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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Epirubicin 2 mg/ml, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Epirubicin Hydrochloride 2 mg/ml

1 ml of solution for injection contains 2 mg of epirubicin hydrochloride.

Each vial of 5 ml of solution contains 10 mg of epirubicin hydrochloride.

Each vial of 10 ml of solution contains 20 mg of epirubicin hydrochloride. Each vial of 25 ml of solution contains 50 mg of epirubicin hydrochloride. Each vial of 50 ml of solution contains 100 mg of epirubicin hydrochloride. Each vial of 100 ml of solution contains 200 mg of epirubicin hydrochloride.

Epirubicin 2 mg/ml, solution for injection contains sodium (3.6 mg/ml or 0.16 mmol/ml).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection A clear red solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

•    Breast and gastric carcinomas,

When administered intravesically, epirubicin 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.

4.2 Posology and method of administration

Epirubicin is for intravenous or intravesical use only.

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 or glucose infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation (see section 4.4). In case of extravasation, administration should be stopped immediately.

Conventional dose

When epirubicin is used as a single agent, the recommended dosage in adults is 60-90 mg/m² body area. Epirubicin 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.

Breast Cancer

In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin 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 epirubicin are commonly used in monotherapy and combination chemotherapy for various tumours, as shown:

	Epirubicin 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 (see section 4.4).

Combination therapy

If epirubicin 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	AST*	Dose Reduction
1.4 - 3 mg/100 ml (24 - 51 pmol/l)		50 %
> 3 mg/100 ml	> 4 times upper	75 %
(> 51 pmol/l)	normal limit

* AST - aspartate aminotransferase

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, lower starting doses should be considered in patients with severe renal impairment (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 (see section 4.3). 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 distilled sterile water).

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 Epirubicin required	Volume of 2 mg/ml Epirubicin injection	Volume of diluent (sterile water for injection or 0.9% sterile saline)	Total volume for bladder instillation
30 mg	15 ml	35 ml	50 ml
50 mg	25 ml	25 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.

4.3. Contraindications

•    Hypersensitivity to epirubicin or to any of the excipients listed in section 6.1, other anthracyclines or anthracenediones

•    Lactation

Contraindications to intravenous administration:

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

•    Severe hepatic impairment

•    Patients treated previously with maximum cumulative doses of epirubicin and/or other anthracyclines such as doxorubicin or daunorubicin and anthracenediones (see section 4.4)

•    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, arrhythmia with serious haemodynamic consequences, myocardiopathy, recent myocardial infarction)

•    Patients with acute systemic infections

•    Patients with unstable angina pectoris

Contraindications to the intravesical administration of epirubicin are:

•    Urinary tract infections

•    Inflammation of the bladder

•    Haematuria

•    Invasive tumours penetrating the bladder

•    Catheterisation problems

•    Vesical inflammation

•    Large volume of residual urine

•    Contracted bladder

4.4. Special warnings and precautions for use

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 or mucositis, neutropenia, thrombocytopenia, and generalised infections) of prior cytotoxic treatment before beginning treatment with epirubicin.

While treatment with high doses of epirubicin (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 epirubicin requires special attention for possible clinical complications due to profound myelosuppression.

Diagnostic and treatment facilities should be readily available management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of epirubicin.

Epirubicin can have genotoxic effects. Men and women treated with epirubicin 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. Therefore, male patients treated with epirubicin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to because of the possibility of infertility due to therapy with epirubicin (see section 4.6).

Women should not become pregnant during treatment with epirubicin. Men and women should use an effective method of contraception during treatment and for six months thereafter (see section 4.6).

Extravasation - Extravasation of epirubicin 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 epirubicin, 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 epirubicin.

Immunosuppressant Effects/Increased Susceptibility to Infections -Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections (see section 4.5). Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

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 (see section 4.2).

Haematologic Toxicity- As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematological profiles should be assessed before and during each cycle of therapy with epirubicin. 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 epirubicin 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 10^th and 14^th day after drug administration; this is usually transient with WBC/neutrophil counts returning to normal in most cases by the 21^st day. Thrombocytopenia (< 100,000 platelets/mm³) is experienced in very few patients, even following high doses of epirubicin. Anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Gastrointestinal - Epirubicin 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.

