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Epirubicin Hydrochloride 50 Mg Powder For Solution For Injection

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Epirubicin Hydrochloride 50 mg powder for solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 50 mg of epirubicin hydrochloride After reconstitution, each vial contains 2 mg/ml epirubicin hydrochloride Also contains methyl hydroxybenzoate, lactose monohydrate, and hydrochloric acid (for pH adjustment).

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder for solution for injection

A sterile freeze dried orange red coloured lyophilised cake.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Epirubicin hydrochloride has produced responses in a wide range of neoplastic conditions, including breast, ovarian, gastric, lung and colorectal carcinomas, malignant lymphomas, leukaemias and multiple myeloma.

Intravesical administration of Epirubicin hydrochloride has been found to be beneficial in the treatment of superficial bladder cancer, carcinoma-in-situ and in the prophylaxis of recurrences after transurethral resection.

4.2 Posology and method of administration Preparation of the freeze-dried powder

The product should be dissolved in 5 ml 0.9% sodium chloride or water for injections to get the final concentration of 2 mg/ml. The vial contents will be under a negative pressure. To minimize aerosol formation during reconstitution, particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided. After gentle agitation the reconstituted solution will be transparent and red in appearance

Intravenous administration:

Epirubicin hydrochloride is not active when given orally and should not be injected intramuscularly or intrathecally.

Paediatric population

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

It is advisable to give the drug via the tubing of a freely running IV saline infusion after checking that the needle is well placed in the vein. This method minimises the risk of drug extravasation and makes sure that the vein is flushed with saline after the administration of the drug. Extravasation of Epirubicin hydrochloride from the vein during injection may give rise to severe tissue lesions, even necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

Conventional doses:

When Epirubicin hydrochloride is used as a single agent, the recommended dosage in adults is 60-90 mg/m² body area; the drug should be injected IV over 3-5 minutes and, depending on the patients' haematomedullary status, the dose should be repeated at 21 day intervals.

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 doses:

Epirubicin hydrochloride as a single agent for the treatment of lung cancer at high doses should be administered according to the following regimens:

Lung cancer

Small cell lung cancer (previously untreated): 120 mg/m day 1, every 3 weeks.

Non-small cell lung cancer (squamous, large cell, and adenocarcinoma previously untreated): 135 mg/m day 1 or 45 mg/m days 1, 2, 3, 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/m (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.

The drug should be given as an I.V. bolus over 3-5 minutes or as an infusion up to 30 minutes. Lower doses (60-75 mg/ m for conventional treatment and 105-120 mg/ m² for high dose schedules) are recommended for patients whose bone marrow function has already 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
Advanced ovarian cancer	60 - 90	50 - 100
Gastric cancer	60 - 90	50
SCLC	120	120
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

When the drug is used in combination with other cytotoxic agents, the doses need to be adequately reduced. Commonly used doses are shown in the table above.

Impaired liver function

Since the major route of elimination of Epirubicin hydrochloride is the hepatobiliary system, the dosage should be reduced in patients with impaired liver function based on serum bilirubin levels as follows:

Serum Bilirubin 24 - 51 pmol/l

Dose Reduction 50%

Impaired renal function

Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of Epirubicin hydrochloride excreted by this route. However, dosage adjustment may be necessary in patients with serum creatinine > 5 mg /dL.

Intravesical administration:

Epirubicin hydrochloride may be given by intravesical administration for the treatment of superficial bladder cancer and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate (see section 4.3). Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.

While many regimens have been used, the following may be helpful as a guide: for therapy 8 x weekly instillations of 50 mg/50 ml (diluted with saline or distilled sterile water). In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg per 50 ml is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg/50 ml. For prophylaxis, 4 x weekly administrations of 50 mg/50 ml followed by 11 x monthly instillations at the same dosage, is the schedule most commonly used

DILUTION TABL	E 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
30 mg	15 ml	35 ml	50 ml
50 mg	25 ml	25 ml	50 ml
80 mg	40 ml	10 ml	50 ml

The solution should be retained intravesically for 1 - 2 hours. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void at the end of the instillation time.

4.3 Contraindications

Epirubicin hydrochloride is contraindicated in:

• Patients who have demonstrated hypersensitivity to the active substance or to any of the excipients

• Patients with marked myelosuppression induced by previous treatment with other antitumour agents or by radiotherapy

• Patients treated with maximal cumulative doses of other anthracyclines such as doxorubicin or daunorubicin.

• Patients with current or previous history of cardiac impairment (including 4^th degree muscular heart failure, acute heart attack and previous heart attack which led to 3^rd and 4^th degree muscular heart failure, acute inflammatory heart diseases, arrhythmia with serious haemodynamic consequences).

• Patients with acute systemic infections

• Lactation

For intravesical administration, epirubicin is contraindicated in:

• Urinary tract infections

• Invasive tumours penetrating the bladder

• Catheterisation problems

• Vesical inflammation.

