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Epirubicin Hydrochloride 2 Mg/Ml Solution For Injection

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Epirubicin hydrochloride 2 mg/ml solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 2 mg epirubicin hydrochloride.

One 5 ml / 10 ml / 25 ml / 50 ml / 100 ml vial contains 10 mg / 20 mg / 50 mg / 100 mg / 200 mg epirubicin hydrochloride.

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:

- 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.

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 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.

Dosage

In order to avoid cardiac toxicity, a total cumulative dose of 900 - 1000 mg/m²epirubicin should not be exceeded (see section 4.4).

Conventional dose

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

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 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 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 other tumours, as shown:

Cancer Indication	Epirubicin 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

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	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 (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 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

epirubicin

required

Volume of 2 mg/ ml epirubicin 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

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.

4.3. Contraindications

Hypersensitivity to epirubicin or any other component of the product, other anthracyclines or anthracenediones.

Lactation (see section 4.6).

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 (see section 4.4)

• 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

• hematuria

• contracted bladder

• big volume of residual urine

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, mucositis, neutropenia, thrombocytopenia, and generalized 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 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 nonspecific 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 edema, dependent edema, 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).

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 epirubicin 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, and concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g. trastuzumab) (see section 4.5).

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.

Hematologic Toxicity - As with other cytotoxic agents, epirubicin may produce myelosuppression. Hematologic 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 hematologic 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 the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary Leukemia - 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).

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.

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 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).

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 (see section 4.2).

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 drug infusion should be immediately discontinued. The patient’s pain may be relieved by cooling down the area and keeping it cool for 24 hours. 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.

Tumor-Lysis Syndrome - Epirubicin may induce hyperuricemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumor-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia 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 epirubicin, may result in serious or fatal infections (see section 4.5).

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, 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).

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 gastro-intestinal effects (see section 4.4).

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. The use of epirubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), requires monitoring of cardiac function throughout treatment.

Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity (see section 4.4).

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.

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.

Cimetidine increased the AUC of epirubicin by 50% and should be discontinued during treatment with epirubicin.

When given prior to epirubicin, paclitaxel can cause increased plasma concentrations of unchanged epirubicin and its metabolites, the latter being, however, neither toxic nor 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.

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

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

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 co-administration of interferon a_2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.

The possibility of a marked disturbance of haematopoiesis needs to be kept in mind when patients have been previously treated with medication which affects the bone marrow (i.e. cytostatic agents, sulphonamides, chloramphenicol, diphenylhydantoin, amidopyrine-derivates, antiretroviral agents).

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

4.6. Pregnancy and lactation

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.

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	Frequency	Undesirable effects
Class

Infections and infestations	Common	Infection
Infections and infestations	Not known	Septic shock, sepsis, pneumonia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Rare	Acute lymphocytic leukemia, acute myelogenous leukemia
Blood and the lymphatic system disorders	Very common	Myelosuppression (leukopenia, granulocytopenia and neutropenia, anemia and febrile neutropenia)
	Uncommon	Thromb ocytop eni a
	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), allergic reactions following intravesical administration
Metabolism and nutrition disorders	Common	Anorexia, dehydration
Metabolism and nutrition disorders	Rare	Hyperuricemia (see section 4.4)
Nervous system disorders	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, arrythmias, cardiomyopathy), ventricular tachycardia, bradycardia, AV block, bundle-branch block (see section 4.4).
Vascular disorders	Common	Hot flashes
	Uncommon	Phlebitis, thrombophlebitis
	Not known	Shock, thromboembolism, including pulmonary emboli
Gastrointestinal disorders	Common	Mucositis, oesophagitis, stomatitis, vomiting, diarrhea, nausea, which can result in loss of appetite and abdominal pain
Skin and subcutaneous tissue disorders	Very common	Alopecia
	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
General disorders and administration site conditions	Rare	Malaise, asthenia, fever, chills
Investigations	Rare	Changes in transaminase levels
Investigations	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 (see section 4.4).

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 year) latency.

Blood and the 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 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.

Overdose

4.9.

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 (see section 4.4). 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.

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 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.

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 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

sodium chloride

hydrochloric acid (for pH adjustment) water for injections

6.2 Incompatibilities

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

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

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6.

6.3. Shelf life

2 years.

In use:

Epimedac may be further diluted, under aseptic conditions, in glucose 5 % solution or sodium chloride 0.9 % solution and administered as an intravenous infusion. The chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C in the absence of light.

However, from a microbiological point of view, the product 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 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 after dilution see section 6.3.

6.5 Nature and contents of container

Clear glass vials Type I with fluoropolymer-coated chlorobutyl rubber stoppers containing 5 ml, 10 ml, 25 ml, 50 ml or 100 ml solution of epirubicin hydrochloride 2 mg/ml.

Pack size: 1 vial.

6.6 Special precautions for disposal and other handling

Epirubicin hydrochloride may be further diluted in glucose 5 % solution or sodium chloride 0.9 % solution and administered as an intravenous infusion. For information on the stability of the infusion solutions please refer to section 6.3.

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.

7 MARKETING AUTHORISATION HOLDER

medac

Gesellschaft fur klinische Spezialpraparate mbH

Fehlandtstr. 3

D-20354 Hamburg

Tel.: +49 / 4103 / 8006-0

Fax: +49 / 4103 / 8006-100

8 MARKETING AUTHORISATION NUMBER(S)

PL 11587/0043

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/04/2008

10 DATE OF REVISION OF THE TEXT

28/05/2010