EPIRUBICIN HYDROCHLORIDE

The safety and efficacy of epirubicin in children has not been established 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 maybe required.

Conventional dose Dosage regimen for conventional doses When epirubicin is used as a single agent, the recommended dose for in adults is 60- 90 mg/m2 of body surface area to be administered via intravenous injection over 5 to10 minutes at 21-day intervals, depending bone marrow conditions.

High dose Dosage regimen for high doses Lung cancer Epirubicin as a single agent in the treatment of lung cancer with high doses must be used according to the following scheme: - Small cell lung cancer (SCLC) in non-pretreated patients: 120 mg/m2 on day 1, every three weeks.

The drug must be administered as an intravenous bolus over 5-10 minutes or as an intravenous infusion over a maximum of 30 minutes. Breast Cancer In the adjuvant treatment of initial breast cancer with positive lymph nodes, the recommended doses vary from 100 mg/m2 to 120 mg/m2 administered every 3-4 weeks.

Lower doses (60-75 mg/m2 or 105-120 mg/m2 in high dosage regimens) are recommended for patients with reduced bone marrow reserves due to previous chemo- and/or radiotherapy, treatments, elderly age, or with bone marrow neoplastic. The total dose per cycle can be divided over 2-3 consecutive days.

The following doses of epirubicin are commonly used in monotherapy and combination chemotherapy for various tumours, as shown: Epirubicin Dose (mg/m2 )a Cancer Indication Monotherapy Combination Therapy Ovarian cancer 60–90 50–100b Gastric cancer 60–90 50 Small cell lung cancer (SCLC) 120 120b Bladder cancer 50 mg/50 ml or 80 mg/50 ml (carcinoma in situ) Prophylaxis: 50 mg/50 ml weekly for 4 weeks then monthly for 11months Breast cancer 100-120c a Doses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals.

b If used in combination with other anticancer drugs, the doses should be appropriately reduced. c Lower doses (60-75 mg/m2 or 105-120 mg/m2 in high dosage regimens) are recommended for patients with reduced bone marrow function. Bladder Cancer 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 intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.

In the treatment of non-invasive transitional cell papillary carcinoma intravesical instillations of 50 mg (in 25-50 ml saline solution or distilled sterile water) are recommended once a week for eight weeks; in case of local toxicity (chemical cystitis), the unit dose must be reduced to 30 mg.

In the treatment of in situ carcinoma, the dose may be increased to 80 mg depending on individual tolerability. In the prophylaxis of relapses after transurethral resection of superficial tumours, intravesical instillations of 50 mg once a week for four weeks are recommended, followed by monthly instillations at the same dose for eleven months.

4-3 mg/100 ml and bromosulfophthalein (BSF) retention is 9-15%, half the normal drug dose is recommended. 4 – 3 mg/100 ml 50% > 3 mg/100 ml > 4 times upper normal limit 75% *AST – aspartate aminotransferase If bilirubin levels and BSF retention are higher still, a quarter of the normal dose is recommended Impaired renal function Moderate impairment of renal function does not seem to require a dose reduction in view of the limited amount of epirubicin excreted by this route.

Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450μmol/l) Method of administration Epirubicin is for intravenous or intravesical use only. Intravenous administration It is advisable to administer epirubicin via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein.

4). In case of extravasation, administration should be stopped immediately. It is advisable to perform intravenous administration over 5-10 minutes. This technique reduces the risk of extravasation of the drug and ensures flushing of the vein at the end of administration.

In case of extravasation of Epirubicin during administration, there is a risk of tissue lesions, including necrosis. Venous sclerosis may occur when the injection is administered into small vessels or is repeated in the same vein. Intravesical administration Epirubicin for instillation via a catheter must be kept in situ for an hour.

