EPIRUBICIN

This medicinal product is intended solely for intravenous or intravesical use. The safety and efficacy of epirubicin in children and adolescents has not been investigated. 4). , as a single therapy or as a combination with other cytotoxic substances) and on the indication.

Standard Posology In monotherapy, the recommended dosage adults is 60-90 mg/m² of body surface area. Epirubicin Hydrochloride should be injected intravenously. over 3-5 minutes. The dosage should be repeated every 21 days, depending on the patient’s blood count and bone marrow function.

If signs of toxicity occur, including severe neutropenia/neutropenic fever and thrombocytopenia (which may persist until day 21), a dose adjustment or postponement of the next subsequent dose may be required. High Posology Small cell lung cancer (not previously treated) When used as monotherapeutic agent for high-dose treatment of lung cancer, epirubicin hydrochloride should be used in accordance with the following schedule: 120 mg/m2 of body surface area on day 1; every 3rd week.

With high-dose treatment, epirubicin hydrochloride may be administered as an intravenous bolus injection over 3–5 minutes or as an infusion for up to 30 minutes. Breast Cancer • Treatment of advanced breast cancer Up to 135 mg/m2 of body surface area of epirubicin hydrochloride in monotherapy and up to 120 mg/m2 of body surface area in combination therapy on day 1, every 3–4 weeks.

• For adjuvant treatment of patients at early stages of the disease with positive lymph node findings, intravenous epirubicin hydrochloride doses of 100 mg/m2 of body surface area (as a single dose on day 1) and 120 mg/m2 (divided into two doses on day 1 and day 8) are recommended every 3–4 weeks in combination with the intravenous administration of cyclophosphamide and 5-fluorouracil, as well as oral administration of tamoxifen.

Lower doses (60-75 mg/m² with standard dosages and 105-120 mg/m² for high dosages) are recommended in patients whose bone marrow function has been compromised through previous chemotherapy or radiotherapy, through age, or through neoplastic infiltration of the bone marrow.

The total dose for one cycle may be administered on 2-3 consecutive days. The following doses of epirubicin hydrochloride are commonly used in monotherapy and combination chemotherapy for the treatment of various other types of tumour: Cancer Indication Epirubicin Hydrochloride Dosage (mg/m2)a Monotherapy Combination Therapy Advanced ovarian cancer 60-90 50-100 Gastric cancer 60–90 50 Small cell lung cancer 120 120 Bladder cancer Intravesical administration of 50 mg/50 ml or 80 mg/50 ml (carcinoma in situ) Prevention: 50 mg/50 ml once per week over 4 weeks then once per month over 11 months a The doses are normally administered on day 1 or day 1, 2 and 3 in 21-day intervals Combination therapy When the drug is used in combination with other cytotoxic medicinal products, the dosage must be adjusted accordingly.

The dosages commonly used are provided in the table above. Specific Dosage Instruction Renal impairment Although no specific dosage recommendations can be made for patients with impaired renal function due to a lack of data, initial dosages should be reduced in patients with severe renal impairment (serum creatinine >5 mg/dl).

2–3 mg/100 ml or BSP retention 9–15%), a reduction of the initial dose by 50% is advisable. With severely impaired liver function (bilirubin >3 mg/100 ml or BSP retention >15%), a reduction in the initial dose by 75% is required. 3 ).

Paediatric population The safety and efficacy of this medicinal product in children has not been established. 4). Intravesical administration Epirubicin hydrochloride can be administered intravesically for the treatment of superficial bladder cancer and carcinoma-in-situ, and as a prophylaxis to prevent recurrence following transurethral resection.

3); systemic or surgical treatment is more appropriate in these situations. Different dosing schedules are used.

The following can be used as guidelines:

Superficial bladder cancer: bladder irrigation weekly with 50 mg/50 ml (diluted with a physiological saline solution or with sterile water) for 8 weeks. A reduction in the dose of 30 mg per 50 ml is recommended in the event of local toxicity (chemical cystitis).

