Components:
Epirubicin
Epirubicin
Method of action:
Antitumour
Antitumour
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Name of the medicinal product

4-Eppedo

Qualitative and quantitative composition

Epirubicin

Therapeutic indications

The information provided in Therapeutic indications of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

4-Eppedo Hydrochloride 2 mg/ml, solution for injection is used in the treatment of a range of neoplastic conditions including:

• Breast and gastric carcinomas,

When administered intravesically, this medicinal product has been shown to be beneficial in the treatment of:

• Papillary transitional cell carcinoma of the bladder,

• Carcinoma-in-situ,

• Prophylaxis of recurrences after transurethral resection.

Epirubicin is used in the treatment of a range of neoplastic conditions including:

• Carcinoma of the breast

• Advanced ovarian cancer

• Gastric cancer

• Small cell lung cancer

When administered intravesically, epirubicin has been shown to be beneficial in the treatment of:

• Papillary transitional cell carcinoma of the bladder

• Carcinoma-in-situ of the bladder

• Intravesical prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection.

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

This medicinal product is for intravenous or intravesical use only.

Intravenous administration

It is advisable to administer 4-Eppedo hydrochloride via the tubing of a free-running intravenous saline or glucose infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation . In case of extravasation, administration should be stopped immediately.

Conventional dose

When 4-Eppedo hydrochloride is used as a single agent, the recommended dosage in adults is 60-90 mg/m2 body area. 4-Eppedo hydrochloride should be injected intravenously over 3-5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient's haematomedullar status.

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.

Breast Cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of 4-Eppedo 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.

For high dose treatment, 4-Eppedo may be given as an intravenous bolus over 3-5 minutes or as an infusion of up to 30 minutes duration.

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 this medicinal product are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

4-Eppedo HCl Dose (mg/m2)a

Cancer Indication

Monotherapy

Combination Therapy

Gastric cancer

60–90

50

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 11 months

a Doses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

A total cumulative dose of 900 – 1000 mg/m2 should not be exceeded due to a potential risk of cardiotoxicity .

Combination therapy

If 4-Eppedo hydrochloride is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above.

Liver impairment The major route of elimination of 4-Eppedo hydrochloride is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

Serum Bilirubin

AST*

Dose Reduction

1.4 – 3 mg/100 ml

(24 – 51 µmol/l)

50 %

> 3 mg/100 ml

(> 51 µmol/l)

> 4 times upper normal limit

75 %

* AST – aspartate aminotransferase

Renal impairment

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of 4-Eppedo hydrochloride excreted by this route. However, lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 5 mg/dl).

Paediatric population

The safety and efficacy of this medicinal product in children has not been established.

Intravesical administration

This medicinal product 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, systemic therapy or surgery is more appropriate in these situations . This medicinal product has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

If local toxicity (chemical cystitis) 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.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

Dose 4-Eppedo HCl required

Volume of 2 mg/ml

Volume of diluent

Total volume for

4-Eppedo HCl injection

(sterile water for injection or 0.9% sterile saline)

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 solution should be retained intravesically for 1-2 hours. 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.

Posology

Epirubicin is for intravenous or intravesical use only.

Paediatric population

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

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. Care should be taken to avoid extravasation . In case of extravasation, administration should be stopped immediately.

Dosage

In order to avoid cardiac toxicity, a total cumulative dose of 900 – 1,000 mg/m² 4-Eppedo should not be exceeded .

Conventional dose

When 4-Eppedo is used as a single agent, the recommended dosage in adults is 60 – 90 mg/m² body surface area. 4-Eppedo 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 4-Eppedo 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 4-Eppedo 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 4-Eppedo are commonly used in monotherapy and combination chemotherapy for various other tumours, as shown:

4-Eppedo 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 4-Eppedo 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. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

Serum bilirubin

SGOT

Dose reduction

1.4 – 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, dosage adjustment may be necessary in patients with serum creatinine > 5 mg/dl.

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, systemic therapy or surgery is more appropriate in these situations . Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline 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.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

Dose 4-Eppedo required

Volume of 2 mg/ ml 4-Eppedo injection

Volume of diluent water for injection or 0.9 % sterile saline

Total volume for bladder installation

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 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.

Contraindications

The information provided in Contraindications of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

•

• Lactation

Contraindications to intravenous administration:

• Patients with marked or persistent myelosuppression induced by previous treatment with either other anti-neoplastic agents or radiotherapy,

• Patients with severe hepatic impairment

• Patients treated previously with maximum cumulative doses of 4-Eppedo and/or other anthracyclines such as doxorubicin or daunorubicin and anthracenediones

• Patients with current or previous history of cardiac impairment (including 4th degree muscular heart failure, acute heart attack and previous heart attack which led to 3rd and 4th degree muscular heart failure, acute inflammatory heart diseases, severe arrhythmia, myocardiopathy, recent myocardial infarction)

• Patients with acute systemic infections

• Patients with unstable angina pectoris

Contraindications to the intravesical administration of 4-Eppedo are:

• Urinary tract infections

• Inflammation of the bladder

• Haematuria

• Invasive tumours penetrating the bladder

• Catheterisation problems

• Large volume of residual urine

• Contracted bladder

<

Lactation .

Intravenous use:

• Persistent myelosuppression

• severe hepatic impairment

• severe myocardial insufficiency

• recent myocardial infarction

• severe arrhythmias

• previous treatments with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones

• patients with acute systemic infections

• unstable angina pectoris

• myocardiopathy

• acute inflammatory heart diseases

Intravesical use:

• urinary tract infections

• invasive tumours penetrating the bladder

• catheterisation problems

• inflammation of the bladder

• haematuria

• contracted bladder

• big volume of residual urine

Special warnings and precautions for use

The information provided in Special warnings and precautions for use of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
more... close
Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

General - 4-Eppedo should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Diagnostic and treatment facilities should be readily available management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of 4-Eppedo.

4-Eppedo is not active when given orally and should not be injected intramuscularly or intrathecally.

Careful baseline monitoring of various laboratory parameters and cardiac function should precede initial treatment with 4-Eppedo.

Patients should recover from acute toxicities (such as stomatitis or mucositis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with 4-Eppedo.

While treatment with high doses of 4-Eppedo (e.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 4-Eppedo requires special attention for possible clinical complications due to profound myelosuppression.

Cardiac Function - Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.

Early (i.e. Acute) Events. Early cardiotoxicity of 4-Eppedo 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 4-Eppedo treatment.

Late (i.e. Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with 4-Eppedo 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.

The risk of developing CHF increases rapidly with increasing total cumulative doses of 4-Eppedo in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution .

Above this level the risk of irreversible congestive heart failure increases greatly.