• Large volume of residual urine

• Contracted bladder.

4.4 Special warnings and precautions for use

Epirubicin hydrochloride should be administered only under the supervision of qualified physicians 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 six months after treatment and to seek advice on conservation of sperm prior to treatment because of the possibility of infertility due to therapy with epirubicin.

Women should not become pregnant during treatment with epirubicin. Men and women should use an effective contraception during treatment and for six months thereafter.

Extravasation of epirubicin from the vein during injection may cause severe tissue lesions and necrosis. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.

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

During treatment with epirubicin, red blood cell, white blood cell, neutrophil and platelet counts should be carefully monitored both before and during each cycle of therapy. Leucopenia and neutropenia are usually transient with conventional and high-dose schedules reaching a nadir between the 10^th and 14^th day, values should return to normal by the 21^st day; they are more severe with high dose schedules. Thrombocytopenia (< 100,000 platelets/mm³) is experienced in very few patients, even following high doses of epirubicin. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, haemorrhage, issues hypoxia, or death.

Patients must have adequately recovered from severe stomatitis or mucositis before starting treatment with epirubicin.

In establishing the maximal cumulative dose of epirubicin, consideration should be given to any concomitant therapy with potentially cardiotoxic drugs. A cumulative dose of 900-1000 mg/m² should only be exceeded with extreme caution with both conventional and high doses of epirubicin. Above this level the risk of irreversible congestive heart failure increases greatly. An ECG is recommended before and after each treatment cycle. Alterations in the ECG tracing, such as flattening or inversion of the T-wave, 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/m , there is evidence that cardiac toxicity rarely occurs. However, cardiac function must be carefully monitored during treatment to minimise the risk of heart failure of the type described for other anthracyclines. In case of cardiac insufficiency, treatment with epirubicin should be discontinued.

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. 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.

Cardiomyopathy induced by anthracyclines, is associated with a 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 hydrochloride 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. The risk of serious cardiac impairment may be decreased through regular monitoring of left ventricular ejection fraction (LVEF) during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function.The preferred 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 an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior to anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict.

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

As with other cytotoxic agents, Epirubicin hydrochloride may induce hyperuricaemia as a result of rapid lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels should therefore be carefully checked 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.

Heart failure may appear even several weeks after discontinuing, therapy with epirubicin and may be unresponsive to specific medical treatment. The potential risk of cardiotoxicity may increase in patients who have received concomitant, or prior, radiotherapy to the mediastinal pericardial area and or who are under medical treatment with potentially cardiotoxic medicinal products (see section 4.5).

Before starting therapy with epirubicin and if possible during treatment, liver function should be evaluated (SGOT, SGT, alkaline phosphatase, bilirubin). (see section 4.2).

Epirubicin hydrochloride may impart a red colour to the urine for 1-2 days after administration.

Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including epirubicin. Secondary leukaemia is more common when such 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 leukaemia's can have a 1- to 3-year latency period.

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.

Excipients

Epirubicin, powder for solution for injection, contains methyl hydroxybenzoate. This may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.

4.5 Interaction with other medicinal products and other forms of interaction

It is not recommended that Epirubicin hydrochloride be mixed with other drugs. But Epirubicin hydrochloride can be used in combination with other anticancer drugs.

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

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

Prior administration of higher doses (900 mg/m and 1200 mg/m ) 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 after 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.

Paclitaxel may affect the pharmacokinetics of epirubicin and its metabolite, epirubicinol. In one study, haematological toxicity was greater when paclitaxel was administered before epirubicin compared with after epirubicin. One study has shown that paclitaxel clearance is reduced by 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.

Cimetidine 400 mg b.i.d given prior to epirubicin 100 mg/m every 3 weeks led to a 50% increase in epirubicin AUC and a 41% increase in epirubicinol AUC (latter <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.

Epirubicin used in combination with other cytotoxic agents may result in additive myelotoxicity.

The possibility of a marked disturbance of haematopoiesis needs to be kept in mind with a (pre-) treatment with medicines which influence the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivative, 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 concomitantly with other medicinal products that may cause heart failure, e.g. calcium channel blockers, then cardiac function must be monitored throughout the course of treatment.

Epirubicin is mainly metabolised in the liver, each concomitant medication which affects hepatic function can also affect the metabolisation or the pharmacokinetics of epirubicin and, consequently, its efficacy and/ or toxicity.

This product is generally not recommended in combination with live attenuated vaccines.

4.6 Fertility, pregnancy and lactation

Impairment of 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.

Pregnancy

Experimental data, however, suggest that epirubicin may harm the foetus. 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 foetus and the possibility of genetic counselling should be considered if they become pregnant during epirubicin therapy. 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 foetus.

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, mothers should discontinue nursing prior to taking this drug.

