 mg/50 ml followed by 11 x monthly instillations at the same dosage, is the schedule most commonly used.

The solution should be retained intravesically for 1 hour. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid 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.

The following undesirable effects have been observed and reported during treatment with epirubicin with the following frequencies: 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 < 1/10,000 Frequency not known (cannot be estimated from the available data) Infections and infestations Infection, Conjunctivitis Sepsis,* Pneumonia* Neoplasms benign, malignant and unspecified (including cysts and polyps) Acute myeloid leukaemia, Acute lymphocytic leukaemia Blood and lymphatic system disorders Anaemia, Leucopoenia, Neutropenia, Thrombocytop enia Febrile neutropenia Immune system disorders Anaphylactic reaction* Metabolism and nutrition disorders Decreased appetite Dehydration* Hyperuricaemi a* Eye disorders Keratitis Cardiac disorders Ventricular tachycardia, Atrioventricula r block, Bundle branch block, Bradycardia, Cardiac failure congestive Vascular disorders Hot flush, Phlebitis* Haemorrhage,* Flushing* Embolism, Embolism arterial,* Thrombophlebi tis* Shock* Respiratory, thoracic and mediastinal disorders Pulmonary embolism* Gastrointestina l disorders Nausea, Vomiting, Stomatitis, Mucosal inflammation, Diarrhoea Gastrointestina l pain,* Gastrointestina l erosion,* Gastrointestina l ulcer* Gastrointestina l haemorrhage* Abdominal discomfort, Pigmentation buccal* Skin and subcutaneous tissue disorders Alopecia, Skin toxicity Rash/Pruritus, Nail pigmentation,* Skin disorder, Skin hyperpigmenta tion* Urticaria* Erythema* Photosensitivit y reaction* Renal and urinary disorders Chromaturia*† Reproductive system and breast disorders Amenorrhoea General disorders and administration site conditions Malaise, Pyrexia* Chills* Asthenia Investigations Transaminases abnormal Ejection fraction decreased Injury, poisoning and procedural complications Chemical cystitis*§ Recall phenomenon*Δ * ADR identified post-marketing.

† Red coloration of urine for 1 to 2 days after administration. § Following intravesical administration. Δ Hypersensitivity to irradiated skin (radiation-recall reaction). 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, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

, ≥ 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 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 drug. 1). 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 hydrochloride should be exceeded only with extreme caution. g. 5) with an increased risk in the elderly.

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzamab 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.

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 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. 5). If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin 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 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. Hematologic Toxicity - As with other cytotoxic agents, epirubicin may produce myelosuppression.

Hematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopoenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin hematologic toxicity and is the most common acute dose-limiting […]

1 or other anthracyclines or anthracenediones. 4) • patients with acute systemic infections • unstable angina pectoris • myocardiopathy Intravesical use: • urinary tract infections • inflammation of the bladder • haematuria • invasive tumours penetrating the bladder • catheterisation problems