Heart failure may appear several weeks after discontinuing therapy with 4-Eppedo and may be unresponsive to specific medical treatment.

In establishing the maximal cumulative dose of 4-Eppedo, consideration should be given to any concomitant therapy with potentially cardiotoxic drugs.

Cardiac function should be assessed before patients undergo treatment with 4-Eppedo 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 4-Eppedo 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 4-Eppedo should be exceeded only with extreme caution.

An ECG is recommended before and after each treatment cycle. Alterations in the ECG tracing, such as flattening or inversion of the Twave, depression of the S-T segment, or the onset of arrhythmias, generally transient and reversible, need not necessarily be taken as indications to discontinue treatment. With cumulative doses < 900 mg/m2, there is evidence that cardiac toxicity rarely occurs. In case of cardiac insufficiency, treatment with 4-Eppedo should be discontinued.

Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving 4-Eppedo treatment is highly important and 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.

Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors, particularly prior anthracycline or anthracenedione use. However cardiotoxicity with 4-Eppedo may occur at lower cumulative doses whether or not risk factors are present. It is probable that the toxicity of 4-Eppedo and other anthracyclines or anthracenediones is additive.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility and/or cardiotoxic drugs (e.g. trastuzumab) 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 4-Eppedo. This may be moderate to severe and has been associated with death.

Trastuzumab and anthracyclines such as 4-Eppedo 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 traztuzumab and anthracyclines.

Because the half-life of trastuzumab is approximately28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as 4-Eppedo 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. If anthracyclines such as 4-Eppedo are used, the patient's cardiac function should be monitored carefully.

If symptomatic cardiac failure develops during trastuzumab therapy after 4-Eppedo therapy, it should be treated with the standard medications for this purpose.

Haematologic Toxicity- As with other cytotoxic agents, 4-Eppedo may produce myelosuppression. Haematological profiles should be assessed before and during each cycle of therapy with 4-Eppedo. Red blood cell, differential white blood cell (WBC), neutrophil and platelet counts should be carefully monitored both before and during each cycle of therapy. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestion of 4-Eppedo haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are generally more severe with high-dose schedules reaching a nadir in most cases between the 10th and 14th day after drug administration; this is usually transient with WBC/neutrophil counts returning to normal in most cases by the 21st day. Thrombocytopenia (< 100,000 platelets/mm3) is experienced in very few patients, even following high doses of 4-Eppedo. Anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukaemia - Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including 4-Eppedo. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a 1- to 3-year latency period. .

Gastrointestinal - 4-Eppedo is emetigenic. Mucositis/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.

Liver Function - The major route of elimination of 4-Eppedo is the hepatobiliary system. Before starting therapy with 4-Eppedo, and during treatment, liver function should be evaluated (SGOT, SGT, alkaline phosphatase, bilirubin, AST). Patients with elevated bilirubin or AST may experience slower clearance of the drug with an increase in overall toxicity. Lower doses are recommended in these patients . Patients with severe hepatic impairment should not receive 4-Eppedo .

Renal Function - Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl .

4-Eppedo may impart a red colour to the urine for one or two days after administration.

Effects at Site of Injection - Phlebosclerosis may result from injection into small vessels or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site .

Extravasation - Extravasation of 4-Eppedo from the vein during injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of 4-Eppedo, the drug infusion should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (please refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool, use of hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.

Other - As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of 4-Eppedo.

Tumor Lysis Syndrome - As with other cytotoxic agents, 4-Eppedo may induce hyperuricaemia because of the extensive purine metabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should therefore be evaluated after initial treatment so that this phenomenon may be recognised and properly managed. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumor-lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections - Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including 4-Eppedo, may result in serious or fatal infections . Vaccination with a live vaccine should be avoided in patients receiving 4-Eppedo. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Reproductive system - 4-Eppedo can have genotoxic effects. Men and women treated with 4-Eppedo should adopt appropriate contraceptive measures. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.

Additional warnings and precautions for other routes of administration

Intravesical route - Administration of 4-Eppedo may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumors).

Intra-arterial route - Intra-arterial administration of 4-Eppedo (transcatheter arterial embolization for the localized or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of 4-Eppedo) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.

4-Eppedo contains sodium.

This medicinal product contains 3.6 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

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 generalized infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

While treatment with high doses of 4-Eppedo (e.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 4-Eppedo does require special attention for possible clinical complications due to profound myelosuppression.

Cardiac function – Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.

Early (i.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.

Late (i.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 dyspnea, 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.

The risk of developing CHF increases rapidly with increasing total cumulative doses of 4-Eppedo in excess of 900 mg/m²; this cumulative dose should only be exceeded with extreme caution .

Monitoring of cardiac function. 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 4-Eppedo 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 (LVEF). Electrocardiogram (ECG) changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other medicinal products with the ability to suppress cardiac contractility or cardiotoxic medicinal products (e.g. trastuzumab) 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.

Cardiotoxicity in combination with trastuzumab. 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 traztuzumab 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. If anthracyclines such as epirubicin are used, the patient's cardiac function should be monitored carefully.

If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin therapy, it should be treated with the standard medications for this purpose.

Haematological toxicity – As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this medicinal product. Leukopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after administration of the medicinal product; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.

Secondary leukaemia – Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin. Secondary leukaemia is more common when such medicinal products are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic medicinal products, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period .

Gastrointestinal – Epirubicin is emetogenic. Mucositis/stomatitis generally appears early after administration of the medicinal product and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.

Liver function – The major route of elimination of epirubicin is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin. Patients with elevated bilirubin or AST may experience slower clearance of the medicinal product with an increase in overall toxicity. Lower doses are recommended in these patients . Patients with severe hepatic impairment should not receive epirubicin .

Renal function – Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl .

Effects at site of injection – Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site .

Extravasation – Extravasation of epirubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of epirubicin the infusion of the medicinal product should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (please refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool, use of hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks. If extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.

Other – As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin.

Tumour-lysis syndrome – Epirubicin may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid lysis of neoplastic cells (tumour-lysis syndrome) induced by the medicinal product. Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumour-lysis syndrome.

Immunosuppressant effects/Increased susceptibility to infections – Vaccination with a live vaccine should be avoided in patients immunocompromised by chemotherapeutic agents including epirubicin as it may result in serious or fatal infections . Killed or inactivated vaccines may be administered to patients receiving epirubicin; however, the response to such vaccines may be diminished.

Reproductive system – Epirubicin can cause genotoxicity. Men and women treated with epirubicin should adopt appropriate contraceptives Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.

Additional warnings and precautions for other routes of administration

Intravesical route – Administration of epirubicin may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumours).

Effects on ability to drive and use machines

The information provided in Effects on ability to drive and use machines of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

There have been no reports of particular adverse events relating to the effects on ability to drive and to use machines.

