SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Epirubicin Hydrochloride 2 mg/ml Solution for Injection/Intravesical Use

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each millilitre contains 2 mg epirubicin hydrochloride For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Solution for Injection (Injection)/Intravesical Use A clear red solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Intravenous use:

•    Breast carcinoma

•    Gastric carcinoma

Intravesical use:

Prophylaxis of recurrences after transurethral resection.

4.2    Posology and method of administration

Epirubicin is for intravenous or intravesical use only.

Intravenous administration

It is advisable to administer epirubicin via the tubing of a free-running intravenous saline infusion after checking that the needle is properly placed in the vein. Care should be taken to avoid extravasation (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 area. Epirubicin should be injected intravenously over 3-5 minutes. The

dose should be repeated at 21-day intervals, depending upon the patient’s haematomedullary 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.

High dose

Epirubicin as a single agent for the high dose treatment of breast cancer should be administered according to the following regimens:

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.

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.

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:

Cancer Indication	Epirubicin Dose (mg/m2)a
	Monotherapy	Combination Therapy
Gastric cancer	60-90	50

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

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:

1.4 - 3 mg/100 ml		50%
>3 mg/100 ml	>4 times upper normal limit	75%

*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. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine >450pmol/l).

Intravesical administration

Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours to prevent recurrence. 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.

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 installation
50 mg	25 ml	25 ml	50 ml

The solution should be retained intravesically for 1 hour. 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

Epirubicin is contraindicated in:

•    Patients who have demonstrated hypersensitivity to epirubicin or to any of the excipients, and/or other anthracyclines or anthracenediones.

•    Lactation

For Intravenous use, epirubicin is contraindicated in:

•    Patients with persistent myelosuppression or myelosuppression induced by previous treatment with either other anti-neoplastic agents or radiotherapy. ¹

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

•    Patients with current or previous history of cardiac impairment such as those who exhibit severe arrhythmias, severe myocardial insufficiency, recent myocardial infarction, myocardiopathy and patients with unstable angina pectoris

•    Patients with acute systemic infections

For Intravesical use, epirubicin is contraindicated in:

•    Patients with urinary tract infections

•    Patients with inflammation of the bladder

•    Patients who have invasive tumours penetrating the bladder

•    Patients with catheterisation problems

4.4 Special warnings and precautions for use

Epirubicin should only be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications due to myelosuppression, especially following treatment with higher doses of epirubicin.

Epirubicin can have genotoxic effects. Therefore, male patients treated with epirubicin are advised not to father a child during and up to 6 months after completion of treatment. Patients are advised to seek medical advice on conversation of sperm prior to initiating treatment due to the possibility of infertility with epirubicin therapy.

Women should not become pregnant during treatment with epirubibin. Men and women should use effective methods of contraception during tretaemnt and for 6 months after terminating treatment with epirubicin.

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

Patients should recover from acute toxicities (such as stomatitis, 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.

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. The effects are rarely considered for clinical significance and are generally not taken as indications to discontinue treatment with epirubicin.

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 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 left ventricular ejection fraction (LVEF). Other signs and symptoms that have been reported include 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 is increased in those patients who receive higher cumulative doses of epirubicin in excess of 900 mg/m². Given the risk of cardiomyopathy, this cumulative dose should only be exceeded with extreme caution (see section 5.1). In the event of establishing the maximum cumulative dose of epirubicin, consideration should also be given to those patients in concomitant therapy who are undergoing medical treatment with other potentially cardiotoxic drugs.

Heart failure may appear several weeks after discontinuing epirubicin therapy and may be unresponsive to specific medical treatment. 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 should be assessed in patients prior to undergoing treatment with epirubicin and must be continuously monitored during the course of treatment to minimise the risk of incurring severe cardiac impairment. The risk may be reduced with the prompt termination of epirubicin at the first sign of impaired function by regularly monitoring the LVEF during the course of treatment. However, treatment with epirubicin should be terminated should the patient show signs for cardiac insufficiency.

The appropriate quantitative method for repeated assessment of cardiac function is evaluation of LVEF measure by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or either an ECHO is recommended, particularly in those patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed particularly for those patients who receive higher cumulative anthracycline doses. The technique used in the evaluation for cardiac function should be consistent throughout the follow-up. It is highly advisable to follow a strict regimen to monitor cardiac function in patients with high risk factors, particularly those previously treated with anthracyclines and anthracenediones.

