EPIRUBICIN HYDROCHLORIDE

Posology Epirubicin hydrochloride is not active when given orally and should not be injected intramuscularly or intrathecally. 9% sodium chloride or water for injections to get the final concentration of 2 mg/ml. The vial contents will be under a negative pressure.

To minimize aerosol formation during reconstitution, particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided. After gentle agitation the reconstituted solution will be transparent and red in appearance.

Intravenous administration:

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 hydrochloride 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.

V. over 3-5 minutes and, depending upon the patients' haematological status the dose should be repeated at 21-day intervals. High doses 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.

- Non-small cell lung cancer (squamous, large cell, and adenocarcinoma previously untreated): 135 mg/m2 day 1 or 45 mg/m2 days 1, 2, 3, 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 schedules) are recommended for patients whose bone marrow function has already 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 in 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 hydrochloride excreted by this route.

Intravesical administration Epirubicin hydrochloride 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 hydrochloride has also been successfully used intravesically 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 at the end of the instillation time.

The following undesirable effects have been observed and reported during treatment with Epirubicin hydrochloride with the following frequencies: 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), not known (frequency cannot be estimated form the available data).

System Organ Class Frequency Undesirable effects Very common Infection, conjunctivitisInfections and infestations Uncommon Sepsis*, pneumonia* Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Uncommon Acute lymphocytic leukaemia, acute myeloid leukaemia Blood and lymphatic system disorders Very common Leukopenia, neutropenia, anaemia, febrile neutropenia, thrombocytopenia Immune system disorders Rare Anaphylactic reactions* Common Decreased appetite, dehydration* Metabolism and nutrition disorders Rare Hyperuricemia* Eye disorders Very common Keratitis Cardiac disorders Common Ventricular tachycardia, atrioventricular block, bundle-branch block, bradycardia, cardiac failure congestive Very common Hot flush, phlebitis* Common Haemorrhage*, flushing* Vascular disorders Uncommon Embolism, embolism arterial*, thrombophlebitis* Not known Shock* Respiratory, thoracic and mediastinal disorders Uncommon Pulmonary embolism* Very common Mucosal inflammation, stomatitis, vomiting, diarrhoea, nausea Common Gastrointestinal pain*, gastrointestinal erosion*, gastrointestinal ulcer* Uncommon G haemorrhage* Gastrointestinal disorders Not known Abdominal discomfort, pigmentation buccal* Very common Alopecia, skin toxicity Common Rash/pruritus, nail pigmentation*, skin disorder, skin hyperpigmentation* Uncommon Urticaria*, erythema* Skin and subcutaneous tissue disorders Not known Photosensitivity reaction* Renal and urinary disorders Very common Chromaturia*† Reproductive system and breast disorders Very common Amenorrhoea Very common Malaise, pyrexia* Common Chills* General disorders and administration site conditions Uncommon Asthenia Very common Transaminases abnormalInvestigations Common Ejection fraction decreased Very common Chemical cystitis*§ Injury, poisoning and procedural complications Not known Recall phenomenon*Δ * ADR identified post-marketing.

† Red colouration 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 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.

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 hydrochloride does require special attention for possible clinical complications due to profound myelosuppression.

e. e. delayed) events. 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 n for the discontinuation of Epirubicin hydrochloride treatment. 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, 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 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. 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 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 o 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 this is not possible, 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.

6). It is probable that the toxicity of Epirubicin hydrochloride and other anthracyclines or anthracenediones is additive. Haematological 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 hydrochloride, including differential white blood cell (WBC) counts. A dose- dependent, reversible leukopenia and/or granulocytopenia […]

1, 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