The effect of 4-Eppedo on the ability to drive or use machinery has not been systematically evaluated.

4-Eppedo may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

The effect of epirubicin on the ability to drive or use machinery has not been systematically evaluated.

Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

Undesirable effects

The information provided in Undesirable effects of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

The following undesirable effects have been observed and reported during treatment with 4-Eppedo 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 (cannot be estimated from the available data).

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

Frequency

Undesirable effects

Infections and infestations

Common

Infection

Not known

Septic shock, sepsis, pneumonia

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rare

Acute lymphocytic leukaemia, acute myelogenous leukaemia with or without a pre-leukaemic phase, in patients treated with 4-Eppedo in combination with DNA-damaging antineoplastic agents. These leukaemias have a short (1-3 years) latency.

Blood and the lymphatic system disorders1

Very common

Myelosuppression (leukopenia, granulocytopenia, neutropenia, anemia and febrile neutropenia)

Uncommon

Thrombocytopenia

Not known

Haemorrhage and tissue hypoxia as result of myelosoppression.

Immune system disorders

Rare

Anaphylaxis (anaphylactic/ anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills)

Metabolism and nutrition disorders

Common

Anorexia, dehydration

Rare

Hyperuricemia as a result of rapid lysis of neoplastic cells

Nervous system disorders

Uncommon

Headache

Rare

Dizziness

Eye disorders

Not known

Conjunctivitis, keratitis

Cardiac disorders

Rare

Congestive heart failure, (dyspnoea; oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusions, gallop rhythm) cardiotoxicity (e.g. ECG abnormalities, arythmias, cardiomyopathy), ventricular tachycardia, bradycardia, AV block, bundle-branch block .

Vascular disorders

Common

Hot flashes

Uncommon

Phlebitis, thrombophlebitis

Not known

Shock, thromboembolism, including pulmonary embolism (in isolated cases with fatal outcome)

Gastrointestinal disorders

Common

Mucositis, oesophagitis, stomatitis, vomiting, diarrhea, nausea

Not known

Oral mucosa erosion, mouth ulceration, oral pain, mucosal burning sensation, mouth haemorrhage, and buccal pigmentation

Skin and subcutaneous tissue disorders

Very common

Alopecia, normally reversible, appears in 60-90% of treated cases; it is accompanied by lack of beard growth in males

Rare

Urticaria

Not known

Local toxicity, rash, itch, skin changes, erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction)

Renal and urinary disorders

Very common

Red coloration of urine for 1 to 2 days after administration

Reproductive system and breast disorders

Rare

Amenorrhea, azoospermia

General disorders and administration site conditions

Common

Infusion site erythema

Rare

Malaise,/asthenia, fever, chills, hyperpyrexia

Not known

Phlebosklerosis, local pain, severe cellulitis, tissue necrosis (following accidental paravenous injection)

Investigations

Rare

Changes in transaminase levels

Not known

Asymptomatic drops in left ventricular ejection fraction

Injury, poisoning and procedural complications

Common

Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration .

1High doses of 4-Eppedo 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.

Intravesical administration:

As only a small amount of active ingredient is reabsorbed after intravesical instillation, severe systemic adverse drug reactions as well as allergic reactions are rare. Commonly reported are local reactions like burning sensation and frequent voiding (pollakisuria).Occasional bacterial or chemical cystitis have been reported . These ADRs 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

The following undesirable 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).

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

Frequency

Undesirable effects

Infections and infestations

Very common (≥ 1/10)

Infection

Not known (cannot be estimated from the available data)

Septic shock, sepsis, pneumonia

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Uncommon (≥1/1,000 to <1/100)

Acute lymphocytic leukaemia, acute myelogenous leukaemia

Blood and lymphatic system disorders

Very common

(≥1/10)

Myelosuppression (leukopenia, granulocytopenia and neutropenia, anaemia and febrile neutropenia, thrombocytopenia)

Not known

(cannot be estimated from the available data)

Haemorrhage and tissue hypoxia as result of myelosuppression

Immune system disorders

Rare (≥1/10,000 to <1/1,000)

Anaphylaxis (anaphylactic/anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills), allergic reactions following intravesical administration

Metabolism and nutrition disorders

Very common (≥1/10)

Loss of appetite

Common (≥1/100 to <1/10)

Dehydration

Rare (≥1/10,000 to <1/1,000)

Hyperuricemia

Nervous system disorders

Rare (≥1/10,000 to <1/1,000)

Dizziness

Eye disorders

Uncommon (≥1/1,000 to <1/100)

Conjunctivitis, keratitis

Cardiac disorders

Common (≥1/100 to <1/10)

Congestive heart failure (CHF) (dyspnoea, oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusions, extrasystoles)

Rare (≥1/10,000 to <1/1,000)

Cardiotoxicity (e.g. ECG abnormalities, arrhythmias, cardiomyopathy), ventricular tachycardia, bradycardia, AV block, bundle-branch block

Vascular disorders

Common

(≥1/100 to <1/10)

Hot flashes

Uncommon

(≥1/1,000 to <1/100)

Phlebitis, thrombophlebitis

Very rare (<1/10,000)

Shock

Not known

(cannot be estimated from the available data)

Thromboembolism, including pulmonary emboli

Gastrointestinal disorders

Very common (≥1/10)

Mucositis, stomatitis, vomiting, diarrhoea, nausea, which can result in loss of appetite and abdominal pain

Common

(≥1/100 to <1/10)

Oral pain, mucosal burning sensation, oesophagitis

Uncommon (≥1/1,000 to <1/100)

Gastric erosion and ulcers, gastrointestinal haemorrhage, hyperpigmentation of the oral mucous membranes

Skin and subcutaneous tissue disorders

Very common

(≥1/10)

Alopecia

Common (≥1/100 to <1/10)

Local skin and tissue toxicity, rash, pruritus

Uncommon (≥1/1,000 to <1/100)

Skin changes, erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction)

Rare

(≥1/10,000 to <1/1,000)

Urticaria

Renal and urinary disorders

Very common

(≥1/10)

Red colouration of urine for 1 to 2 days after administration

Reproductive system and breast disorders

Common (≥1/100 to <1/10)

Amenorrhoea

Rare

(≥1/10,000 to <1/1,000)

Azoospermia

General disorders and administration site conditions

Common

(≥1/100 to <1/10)

Infusion site erythema. Paravenous injection can cause tissue necrosis. Malaise, asthenia, fever

Rare

(≥1/10,000 to <1/1,000)

Chills

Not known

(cannot be estimated from the available data)

Phlebosclerosis, local pain, severe cellulitis

Investigations

Common (≥1/100 to <1/10)

Changes in transaminase levels,

Asymptomatic decreases in left ventricular ejection fraction (LVEF)

Injury, poisoning and procedural complications

Common

(≥1/100 to <1/10)

Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration

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 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). Occasional bacterial or chemical cystitis have been reported . These ADRs 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. Healthcare professionals are asked to report any suspected adverse reactions via www.mhra.gov.uk/yellowcard.