The potential risk of cardiotoxicity may increase in those patients who exhibit active or dormant cardiovascular disease, and in those who received previous or concomitant radiotherapy to the mediastinal/ pericardial areas. This includes previous therapy with other anthracyclines or anthracenediones, and the 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 assessed in patients receiving higher cumulative doses and in those with risk factors. However, cardiotoxicity may occur following lower cumulative doses of epirubicin whether or not cardiac risk factors have been identified. It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive.

Haematologic Toxicity - As with other cytotoxic agents, epirubicin may produce myelosuppression. Haematologic profiles should be assessed both before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts, red blood cell, neutrophil and platelet counts. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopenia and neutropenia are generally more severe with high-dose schedules, reaching a nadir in most cases between days 10 and 14 following drug administration. However, this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopenia (<100,000 platelets/mm³) is reported in very few patients and anaemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, haemorrhage, 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 or in combination with radiation treatment, or patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. This type of leukemia can have a 1 to 3-year latency period. (See section 5.1).

Gastrointestinal - Epirubicin is emetogenic. 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. Therefore serum total bilirubin and alkaline phosphatise levels (AST and ALT) should be evaluated prior to initiating treatment and during the course of treatment. Patients with elevated bilirubin or AST levels may experience slower clearance of epirubicin, which may lead to an increased toxicity. For those patients a lower dose is recommended (see sections 4.2 and 5.2). Patients with severe hepatic impairment should not be treated with epirubicin (see section 4.3).

Renal Function - For patients with reduced renal function serum creatinine levels should be assessed prior to and during therapy. For those patients with increased serum creatinine levels (> 5 mg/dL) a dosage reduction is necessary (see section 4.2).

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

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 minimise the risk of phlebitis/thrombophlebitis at the injection site (see section 4.2).

Extravasation - Extravasation of epirubicin from the vein during intravenous administration may cause local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

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 several weeks after 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 the rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate and creatinine levels should therefore be evaluated after initial treatment. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricemia may minimise potential complications of tumour-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 contraceptive methods. 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 catheterisation problems (e.g., uretheral obstruction due to massive intravesical tumours).

Intra-arterial route - Intra-arterial administration of epirubicin (transcatheter arterial embolisation for the localised 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) localised 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 and is not recommended.

4.5 Interaction with other medicinal products and other forms of interaction

It is not recommended that Epirubicin Hydrochloride 2 mg/ml Injection be mixed with other medicinal products.

Epirubicin can be used in combination with other anti-cancer agents but patients should be monitored for additive toxicity. Additive toxicity may occur especially with regard to bone marrow/ haematologic and gastro-intestinal effects (see section 4.4). The use of epirubicin in combination chemotherapy with other potentially cardiotoxic drugs (e.g., 5-fluorouracil, cyclophosphamide, cisplatin and taxanes), as well as the concomitant use of other cardioactive compounds (e.g., calcium channel blockers), requires monitoring of cardiac function throughout the course of treatment.

Epirubicin is extensively metabolised 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).

The cardiotoxicity of epirubicin is enhanced by certain radiotherapeutic treatments and can potentiate the effect of radiation.

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 discontinuing treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at high 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 discontinuing trastuzumab. If anthracyclines are used before this length of 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.

Drug interactions with epirubicin have been observed with cimetidine, dexverapamil, dexrazoxane, docetaxel, interferon alpha-2b, paclitaxel and quinine.

Medicinal products that induce the cyctochrome P450 system (e.g. rifampicin and barbiturates) can enhance epirubicin metabolism, which consequently reduces the efficacy. Conversely, certain medicinal products (e.g. cimetidine) can potentiate the clinical effect of epirubicin by inhibiting its metabolism.

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-deoxy-doxorubicinol 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.

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.

Co-administration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin when epirubicin was administered prior to the taxane. In one study, haematological toxicity was greater when paclitaxel was administered before epirubicin compared with after epirubicin.

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 two agents.

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.

One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites when administered immediately following 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 alpha-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 with a (pre) treatment with medications which influences the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate and antiretroviral agents).

4.6 Pregnancy and lactation

(Also see section 5.3)

Impairment of Fertility

Epirubicin could induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should use effective contraceptive methods and if necessary, seek medical advice on sperm preservation due to the possibility of irreversible infertility caused by the therapy.

Due to the genotoxicity effects of epirubicin, male patients are advised not to father a child during and up to 6-months following the discontinuation of epirubicin treatment.

Epirubicin may cause amenorrhoea or premature menopause in premenopausal women.

Pregnancy

Both men and women receiving epirubicin should be informed of the potential risk of adverse effects on reproduction. Epirubicin exhibit teratogenic properties and experimental data in animals suggest that epirubicin may cause foetal harm leading to miscarriage, embryotoxicity or foetal damage when administered to a pregnant woman.