The patient should be instructed not to drink any fluid in the 12 hours prior instillation. During instillation, it may be advisable to rotate the patient’s pelvis to ensure broader contact of the solution with the bladder mucosa. 9% sterile saline Total volume for bladder instillation 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 following adverse effects have been observed and reported during treatment with epirubicin with the following frequencies: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Over 10% of patients treated can develop undesirable effects. The most common undesirable effects are myelosuppression, gastrointestinal disorders, anorexia, alopecia and infections System Organ Class Very Common Common Uncomm on Rare Very Rare Not known Infection s and infestatio ns Infection, Conjuncti vitis Sepsis,* pneumoni a* Septic shock, Cellulitis Neoplas ms benign, malignan t and unspecifi ed (includin g cysts and polyps) Acute myeloid leukaemia, Acute lymphocyt ic leukaemia Blood and lymphati c system disorders Myelosup pression (Anaemia, Leukopeni a, Neutropen ia, granulocyt openia, Thromboc ytopenia, Febrile neutropeni a) Immune system disorders Hypersensi tivity§, Anaphylac tic reaction* Metaboli sm and nutrition disorders Decreased appetite Dehydratio n* Hyperurica emia* Nerv ous syste m disorders Burning sensation§ Dizziness Eye disorders Keratitis Cardiac disorders Ventricular tachycardia, Atrioventric ular block, Bundle branch block, Bradycardia , congestive heart failure Cardiotoxi city Vascular disorders Hot flushes, Phlebitis* Bleeding,* Flushing* Embolism, Embolism arterial,* Thrombop hlebitis* Shock* Respirat ory, thoracic and mediasti nal disorders Pulmonar y embolism * Hypoxia** Gastroint estinal disorders Nausea, Vomiting, Stomatitis, Mucosal inflammat ion, Diarrhoea Gastrointest inal pain,* Gastrointest inal erosion,* Oesophagiti s Gastrointest inal ulcer* Gastrointe stinal haemorrha ge* Abdominal discomfort, oral mucosa erosion, Mouth ulceration, Oral pain, Burning sensation of the mucous membranes, Mouth haemorrhage, Pigmentation buccal* Skin and subcutan eous tissue disorders Alopecia, Skin toxicity Rash/Prurit us, Nail pigmentatio n,* Skin disorder, Urticaria* Erythema * Photosensitivit y reaction* Skin hyperpigme ntation* Renal and urinary disorders Chromatur ia*† Pollakiuria§ Reprodu ctive system and breast disorders Amenorrh oea Azoosper mia General disorders and administ ration site conditio ns Malaise, Pyrexia*, Administrat ion site erythema, Chills* Asthenia Phlebosclerosi s, Pain, Soft tissue necrosis Investiga tions Transamin ases abnormal Ejection fraction decreased Injury, poisonin g and procedur al complica tions Chemical cystitis*§ Recall phenomenon* Δ * ADR identified post-marketing.

** induced by myelosuppression † Red colouration of urine for 1 to 2 days after administration. following accidental paravenous injection § Following intravesical administration. Δ Hypersensitivity to irradiated skin (radiation-recall reaction).

^ (dyspnoea, oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusion, gallop rhythm) 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 must be administered under the supervision of doctors who are experts in the use of cytotoxic therapies. Before starting treatment with epirubicin hydrochloride, patients must recover from the acute toxicity of the previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia, and generalised infections).

, ≥ 90 mg/m2 every 3 or 4 weeks) causes undesirable effects that are generally similar to those observed with standard doses (< 90 mg/m2 every 3 or 4 weeks), neutropenia and stomatitis/mucositis may be more severe. Treatment with high doses of epirubicin hydrochloride requires particular care because of the possible complications due to severe myelosuppression.

Cardiac Function - Cardiotoxicity is a risk of treatment with anthracyclines, which can manifest with acute or delayed events. Acute toxicity. Early cardiotoxicity of epirubicin hydrochloride consists mainly of sinus tachycardia and/or 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.

Delayed toxicity. 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 or 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 must be evaluated prior to starting treatment with epirubicin hydrochloride and cardiac monitoring of patients receiving epirubicin treatment is highly important to minimise the risk of serious cardiac damage.

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.

The risk of serious cardiac impairment may be decreased through regular monitoring of left ventricular ejection fraction (LVEF) during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function.

The preferred method for repeated assessment of cardiac function is evaluation of LVEF measure by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity.

Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict.

In view of the risk of cardiomyopathy, a cumulative dose of 900 mg/m2 of epirubicin hydrochloride must only be exceeded with extreme caution. 5). The risk of cardiotoxicity is also increased in the elderly. Cardiac failure (New York Heart Association NYHA class II-IV) was observed in patients receiving therapy with trastuzumab alone or in combination with anthracyclines such as epirubicin.

This can be moderate or severe and has been associated with death. Trastuzumab and anthracyclines such as epirubicin must not usually be used in combination, except in well-controlled clinical studies 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.

It has been reported that trastuzumab has a variable half-life. Trastuzumab can remain in the circulation for up to seven months after interruption of treatment. Patients who receive anthracyclines, such as epirubicin, can be at increased risk of cardiotoxicity after interruption of treatment with trastuzumab.

Whenever possible, the doctor must avoid anthracycline-based therapies for up to seven months after interruption or stopping of trastuzumab. If anthracyclines such as epirubicin are used, the patient’s cardiac function must be carefully monitored.

If symptoms of cardiac failure develops during treatment with trastuzumab, following treatment with epirubicin hydrochloride, this must be treated with standard medical therapy. Cardiac function must be carefully monitored in patients who take high cumulative doses and in those with risk factors.

However, cardiotoxicity with epirubicin hydrochloride can occur with lower cumulative doses in the presence or absence of […]

1, other anthracyclines or anthracenediones. 4) • patients with acute systemic infections • unstable angina pectoris • cardiomyopathy. Intravesical use: • Urinary tract infections. • Invasive bladder tumours. • Catheterisation problems.

• Inflammation of the bladder. • Haematuria