Overdose

The information provided in Overdose of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

Symptoms:

Acute overdosage with 4-Eppedo will result in severe myelosuppression within 10-14 days (mainly leucopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and cardiac complications (acute myocardial degeneration within 24 hours). During this period a blood transfusion is required as well as isolation in a sterile room. Latent cardiac failure has been observed with anthracyclines several months (up to 6 months) to years after completion of treatment . Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic.

4-Eppedo cannot be removed by dialysis.

Acute overdosage with epirubicin will result in severe myelosuppression (within 10 – 14 days; mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications (within 24 hours). Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment . Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic. Epirubicin cannot be removed by dialysis.

Pharmacodynamic properties

The information provided in Pharmacodynamic properties of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

4-Eppedo is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of 4-Eppedo is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. 4-Eppedo has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

Epirubicin is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of epirubicin is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m2 of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are 4-Eppedool (13-OH 4-Eppedo) and glucuronides of 4-Eppedo and 4-Eppedool.

The 4'-O-glucuronidation distinguishes 4-Eppedo from doxorubicin and may account for the faster elimination of 4-Eppedo and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (4-Eppedool) are consistently lower and virtually parallel than those of the unchanged drug.

4-Eppedo is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution. Urinary excretion accounts for approximately 9-10% of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The drug does not cross the blood brain barrier.

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m² of the medicinal product follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. Between 60 and 120 mg/m² there is an extensive linear pharmacokinetic, 150 mg/m² is at the margin of dose linearity. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.

In pharmacokinetic studies of patients with carcinoma in situ of the bladder the plasma levels of epirubicin after intravesical instillation are typically low (< 10 ng/ml). A significant systemic resorption can therefore not be assumed. In patients with lesions of the mucosa of the bladder (e.g. tumour, cystitis, operations), a higher resorption rate can be expected.

The 4'-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged active substance.

Epirubicin is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution. Urinary excretion accounts for approximately 9 – 10 % of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40 % of the administered dose being recovered in the bile in 72 hours. The active substance does not cross the blood brain barrier.

Pharmacotherapeutic group

The information provided in Pharmacotherapeutic group of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Antineoplastic agent. ATC code: L01D B03

Preclinical safety data

The information provided in Preclinical safety data of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

Following repeated dosing with 4-Eppedo, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. 4-Eppedo was also cardiotoxic in the rat, rabbit and dog.

4-Eppedo, like other anthracyclines, was mutagenic, genotoxic, embryotoxic and carcinogenic in rats. No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, 4-Eppedo must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of 4-Eppedo causes tissue necrosis.

Following repeated dosing with epirubicin, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin was also cardiotoxic in the rat, rabbit and dog.

Epirubicin, like other anthracyclines, was mutagenic, genotoxic and carcinogenic in rats. Embryotoxicity was seen in rats at clinically relevant doses.

No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic active substances, epirubicin must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.

Incompatibilities

The information provided in Incompatibilities of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug, which includes sodium bicarbonate containing solutions.

Neither the injection nor any diluted solution should be mixed with any other drugs (a physical incompatibility with heparin has been reported).

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Prolonged contact of the medicinal product with any solution of an alkaline pH (including sodium bicarbonate solutions) should be avoided; this will result in hydrolysis (degradation) of the active substance.

A physical incompatibility of the medicinal product with heparin has been reported.

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Special precautions for disposal and other handling

The information provided in Special precautions for disposal and other handling of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance
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As with other potentially toxic compounds, caution should be exercised when handling 4-Eppedo (hydrochloride) 2 mg/ml, solution for injection.

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and his surroundings.

4-Eppedo (hydrochloride) 2 mg/ml, solution for injection may be further diluted in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. The infusion solution should be prepared immediately before use.

The injection solution contains no preservative and any unused portion of the vial should be discarded immediately.

Guidelines for the safe handling and disposal of antineoplastic agents:

1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.

2. Preparation of an infusion solution should be performed in a designated aseptic area.

3. Adequate protective disposable gloves, goggles, gown and mask should be worn.

4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9% sodium chloride solution. Then seek medical evaluation by a physician.

5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.

6. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed below.

7. Pregnant staff should not handle the cytotoxic preparation.

8. Adequate care and precautions should be taken in the disposal of items (syringes, needles, etc) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

4-Eppedo may be further diluted in glucose 5 % solution or sodium chloride 0.9 % solution and administered as an intravenous infusion.

The injection solution contains no preservative and any unused portion of the vial should be disposed of immediately in accordance with local requirements.

Guidelines for the safe handling and disposal of antineoplastic agents:

1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.

2. Preparation of an infusion solution should be performed in a designated aseptic area.

3. Adequate protective disposable gloves, goggles, gown and mask should be worn.

4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9 % sodium chloride solution. Then seek medical evaluation by a physician.

5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.

6. Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed below.

7. Pregnant staff should not handle the cytotoxic preparation.

8. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc.) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste material should be disposed of in accordance with local requirements.

Name of the medicinal product
4-Eppedo
Qualitative and quantitative composition
Epirubicin
Therapeutic indications
The information provided in Therapeutic indications of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

4-Eppedo Hydrochloride 2 mg/ml, solution for injection is used in the treatment of a range of neoplastic conditions including:

• Breast and gastric carcinomas,

When administered intravesically, this medicinal product has been shown to be beneficial in the treatment of:

• Papillary transitional cell carcinoma of the bladder,

• Carcinoma-in-situ,

• Prophylaxis of recurrences after transurethral resection.

Epirubicin is used in the treatment of a range of neoplastic conditions including:

• Carcinoma of the breast

• Advanced ovarian cancer

• Gastric cancer

• Small cell lung cancer

When administered intravesically, epirubicin has been shown to be beneficial in the treatment of:

• Papillary transitional cell carcinoma of the bladder

• Carcinoma-in-situ of the bladder

• Intravesical prophylaxis of recurrences of superficial bladder carcinoma following transurethral resection.

Dosage (Posology) and method of administration
The information provided in Dosage (Posology) and method of administration of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

This medicinal product is for intravenous or intravesical use only.

Intravenous administration

It is advisable to administer 4-Eppedo hydrochloride via the tubing of a free-running intravenous saline or glucose infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation . In case of extravasation, administration should be stopped immediately.