There are no studies in pregnant women. Women of childbearing potential should be fully informed of the potential risks to the foetus and the possibility of genetic counselling should be considered if they become pregnant during epirubicin therapy. However should pregnancy occur and provided that the favourable benefits of the drug to the mother have been considered, cytostatic drugs should only be administered under strict indications during the first trimester.

In cancer chemotherapy, it is noted that 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 foetus.

Lactation

It is not known whether epirubicin is excreted in human milk. However, a risk to the breast-feeding infant cannot be excluded, because many drugs, including other anthracyclines are excreted in human milk which may lead to potential serious

adverse reactions in nursing infants. Mothers should therefore discontinue nursing prior to undergoing treatment with epirubicin.

Epirubicin should not normally be administered to patients who are breast-feeding.

4.7 Effects on ability to drive and use machines

There have been no reports of particular adverse events relating to the effects on ability to drive and to use machines. The effect of epirubicin on the ability to drive or use machinery has not been systematically evaluated.

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 form 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 and infection.

System Organ Class	Frequency	Undesirable effects
Infections and	Common	Infection
infestations	Not Known	Septic shock, sepsis, pneumonia
Neoplasms benign,	Rare	Acute lymphocytic leukemia,
malignant and unspecified (incl cysts and polyps)		acute myelogenous leukemia
Blood and the lymphatic system disorders	Very Common	Myelosuppression (leukopenia, granulocytopenia and neutropenia, anaemia and febrile neutropenia)
	Uncommon	Thrombocytopenia
	Not known	Haemorrhage and tissue hypoxia as result of myelosoppression.
Immune system disorders	Rare	Anaphylaxis
Metabolism and nutrition disorders	Common	Anorexia, dehydration
	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
Vascular disorders	Common	Hot flushes
	Uncommon	Phlebitis, thrombophebitis
	Not known	Shock, thromboembolism, including pulmonary emboli
Gastrointestinal disorders	Common	Mucositis, oesophagitis, stomatitis, vomiting, diarrhoea, nausea
Skin and subcutaneous tissue disorders	Very Common	Alopecia 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	Amenorrhoea, azoospermia
General disorders and administration site conditions	Common	Infusion site erythema
	Rare	Malaise, asthenia, fever, chills
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 (see section 4.4).

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

Acute overdosage with epirubicin 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). Treatment should aim to support the patient during this period and should utilise such measures as blood transfusion, administering antibiotics and reverse barrier nursing. Latent cardiac failure has been observed with anthracyclines several months (up to 6 months) to years after completion of treatment (see section 4.4). Patients should be carefully monitored and 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:Anthracyclines and related substances. ATC code: L01D B03.

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. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.

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 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

Epirubicin, as other anthracyclines and cytotoxic drugs, has been shown to be genotoxic in in vitro and in in vivo studies as well as carcinogenic in rat. Epirubicin is toxic to reproductive organs and emryotoxic in rat. No malformations were evident in rat or rabbit. Epirubicin, as other anthracyclines and cytotoxic drugs, should be considered a potential teratogen. Peri/postnatal studies in rat indicate advers effects on the offspring at clinical doses. It is not known whether epirubicin is excreted in breast milk. Animal studies indicate that epirubicin has a more favourable therapeutic index and a lower systemic and cardiac toxicity than doxorubicin.

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.

Shelf life

Clear glass and ONCO-TAIN® vials: 3 years

In use: Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted, under aseptic conditions, in Glucose 5% or Sodium Chloride 0.9% and administered as an intravenous infusion. The infusion solution is chemically stable when stored in PVC infusion bags, prepared under full aseptically controlled conditions, for 14 days at 25°C ± 2°C or for 28 days at 2-8°C in the absence of light. From a microbiological point of view however, 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.

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 ‘in-use’ storage conditions, see section 6.3.

6.5    Nature and contents of container

Epirubicin Hydrochloride 2 mg/ml Injection is supplied in clear Type I glass vials with a rubber (chlorobutyl) stopper. Vials may be wrapped in a protective plastic (ONCO-TAINED®). The vials contain 5ml, 25ml, 50ml or 100ml of sterile solution of epirubicin hydrochloride 2 mg/ml. These are supplied in both individually packed single vials and packs of 5 vials.

Not all packs may be marketed.

6.6    Special precautions for disposal and other handling

Epirubicin Hydrochloride 2 mg/ml 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 product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04515/0160

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/12/2010

10    DATE OF REVISION OF THE TEXT

07/12/2010

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   Patients with severe hepatic impairment