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 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 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 epirubicin in excess of 900 mg/m²; this cumulative dose should only be exceeded with extreme caution (see section 5.1). Above this level the risk of irreversible congestive heart failure increases greatly.

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

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

Cardiac function should be assessed before patients undergo treatment with epirubicin and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.

Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m² epirubicin 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 epirubicin 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 epirubicin 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 epirubicin may occur at lower cumulative doses whether or not risk factors are present. It is probable that the toxicity of epirubicin 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) (see section 4.5) with an increased risk in the elderly.

Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in patients receiving trastuzamab therapy alone or in combination with anthracyclines such as epirubicin. This may be moderate to severe and has been associated with death.

Trastuzumab and anthracyclines such as epirubicin should not be used currently in combination except in a well-controlled clinical trial setting with cardiac monitoring. Patients who have previously received anthracyclines are also at risk of cardiotoxicity with trastuzumab treatment, although the risk is lower than with concurrent use of traztuzumab and anthracyclines.

Because the half-life of trastuzumab is approximately 4-5 weeks, trastuzumab may persist in the circulation for up to 20-25 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 25 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.

Secondary Leukaemia - Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including epirubicin. 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. (See section 5.1).

Tumor Lysis Syndrome - As with other cytotoxic agents, epirubicin 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.

Liver Function - The major route of elimination of epirubicin is the hepatobiliary system. Before starting therapy with epirubicin, 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 (see sections 4.2 and 5.2). Patients with severe hepatic impairment should not receive epirubicin (see section 4.3).

Renal Function - Serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine > 5 mg/dl (see section 4.2).

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

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, 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 epirubicin (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 epirubicin) 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 druginduced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue.

Epirubicin contains sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially ‘sodium- free’.

4.5. Interaction with other medicinal products and other forms of interaction

Epirubicin is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/hematologic and gastrointestinal effects (see section 4.4). Patients should be monitored for additive toxicity, especially myelotoxicity and gastrointestinal toxicity.

Drug interactions with epirubicin have been observed with cimetidine, dexverapamil, dexrazoxane, docetaxel, interferon a2b, paclitaxel, trastuzumab and quinine.

Cimetidine 400 mg b.i.d given prior to epirubicin 100 mg/m² every 3 weeks led to a 50% increase in epirubicin AUC and a 41% increase in epirubicinol AUC (latter p<0.05). The AUC of the 7- eoxydoxorubicinol aglycone and liver blood flow were not reduced, so results are not explained by reduced cytochrome P-450 activity. Cimetidine should be discontinued during treatment with epirubicin.

Dexverapamil may alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects.

Prior administration of higher doses (900 mg/m2 and 1200 mg/m2) of dexrazoxane may increase the systemic clearance of epirubicin and result in a decrease in AUC.

Increase in myelosuppression may occur in patients receiving combination therapy of anthracycline and dexrazoxane.

One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites when administered immediately after epirubicin.

The co-administration of interferon a2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.

When given prior to epirubicin, paclitaxel has been show to increase plasma concentrations of unchanged epirubicin and its metabolites, the latter being, however, neither toxic or active. Coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin when epirubicin was administered prior to the taxane.

This combination may be used if using staggered administration between the two agents. Infusion of epirubicin and paclitaxel should be performed with at least a 24 hour interval between the 2 agents.

Quinine may accelerate the initial distribution of epirubicin from blood into the tissues and may have an influence on the red blood cells partitioning of epirubicin.

The possibility of a marked disturbance of haematopoiesis needs to be kept in mind with a (pre-) treatment with medications which influence the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, antiretroviral agents).

The potential risk of cardiotoxicity may increase in patients who have received concomitant cardiotoxic agents (e.g. 5-fluorouracil, cyclophosphamide, cisplatin, taxanes), or concomitant (or prior) radiotherapy to the mediastinal area.

If epirubicin is used in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardiotoxic compounds that may cause heart failure, e.g. calcium channel blockers, then cardiac function must be monitored throughout the course of treatment.

Anthracyclines including epirubicin should not be administered in combination with other cardiotoxic agents unless the patient’s cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The half-life of trastuzumab is approximately 28.5 days and may persist in the circulation for up to 24 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 24 weeks after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.

Epirubicin is extensively metabolised in the liver. Changes in hepatic function induced by concomitant therapies may affect the metabolism or the pharmacokinetics of epirubicin and, consequently, its efficacy and/or toxicity(see Section 4.4).

Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

4.6. Fertility, pregnancy and lactation

Pregnancy

Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods.

There is no conclusive information as to whether epirubicin may adversely affect human fertility or cause teratogenesis.

Experimental data, however, suggest that epirubicin may harm the fetus when administered to a pregnant woman. Like most other anti-cancer agents, epirubicin has shown mutagenic and carcinogenic properties in animals. Both men and women receiving epirubicin should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the fetus. If epirubicin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus; the possibility of genetic counselling should be considered if they become pregnant during epirubicin therapy. There are no studies in pregnant women. In cancer chemotherapy, epirubicin should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the fetus (see section 4.4).

Breast-feeding

It is not known whether epirubicin is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from epirubicin, breastfeeding must be discontinued before therapy with epirubicin.

Fertility

Epirubicin could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should use effective contraceptive methods and if appropriate and available, seek advice on sperm preservation due to the possibility

of irreversible infertility caused by therapy. Epirubicin may cause amenorrhea or premature menopause in premenopausal women.

4.7. Effects on ability to drive and use machines

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

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

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

4.8. Undesirable effects

The following undesirable effects have been observed and reported during treatment with epirubicin 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
	Common	Infection
Infections and infestations	Not known	Septic shock, sepsis, pneumonia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Rare	Acute lymphocytic leukaemia, secondary acute myelogenous 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 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)
	Common	Anorexia, dehydration
Metabolism and nutrition disorders	Rare	Hyperuricemia as a result of rapid lysis of neoplastic cells (see section 4.4)
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), tachycardia, ventricular tachycardia, bradycardia, AV block, bundle-branch block(see section 4.4).
	Common	Hot flashes
	Uncommon	Phlebitis, thrombophlebitis
Vascular disorders	Not known	Shock, thromboembolism, including pulmonary embolism (in isolated cases with fatal outcome)
	Common	Mucositis2, oesophagitis, stomatitis, vomiting, diarrhea, nausea3
Gastrointestinal disorders	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 6090% 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
	Common	Infusion site erythema, local phlebitis
General disorders and administration site conditions	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 function
Injury, poisoning and procedural complications	Common	Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration (see section 4.4).

'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.

²May 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.

³Nausea, vomiting, diarrhoea, which can result in dehydration, loss of appetite and abdominal pain

Fever, infections, pneumonia, sepsis and septic shock may occur as a result of myelosuppression.

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 (see section 4.4). These ADRs are mostly reversible.

4.9. Overdose

Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression (mainly leucopenia and thrombocytopenia) within 10-14 days, gastrointestinal toxic effects (mainly mucositis) and acute cardiac complications.

Latent cardiac failure has been seen with the anthracyclines several months to years after the completion of treatment (see section 4.4).

Treatment: Symptomatic.

Treatment should aim to support the patient during this period and should use such measures as antibiotics, blood transfusion and reverse barrier nursing.

Patients should be carefully monitored. If signs of cardiac failure occur, patients should be treated along conventional guidelines.

Epirubicin cannot be removed by dialysis.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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).

5.2 Pharmacokinetic properties

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. 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 than those of the unchanged drug.

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 drug does not cross the blood brain barrier.

5.3 Preclinical safety data

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

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride

Water for Injections Hydrochloric acid for pH adjustment

6.2 Incompatibilities

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. Only the diluents detailed in section 6.3 should be used.

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

Epirubicin should not be mixed with other drugs.

6.3    Shelf life

Before first opening: 3 years.

After dilution: after dilution in Glucose 5% or Sodium Chloride 0.9%, chemical and physical in-use stability has been demonstrated for 60 minutes at +25°C.

From a microbiological point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5. Nature and contents of container

5ml, 10 ml, 25 ml, 50 ml, 100 ml type I colourless glass vials, with a bromobutyl rubber stopper and flip-off cap. Box of 1, 5 or 10.

Not all pack sizes may be marketed.

6.6. Special precautions for disposal and handling

For methods of administration, see section 4.2.

As with other potentially toxic compounds, caution should be exercised when handling Epirubicin 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.

Epirubicin 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.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom.

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/0983

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 23/12/2011

10 DATE OF REVISION OF THE TEXT

10/01/2013