Conventional dose

When 4-Eppedo hydrochloride is used as a single agent, the recommended dosage in adults is 60-90 mg/m2 body area. 4-Eppedo hydrochloride should be injected intravenously over 3-5 minutes. The dose should be repeated at 21-day intervals, depending upon the patient's haematomedullar status.

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.

Breast Cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of 4-Eppedo 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.

For high dose treatment, 4-Eppedo may be given as an intravenous bolus over 3-5 minutes or as an infusion of up to 30 minutes duration.

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 this medicinal product are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

4-Eppedo HCl Dose (mg/m2)a

Cancer Indication

Monotherapy

Combination Therapy

Gastric cancer

60–90

50

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 11 months

a Doses generally given Day 1 or Day 1, 2 and 3 at 21-day intervals

A total cumulative dose of 900 – 1000 mg/m2 should not be exceeded due to a potential risk of cardiotoxicity .

Combination therapy

If 4-Eppedo hydrochloride is used in combination with other cytotoxic products, the dose should be reduced accordingly. Commonly used doses are shown in the table above.

Liver impairment The major route of elimination of 4-Eppedo hydrochloride is the hepatobiliary system. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

Serum Bilirubin

AST*

Dose Reduction

1.4 – 3 mg/100 ml

(24 – 51 µmol/l)

50 %

> 3 mg/100 ml

(> 51 µmol/l)

> 4 times upper normal limit

75 %

* AST – aspartate aminotransferase

Renal impairment

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of 4-Eppedo hydrochloride excreted by this route. However, lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 5 mg/dl).

Paediatric population

The safety and efficacy of this medicinal product in children has not been established.

Intravesical administration

This medicinal product 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, systemic therapy or surgery is more appropriate in these situations . This medicinal product has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water).

If local toxicity (chemical cystitis) 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.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

Dose 4-Eppedo HCl required

Volume of 2 mg/ml

Volume of diluent

Total volume for

4-Eppedo HCl injection

(sterile water for injection or 0.9% sterile saline)

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 solution should be retained intravesically for 1-2 hours. 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.

Posology

Epirubicin is for intravenous or intravesical use only.

Paediatric population

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

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. Care should be taken to avoid extravasation . In case of extravasation, administration should be stopped immediately.

Dosage

In order to avoid cardiac toxicity, a total cumulative dose of 900 – 1,000 mg/m² 4-Eppedo should not be exceeded .

Conventional dose

When 4-Eppedo is used as a single agent, the recommended dosage in adults is 60 – 90 mg/m² body surface area. 4-Eppedo 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 4-Eppedo 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 4-Eppedo 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 4-Eppedo are commonly used in monotherapy and combination chemotherapy for various other tumours, as shown:

4-Eppedo 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 4-Eppedo 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. In patients with impaired liver function the dose should be reduced based on serum bilirubin levels as follows:

Serum bilirubin

SGOT

Dose reduction

1.4 – 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, dosage adjustment may be necessary in patients with serum creatinine > 5 mg/dl.

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, systemic therapy or surgery is more appropriate in these situations . Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence.

For the treatment of superficial bladder cancer the following regimen is recommended, using the dilution table below:

8 weekly instillations of 50 mg/50 ml (diluted with saline 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.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

Dose 4-Eppedo required

Volume of 2 mg/ ml 4-Eppedo injection

Volume of diluent water for injection or 0.9 % sterile saline

Total volume for bladder installation

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 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.

Contraindications
The information provided in Contraindications of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

•

• Lactation

Contraindications to intravenous administration:

• Patients with marked or persistent myelosuppression induced by previous treatment with either other anti-neoplastic agents or radiotherapy,

• Patients with severe hepatic impairment

• Patients treated previously with maximum cumulative doses of 4-Eppedo and/or other anthracyclines such as doxorubicin or daunorubicin and anthracenediones

• Patients with current or previous history of cardiac impairment (including 4th degree muscular heart failure, acute heart attack and previous heart attack which led to 3rd and 4th degree muscular heart failure, acute inflammatory heart diseases, severe arrhythmia, myocardiopathy, recent myocardial infarction)

• Patients with acute systemic infections

• Patients with unstable angina pectoris

Contraindications to the intravesical administration of 4-Eppedo are:

• Urinary tract infections

• Inflammation of the bladder

• Haematuria

• Invasive tumours penetrating the bladder

• Catheterisation problems

• Large volume of residual urine

• Contracted bladder

<

Lactation .

Intravenous use:

• Persistent myelosuppression

• severe hepatic impairment

• severe myocardial insufficiency

• recent myocardial infarction

• severe arrhythmias

• previous treatments with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones

• patients with acute systemic infections

• unstable angina pectoris

• myocardiopathy

• acute inflammatory heart diseases

Intravesical use:

• urinary tract infections

• invasive tumours penetrating the bladder

• catheterisation problems

• inflammation of the bladder

• haematuria

• contracted bladder

• big volume of residual urine

Special warnings and precautions for use
The information provided in Special warnings and precautions for use of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

General - 4-Eppedo should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Diagnostic and treatment facilities should be readily available management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of 4-Eppedo.

4-Eppedo is not active when given orally and should not be injected intramuscularly or intrathecally.

Careful baseline monitoring of various laboratory parameters and cardiac function should precede initial treatment with 4-Eppedo.

Patients should recover from acute toxicities (such as stomatitis or mucositis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with 4-Eppedo.

While treatment with high doses of 4-Eppedo (e.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 4-Eppedo requires special attention for possible clinical complications due to profound myelosuppression.

Cardiac Function - Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.

Early (i.e. Acute) Events. Early cardiotoxicity of 4-Eppedo 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 4-Eppedo treatment.

Late (i.e. Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy with 4-Eppedo 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.

The risk of developing CHF increases rapidly with increasing total cumulative doses of 4-Eppedo in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution .

Above this level the risk of irreversible congestive heart failure increases greatly.

Heart failure may appear several weeks after discontinuing therapy with 4-Eppedo and may be unresponsive to specific medical treatment.

In establishing the maximal cumulative dose of 4-Eppedo, consideration should be given to any concomitant therapy with potentially cardiotoxic drugs.

Cardiac function should be assessed before patients undergo treatment with 4-Eppedo 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 4-Eppedo 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 4-Eppedo should be exceeded only with extreme caution.

An ECG is recommended before and after each treatment cycle. Alterations in the ECG tracing, such as flattening or inversion of the Twave, depression of the S-T segment, or the onset of arrhythmias, generally transient and reversible, need not necessarily be taken as indications to discontinue treatment. With cumulative doses < 900 mg/m2, there is evidence that cardiac toxicity rarely occurs. In case of cardiac insufficiency, treatment with 4-Eppedo should be discontinued.

Cardiomyopathy induced by anthracyclines is associated with persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving 4-Eppedo treatment is highly important and 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.

Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors, particularly prior anthracycline or anthracenedione use. However cardiotoxicity with 4-Eppedo may occur at lower cumulative doses whether or not risk factors are present. It is probable that the toxicity of 4-Eppedo and other anthracyclines or anthracenediones is additive.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility and/or cardiotoxic drugs (e.g. trastuzumab) 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 4-Eppedo. This may be moderate to severe and has been associated with death.

Trastuzumab and anthracyclines such as 4-Eppedo 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 traztuzumab and anthracyclines.

Because the half-life of trastuzumab is approximately28-38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping trastuzumab treatment. Patients who receive anthracyclines such as 4-Eppedo 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. If anthracyclines such as 4-Eppedo are used, the patient's cardiac function should be monitored carefully.

If symptomatic cardiac failure develops during trastuzumab therapy after 4-Eppedo therapy, it should be treated with the standard medications for this purpose.

Haematologic Toxicity- As with other cytotoxic agents, 4-Eppedo may produce myelosuppression. Haematological profiles should be assessed before and during each cycle of therapy with 4-Eppedo. Red blood cell, differential white blood cell (WBC), neutrophil and platelet counts should be carefully monitored both before and during each cycle of therapy. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestion of 4-Eppedo haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are generally more severe with high-dose schedules reaching a nadir in most cases between the 10th and 14th day after drug administration; this is usually transient with WBC/neutrophil counts returning to normal in most cases by the 21st day. Thrombocytopenia (< 100,000 platelets/mm3) is experienced in very few patients, even following high doses of 4-Eppedo. Anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukaemia - Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including 4-Eppedo. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a 1- to 3-year latency period. .

Gastrointestinal - 4-Eppedo is emetigenic. Mucositis/stomatitis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.

Liver Function - The major route of elimination of 4-Eppedo is the hepatobiliary system. Before starting therapy with 4-Eppedo, and during treatment, liver function should be evaluated (SGOT, SGT, alkaline phosphatase, bilirubin, AST). Patients with elevated bilirubin or AST may experience slower clearance of the drug with an increase in overall toxicity. Lower doses are recommended in these patients . Patients with severe hepatic impairment should not receive 4-Eppedo .

Renal Function - Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl .

4-Eppedo may impart a red colour to the urine for one or two days after administration.

Effects at Site of Injection - Phlebosclerosis may result from injection into small vessels or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site .

Extravasation - Extravasation of 4-Eppedo from the vein during injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of 4-Eppedo, the drug infusion should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (please refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool, use of hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.

Other - As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of 4-Eppedo.

Tumor Lysis Syndrome - As with other cytotoxic agents, 4-Eppedo may induce hyperuricaemia because of the extensive purine metabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should therefore be evaluated after initial treatment so that this phenomenon may be recognised and properly managed. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumor-lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections - Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including 4-Eppedo, may result in serious or fatal infections . Vaccination with a live vaccine should be avoided in patients receiving 4-Eppedo. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Reproductive system - 4-Eppedo can have genotoxic effects. Men and women treated with 4-Eppedo should adopt appropriate contraceptive measures. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.

Additional warnings and precautions for other routes of administration

Intravesical route - Administration of 4-Eppedo may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumors).

Intra-arterial route - Intra-arterial administration of 4-Eppedo (transcatheter arterial embolization for the localized or regional therapies of primary hepatocellular carcinoma or liver metastases) may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of 4-Eppedo) localized or regional events which include gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.

4-Eppedo contains sodium.

This medicinal product contains 3.6 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

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 generalized infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

While treatment with high doses of 4-Eppedo (e.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 4-Eppedo does require special attention for possible clinical complications due to profound myelosuppression.

Cardiac function – Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.

Early (i.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.

Late (i.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 dyspnea, 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.

The risk of developing CHF increases rapidly with increasing total cumulative doses of 4-Eppedo in excess of 900 mg/m²; this cumulative dose should only be exceeded with extreme caution .

Monitoring of cardiac function. 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 4-Eppedo 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 (LVEF). Electrocardiogram (ECG) changes may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other medicinal products with the ability to suppress cardiac contractility or cardiotoxic medicinal products (e.g. trastuzumab) 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.

Cardiotoxicity in combination with trastuzumab. 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 traztuzumab 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. If anthracyclines such as epirubicin are used, the patient's cardiac function should be monitored carefully.

If symptomatic cardiac failure develops during trastuzumab therapy after epirubicin therapy, it should be treated with the standard medications for this purpose.

Haematological toxicity – As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this medicinal product. Leukopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after administration of the medicinal product; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia, or death.

Secondary leukaemia – Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin. Secondary leukaemia is more common when such medicinal products are given in combination with DNA-damaging antineoplastic agents, in combination with radiation treatment, when patients have been heavily pre-treated with cytotoxic medicinal products, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period .

Gastrointestinal – Epirubicin is emetogenic. Mucositis/stomatitis generally appears early after administration of the medicinal product and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.

Liver function – The major route of elimination of epirubicin is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with epirubicin. Patients with elevated bilirubin or AST may experience slower clearance of the medicinal product with an increase in overall toxicity. Lower doses are recommended in these patients . Patients with severe hepatic impairment should not receive epirubicin .

Renal function – Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl .

Effects at site of injection – Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site .

Extravasation – Extravasation of epirubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of epirubicin the infusion of the medicinal product should be immediately discontinued. The adverse effect of extravasation of anthracyclines may be prevented or reduced by immediate use of a specific treatment e.g. dexrazoxane (please refer to relevant labels for use). The patient's pain may be relieved by cooling down the area and keeping it cool, use of hyaluronic acid and DMSO. The patient should be monitored closely during the subsequent period of time, as necrosis may occur after several weeks. If extravasation occurs, a plastic surgeon should be consulted with a view to possible excision.

Other – As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of epirubicin.

Tumour-lysis syndrome – Epirubicin may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid lysis of neoplastic cells (tumour-lysis syndrome) induced by the medicinal product. Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumour-lysis syndrome.

Immunosuppressant effects/Increased susceptibility to infections – Vaccination with a live vaccine should be avoided in patients immunocompromised by chemotherapeutic agents including epirubicin as it may result in serious or fatal infections . Killed or inactivated vaccines may be administered to patients receiving epirubicin; however, the response to such vaccines may be diminished.

Reproductive system – Epirubicin can cause genotoxicity. Men and women treated with epirubicin should adopt appropriate contraceptives Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available.

Additional warnings and precautions for other routes of administration

Intravesical route – Administration of epirubicin may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterization problems (e.g., uretheral obstruction due to massive intravesical tumours).

Effects on ability to drive and use machines
The information provided in Effects on ability to drive and use machines of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

There have been no reports of particular adverse events relating to the effects on ability to drive and to use machines.