This product should not normally be administered to patients who are pregnant or to mothers 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 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

\Frequency

Organ

System

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)

Infections

and

infestations

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

Neoplasms benign, malignant & unspecified

Secondary

acute

myeloid

leukaemia

(including cysts & po^lyps)		with or without a pre leukaemic phase in patients treated with epirubicin in combination with DNA -damaging antineoplastic agents. These leukaemia’s have short (1 3 years) latency.
Blood and the lymphatic system disorders			Myelosuppre ssion* (leucopenia, neutropenia, febrile neutropenia, thrombocytopenia, anaemia). and tissue hypoxia (as a result of myelosuppres sion) may occur.
Immune system disorders	allergic reactions following intravesical administratio n	Anaphylaxis
Metabolism and nutrition disorders		Hyperuricae mia (as a result of rapid lysis of neoplastic cells)
Cardiac disorders		Cardiotoxicit y (ECG changes, tachycardia, arrhythmia, cardiomyopat ^h^

congestive

heart failure

(dyspnoea,

oedema,

enlargement

of the liver,

ascites,

pulmonary

oedema,

pleural

effusions,

gallop

rhythm),

ventricular

tachycardia,

bradycardia,

AV block,

bundle-

branch block

(see section

4.4)

Vascular

disorders

Thrombophle

bitis

Coincident

al cases of

thromboem

bolic

events

(including

pulmonary

embolism

[in isolated

cases with

fatal

outcome])

Gastrointesti nal disorders

Nausea, vomiting and diarrhoea, which can result in dehydration, loss

of appetite and

abdominal

pain.

Oesophagitis

and

hyperpigment ation of the oral mucosa may also

		occur.
Skin and subcutaneous tissue disorders	Alopecia, normally reversible, appears in 60 -90% of treated cases; it is accompanie d by lack of beard growth in males	Hot flushes	Hyperpigmen tation of skin and nails. Skin reddening.	Urticaria	Local toxicity, rash, itch, skin changes, erythema, flushes, skin and nail hyperpigment ation, photosensitiv ity, hypersensitiv ity to irradiated skin (radiation- recall reaction)
Reproductive system and breast disorders				Amenorrhea, azoospermia
General disorders and administratio n site conditions		Mucositis may appear 5-10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, mainly along the side of the tongue and the sublingual mucosa. Redness along the infusion vein. Local phlebitis, phleboscleros is. Local pain and tissue necrosis (following	Headache	Fever, chills, dizziness, , hyperpyrexia, malaise, weakness

accidental paravenous injection) may occur.

Investigation

Increased

transaminase

levels

Injury

poisoning

and

procedural

complication

Chemical cystitis, in some cases

haemorrhagic

, is observed

following

intravesical

administratio

* 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 no 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.

4.9 Overdose

Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression within 10-14 days. Treatment should aim to support the patient during this period and should utilise such measures as antibiotics, blood transfusion and reverse barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to 6 months after the overdose. Patients should be observed carefully and should, if signs of cardiac failure arise, be treated along conventional lines.

Treatment:

Symptomatic.

Epirubicin cannot be removed by dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: L01DB03

Pharmacotherapeutic group: anthracyclines and related substances

The mechanism of action of Epirubicin hydrochloride 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 hydrochloride 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 I.V. injection of 60-150 mg/m of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean halflife of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. Between 60-120 mg/m 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). Asignificant systemic resorption can therefore not be assumed. In patients with lesions of the mucosa of the bladder (e.g. tumor, 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 hydrochloride 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 910% 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

The main target organs in rat, rabbit and dog following repeated dosing were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin was also cardiotoxic in the species tested.

Epirubicin was, like other anthracyclines , mutagenetic, 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

Methyl hydroxybenzoate E218 Lactose monohydrate Hydrochloric acid Water for injection

6.2 Incompatibilities

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

6.3 Shelf life

Shelf life of the product as packaged for sale: 2 years Shelf life after reconstitution according to directions:

In-use stability has been demonstrated for 24 hours at 15°C - 25°C and for 48 hours at 2 - 8°C in water for injections and 0.9% w/v sodium chloride solution. However from a microbiological point of view, it is recommended that 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 below 30°C. Keep the container in the outer carton.

For storage conditions of the reconstituted medicinal product, see section 6.3

6.5 Nature and contents of container

Epirubicin hydrochloride 50 mg is produced in 50 ml Type I moulded flint glass vial with 20 mm bromo butyl rubber stoppers and 20 mm aluminium flip-off tear-off seal.

1 vial per pack

6.6 Special precautions for disposal and other handling

Epirubicin hydrochloride may be further diluted in Glucose 5% or Sodium Chloride 0.9% 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 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

Cipla (EU) Limited,

Hillbrow House,

Hillbrow Road,

Esher,

Surrey,

KT10 9NW

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0109

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/04/2011

10 DATE OF REVISION OF THE TEXT

07/10/2014