Carcinoma in situ: up to 80 mg/50 ml (depending on the tolerance for the patient) A recurrence prophylaxis following transurethral resection: Administration of 50 mg/50 ml 4 times weekly followed by instillation of the same dose 11 times monthly The patient should not ingest any more liquid 12 hours before instillation in order to prevent any unwanted dilution with the urine.

This should limit urine production to around 50 ml per hour. The patient must be rotated one quarter of a turn every 15 minutes in situ during the drug dwelling time in order to ensure that as much of the bladder mucosa in the pelvis as possible comes into contact with the solution.

In general, a period of exposure of one hour is indicated, after which the patient should be encouraged to urinate. 6 for instructions on dilution of the medicinal product prior to […]

The following adverse reactions have been observed and described 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 t o ≤ 1/100) Rare (≥ 1/10,000 to ≤ 1/1,000) Very rare (≤ 1/10,000) Not known (Frequency cannot be estimated based on available data) Infections and infestations Infection conjunctiviti s Sepsis* Pneumonia* Septic shock Benign, malignant and non- specific neoplasms Acute myeloid leukaemia Acute lymphocytic leukaemia Blood and lymphatic system disorders Anaemia Leukopenia Granulocyto penia Neutropenia Thrombocyt openia febrile Neutropenia Haemorrhag e and tissue hypoxia as a result of bone marrow depression Immune system disorders Anaphylactic reaction* Metabolism and nutrition disorders Reduced appetite Dehydration* Hyperuricaemi a* Nervous system disorders Dizziness Eye disorders Keratitis Cardiac disorders Ventricular tachycardia AV-block bundle Branch block Bradycardia Congestive heart failure Cardiotoxicity (ECG Anomalies, Arrhythmia, Cardiomyopat hy) System organ class Very common (>1/10) Common (≥ 1/100 to <1/10) Uncommon (≥ 1/1,000 t o ≤ 1/100) Rare (≥ 1/10,000 to ≤ 1/1,000) Very rare (≤ 1/10,000) Not known (Frequency cannot be estimated based on available data) Vascular disorders Hot flush Phlebitis* Haemorrhage* Flushing* Embolism arterial Embolism* Thrombophl ebitis* Shock* Respiratory, thoracic and mediastinal disorders Pulmonary embolism* Gastrointesti nal disorders Nausea Vomiting Stomatitis Mucosal inflammatio n Diarrhoea Gastrointestinal pains* Gastrointestinal erosion* Gastrointestinal ulcer* Mucositis oesophagitis Gastrointest inal haemorrhag e* Abdominal complaints Hyperpigme ntation of the oral mucosa* Pain or burning sensation Skin and subcutaneou s tissue disorders Alopecia skin toxicity Rash/Pruritus Pigmentation of the nails* Skin disorders hyperpigmentati on of the skin* Urticaria* Erythema* Photosensiti vity reaction* Renal and urinary disorders Chromaturia * Reproductiv e system and breast disorders Amenorrhoe a Azoospermia General disorders and administrati on site conditions General health disorder Fever* Infusion site erythema chills* Asthenia System organ class Very common (>1/10) Common (≥ 1/100 to <1/10) Uncommon (≥ 1/1,000 t o ≤ 1/100) Rare (≥ 1/10,000 to ≤ 1/1,000) Very rare (≤ 1/10,000) Not known (Frequency cannot be estimated based on available data) Investigation s Abnormal transaminas e values Reduced left ventricular ejection fraction Injury, poisoning and procedural complication s Chemical cystitis*§ Recall phenomeno n*Δ * Adverse reaction reported following market launch † Red coloration of urine for 1 to 2 days following use § Following intravesical administration Δ Hypersensitivity of the irradiated skin 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 Treatment should only be provided under the supervision of doctors with corresponding experience in the treatment of tumours. The medicinal product must be used strictly in accordance with the instructions. Patients should recover from acute toxic effects of previous cytotoxic therapies (such as stomatitis, neutropenia, thrombocytopenia, and generalised infections) before treatment with epirubicin is initiated.