The effect of 4-Eppedo on the ability to drive or use machinery has not been systematically evaluated.

4-Eppedo may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

The effect of epirubicin on the ability to drive or use machinery has not been systematically evaluated.

Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.

Undesirable effects
The information provided in Undesirable effects of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

The following undesirable effects have been observed and reported during treatment with 4-Eppedo 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 (cannot be estimated from the available data).

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

Frequency

Undesirable effects

Infections and infestations

Common

Infection

Not known

Septic shock, sepsis, pneumonia

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rare

Acute lymphocytic leukaemia, acute myelogenous leukaemia with or without a pre-leukaemic phase, in patients treated with 4-Eppedo in combination with DNA-damaging antineoplastic agents. These leukaemias have a short (1-3 years) latency.

Blood and the lymphatic system disorders1

Very common

Myelosuppression (leukopenia, granulocytopenia, neutropenia, anemia and febrile neutropenia)

Uncommon

Thrombocytopenia

Not known

Haemorrhage and tissue hypoxia as result of myelosoppression.

Immune system disorders

Rare

Anaphylaxis (anaphylactic/ anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills)

Metabolism and nutrition disorders

Common

Anorexia, dehydration

Rare

Hyperuricemia as a result of rapid lysis of neoplastic cells

Nervous system disorders

Uncommon

Headache

Rare

Dizziness

Eye disorders

Not known

Conjunctivitis, keratitis

Cardiac disorders

Rare

Congestive heart failure, (dyspnoea; oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusions, gallop rhythm) cardiotoxicity (e.g. ECG abnormalities, arythmias, cardiomyopathy), ventricular tachycardia, bradycardia, AV block, bundle-branch block .

Vascular disorders

Common

Hot flashes

Uncommon

Phlebitis, thrombophlebitis

Not known

Shock, thromboembolism, including pulmonary embolism (in isolated cases with fatal outcome)

Gastrointestinal disorders

Common

Mucositis, oesophagitis, stomatitis, vomiting, diarrhea, nausea

Not known

Oral mucosa erosion, mouth ulceration, oral pain, mucosal burning sensation, mouth haemorrhage, and buccal pigmentation

Skin and subcutaneous tissue disorders

Very common

Alopecia, normally reversible, appears in 60-90% of treated cases; it is accompanied by lack of beard growth in males

Rare

Urticaria

Not known

Local toxicity, rash, itch, skin changes, erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction)

Renal and urinary disorders

Very common

Red coloration of urine for 1 to 2 days after administration

Reproductive system and breast disorders

Rare

Amenorrhea, azoospermia

General disorders and administration site conditions

Common

Infusion site erythema

Rare

Malaise,/asthenia, fever, chills, hyperpyrexia

Not known

Phlebosklerosis, local pain, severe cellulitis, tissue necrosis (following accidental paravenous injection)

Investigations

Rare

Changes in transaminase levels

Not known

Asymptomatic drops in left ventricular ejection fraction

Injury, poisoning and procedural complications

Common

Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration .

1High doses of 4-Eppedo 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.

Intravesical administration:

As only a small amount of active ingredient is reabsorbed after intravesical instillation, severe systemic adverse drug reactions as well as allergic reactions are rare. Commonly reported are local reactions like burning sensation and frequent voiding (pollakisuria).Occasional bacterial or chemical cystitis have been reported . These ADRs 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

The following undesirable 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).

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

Frequency

Undesirable effects

Infections and infestations

Very common (≥ 1/10)

Infection

Not known (cannot be estimated from the available data)

Septic shock, sepsis, pneumonia

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Uncommon (≥1/1,000 to <1/100)

Acute lymphocytic leukaemia, acute myelogenous leukaemia

Blood and lymphatic system disorders

Very common

(≥1/10)

Myelosuppression (leukopenia, granulocytopenia and neutropenia, anaemia and febrile neutropenia, thrombocytopenia)

Not known

(cannot be estimated from the available data)

Haemorrhage and tissue hypoxia as result of myelosuppression

Immune system disorders

Rare (≥1/10,000 to <1/1,000)

Anaphylaxis (anaphylactic/anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills), allergic reactions following intravesical administration

Metabolism and nutrition disorders

Very common (≥1/10)

Loss of appetite

Common (≥1/100 to <1/10)

Dehydration

Rare (≥1/10,000 to <1/1,000)

Hyperuricemia

Nervous system disorders

Rare (≥1/10,000 to <1/1,000)

Dizziness

Eye disorders

Uncommon (≥1/1,000 to <1/100)

Conjunctivitis, keratitis

Cardiac disorders

Common (≥1/100 to <1/10)

Congestive heart failure (CHF) (dyspnoea, oedema, hepatomegaly, ascites, pulmonary oedema, pleural effusions, extrasystoles)

Rare (≥1/10,000 to <1/1,000)

Cardiotoxicity (e.g. ECG abnormalities, arrhythmias, cardiomyopathy), ventricular tachycardia, bradycardia, AV block, bundle-branch block

Vascular disorders

Common

(≥1/100 to <1/10)

Hot flashes

Uncommon

(≥1/1,000 to <1/100)

Phlebitis, thrombophlebitis

Very rare (<1/10,000)

Shock

Not known

(cannot be estimated from the available data)

Thromboembolism, including pulmonary emboli

Gastrointestinal disorders

Very common (≥1/10)

Mucositis, stomatitis, vomiting, diarrhoea, nausea, which can result in loss of appetite and abdominal pain

Common

(≥1/100 to <1/10)

Oral pain, mucosal burning sensation, oesophagitis

Uncommon (≥1/1,000 to <1/100)

Gastric erosion and ulcers, gastrointestinal haemorrhage, hyperpigmentation of the oral mucous membranes

Skin and subcutaneous tissue disorders

Very common

(≥1/10)

Alopecia

Common (≥1/100 to <1/10)

Local skin and tissue toxicity, rash, pruritus

Uncommon (≥1/1,000 to <1/100)

Skin changes, erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction)

Rare

(≥1/10,000 to <1/1,000)

Urticaria

Renal and urinary disorders

Very common

(≥1/10)

Red colouration of urine for 1 to 2 days after administration

Reproductive system and breast disorders

Common (≥1/100 to <1/10)

Amenorrhoea

Rare

(≥1/10,000 to <1/1,000)

Azoospermia

General disorders and administration site conditions

Common

(≥1/100 to <1/10)

Infusion site erythema. Paravenous injection can cause tissue necrosis. Malaise, asthenia, fever

Rare

(≥1/10,000 to <1/1,000)

Chills

Not known

(cannot be estimated from the available data)

Phlebosclerosis, local pain, severe cellulitis

Investigations

Common (≥1/100 to <1/10)

Changes in transaminase levels,

Asymptomatic decreases in left ventricular ejection fraction (LVEF)

Injury, poisoning and procedural complications

Common

(≥1/100 to <1/10)

Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration

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 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). Occasional bacterial or chemical cystitis have been reported . These ADRs 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. Healthcare professionals are asked to report any suspected adverse reactions via www.mhra.gov.uk/yellowcard.