, ≥ 90 mg/m2 every 3 to 4 weeks) are comparable with those observed during treatment with standard doses (< 90 mg/m2 every 3 to 4 weeks). However, the severity of the neutropenia or stomatitis/mucositis may be more pronounced. Treatment with high doses of epirubicin hydrochloride requires particular attention to be paid to possible clinical complications caused by severe bone marrow depression.

, delayed) adverse reactions. , acute) adverse reactions (immediate type): The IMMEDIATE TYPE is independent of dose and characterised by non- specific ECG changes (ST segment depression, sinus tachycardia and supraventricular and ventricular extrasystoles, ventricular tachycardia, and bradycardia, as well as AV block and bundle branch block.

These disorders are rarely of clinical relevance, and are generally reversible. The therapy can generally be continued. , delayed) adverse reactions (delayed type): The DELAYED TYPE is dependent on dose and represents a cumulative organ toxicity in the form of a cardiomyopathy.

Delayed cardiotoxicity usually occurs at a later stage or within 2 to 3 months following treatment with epirubicin, although adverse reactions have also been reported that occur at an even later stage (several months to years after treatment has been completed).

Late onset cardiomyopathy is expressed by a reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm.

Life- threatening congestive heart failure is the most severe form of anthracycline- induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug. The risk of congestive heart failure increases rapidly with an increase in the total cumulative dose of epirubicin hydrochloride that is greater than 900 mg/m2.

1). The cardiac function should be checked before initiating treatment with epirubicin hydrochloride and must also be monitored during the therapy in order to minimize the risk of severe cardiac impairment. This risk can be reduced through regular checks on the left ventricular ejection fraction (LVEF) during the treatment.

Epirubicin should be discontinued immediately following the first signs of dysfunction. Quantitative methods for repeated checks on cardiac function (determination of the LVEF) include multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO).

Checks on cardiac function with an ECG and either a MUGA or echocardiography are recommended before initiating treatment, particularly in patients with risk factors for increased cardiotoxicity. Repeated checks should be performed on the left ventricular ejection fraction by MUGA or echocardiography, particularly at higher, cumulative anthracycline doses.

The investigation method used should be the same for all follow-up controls and within the scope of subsequent monitoring. Given the risk of cardiomyopathy, a cumulative epirubicin hydrochloride dose of 900 mg/m2 should only be exceeded with extreme caution.

Cardiomyopathy induced by anthracyclines is associated with persistent QRS low voltage, an extension in the systolic time interval above the normal values (PEP) and a decrease in ejection fraction (LVET). Changes in the electrocardiogram (ECG) may indicate anthracycline-induced cardiomyopathy, but the ECG is not a sensitive or a specific method in tracking anthracycline-induced cardiotoxicity.

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 as a monotherapy or in combination with anthracyclines such as epirubicin.

The heart failure can be moderate to severe and can result in death. Trastuzumab and anthracyclines such as epirubicin may currently only be given in combination within the scope of a strictly controlled clinical trial setting with cardiological monitoring.

In the case of patients who have previously received anthracyclines, there is also a risk of cardiotoxicity following treatment with trastuzumab, although the risk is lower than with concurrent use of trastuzumab and anthracyclines.

The reported half-life of trastuzumab is variable. The substance can remain in the bloodstream for up to 7 months. Doctors should therefore 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 heart failure develops during trastuzumab therapy after epirubicin therapy, it should be treated with the appropriate medications for this purpose.

Cardiac function must be monitored particularly closely in patients receiving high cumulative doses and in those patients with risk factors. However, cardiac […]

1. 6). 4) Intravesical application: • urinary tract infections • inflammation of the bladder • haematuria • invasive tumours with penetration of the bladder • catheterisation problems