Overdose
The information provided in Overdose of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

Symptoms:

Acute overdosage with 4-Eppedo will result in severe myelosuppression within 10-14 days (mainly leucopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and cardiac complications (acute myocardial degeneration within 24 hours). During this period a blood transfusion is required as well as isolation in a sterile room. Latent cardiac failure has been observed with anthracyclines several months (up to 6 months) to years after completion of treatment . Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic.

4-Eppedo cannot be removed by dialysis.

Acute overdosage with epirubicin will result in severe myelosuppression (within 10 – 14 days; mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications (within 24 hours). Latent cardiac failure has been observed with anthracyclines several months to years after completion of treatment . Patients must be carefully monitored. If signs of cardiac failure occur, patients should be treated according to conventional guidelines.

Treatment:

Symptomatic. Epirubicin cannot be removed by dialysis.

Pharmacodynamic properties
The information provided in Pharmacodynamic properties of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

4-Eppedo is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of 4-Eppedo is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. 4-Eppedo has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

Pharmacotherapeutic group: Antineoplastic agent. ATC code: L01D B03

Epirubicin is a cytotoxic active antibiotic from the anthracycline group.

The mechanism of action of epirubicin is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).

Pharmacokinetic properties
The information provided in Pharmacokinetic properties of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m2 of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are 4-Eppedool (13-OH 4-Eppedo) and glucuronides of 4-Eppedo and 4-Eppedool.

The 4'-O-glucuronidation distinguishes 4-Eppedo from doxorubicin and may account for the faster elimination of 4-Eppedo and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (4-Eppedool) are consistently lower and virtually parallel than those of the unchanged drug.

4-Eppedo is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution. Urinary excretion accounts for approximately 9-10% of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The drug does not cross the blood brain barrier.

In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m² of the medicinal product follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. Between 60 and 120 mg/m² there is an extensive linear pharmacokinetic, 150 mg/m² is at the margin of dose linearity. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.

In pharmacokinetic studies of patients with carcinoma in situ of the bladder the plasma levels of epirubicin after intravesical instillation are typically low (< 10 ng/ml). A significant systemic resorption can therefore not be assumed. In patients with lesions of the mucosa of the bladder (e.g. tumour, cystitis, operations), a higher resorption rate can be expected.

The 4'-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged active substance.

Epirubicin is eliminated mainly through the liver; high plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution. Urinary excretion accounts for approximately 9 – 10 % of the administered dose in 48 hours.

Biliary excretion represents the major route of elimination, about 40 % of the administered dose being recovered in the bile in 72 hours. The active substance does not cross the blood brain barrier.

Pharmacotherapeutic group
The information provided in Pharmacotherapeutic group of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Antineoplastic agent. ATC code: L01D B03
Preclinical safety data
The information provided in Preclinical safety data of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Substance

Following repeated dosing with 4-Eppedo, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. 4-Eppedo was also cardiotoxic in the rat, rabbit and dog.

4-Eppedo, like other anthracyclines, was mutagenic, genotoxic, embryotoxic and carcinogenic in rats. No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, 4-Eppedo must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of 4-Eppedo causes tissue necrosis.

Following repeated dosing with epirubicin, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin was also cardiotoxic in the rat, rabbit and dog.

Epirubicin, like other anthracyclines, was mutagenic, genotoxic and carcinogenic in rats. Embryotoxicity was seen in rats at clinically relevant doses.

No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic active substances, epirubicin must be considered potentially teratogenic.

A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.

Incompatibilities
The information provided in Incompatibilities of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug, which includes sodium bicarbonate containing solutions.

Neither the injection nor any diluted solution should be mixed with any other drugs (a physical incompatibility with heparin has been reported).

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Prolonged contact of the medicinal product with any solution of an alkaline pH (including sodium bicarbonate solutions) should be avoided; this will result in hydrolysis (degradation) of the active substance.

A physical incompatibility of the medicinal product with heparin has been reported.

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Special precautions for disposal and other handling
The information provided in Special precautions for disposal and other handling of 4-Eppedo is based on data of another medicine with exactly the same composition as the 4-Eppedo of the medicine (Epirubicin). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug 4-Eppedo directly from the package or from the pharmacist at the pharmacy.
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Concentrate for solution preparation for intravenous and intracavitary administration; Lyophilizate for the preparation of a solution for intravascular and intravesical administration
Substance
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As with other potentially toxic compounds, caution should be exercised when handling 4-Eppedo (hydrochloride) 2 mg/ml, solution for injection.

The handling of this cytotoxic agent by nursing or medical personnel requires every precaution to guarantee the protection of the handler and his surroundings.

4-Eppedo (hydrochloride) 2 mg/ml, solution for injection may be further diluted in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. The infusion solution should be prepared immediately before use.

The injection solution contains no preservative and any unused portion of the vial should be discarded immediately.

Guidelines for the safe handling and disposal of antineoplastic agents:

1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.

2. Preparation of an infusion solution should be performed in a designated aseptic area.

3. Adequate protective disposable gloves, goggles, gown and mask should be worn.

4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9% sodium chloride solution. Then seek medical evaluation by a physician.

5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.

6. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed below.

7. Pregnant staff should not handle the cytotoxic preparation.

8. Adequate care and precautions should be taken in the disposal of items (syringes, needles, etc) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

4-Eppedo may be further diluted in glucose 5 % solution or sodium chloride 0.9 % solution and administered as an intravenous infusion.

The injection solution contains no preservative and any unused portion of the vial should be disposed of immediately in accordance with local requirements.

Guidelines for the safe handling and disposal of antineoplastic agents:

1. If an infusion solution is to be prepared, this should be performed by trained personnel under aseptic conditions.

2. Preparation of an infusion solution should be performed in a designated aseptic area.

3. Adequate protective disposable gloves, goggles, gown and mask should be worn.

4. Precautions should be taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or 0.9 % sodium chloride solution. Then seek medical evaluation by a physician.

5. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Always wash hands after removing gloves.

6. Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as detailed below.

7. Pregnant staff should not handle the cytotoxic preparation.

8. Adequate care and precautions should be taken in the disposal of items (syringes, needles etc.) used to reconstitute and/or dilute cytotoxic medicinal products. Any unused product or waste material should be disposed of in accordance with local requirements.

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