Version: 2    10 June 2014

TEVA UK Ref: 231-30-87028-P LEA EPIRUBICIN 2MG/ML SOL 5ML TEVAH FrPCH

93.130.865-G

The following information is intended for medical and healthcare professional only:

PREPARATION GUIDE FOR USE WITH EPIRUBICIN HYDROCHLORIDE 2 mg/ml, SOLUTION FOR INJECTION OR INFUSION

It is important that you read the entire contents of this procedure prior to the preparation of either the Epirubicin hydrochloride 2 mg/ml solution for injection or infusion.

1.    FORMULATION

Epirubicin hydrochloride 2 mg per ml solution for injection or infusion. Excipients: sodium chloride

hydrochloric acid, for pH adjustment water for injections.

2.    PRESENTATION

Store in the refrigerator (2-8°C).

Store and transport refrigerated.

Do not freeze.

Chemical and physical in-use stability is as follows.

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 2-8°C.

Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to a mobile solution after two to a maximum of four hours equilibration at controlled room temperature (15-25°C).

2.1    Epirubicin hydrochloride vial:

Epirubicin hydrochloride 2 mg/ml is delivered in colourless, Type 1 glass vials with bromobutyl rubber cap, aluminium closing and snap-cap, with resp. 5 ml, 10 ml, 25 ml, 75 ml and 100 ml solution for injection or infusion.

Each carton contains a single vial.

Not all pack sizes may be marketed.

2.2    Solvent for epirubicin hydrochloride

Epirubicin hydrochloride 2 mg/ml can be diluted in NaCl 0.9% or Glucose 5% and be administered intravenously. The solution must be prepared immediately prior to use.

For intravesical administration the product must be diluted with NaCl 0.9% or sterile water. The concentration of the dilution has to be 0.6-1.6 mg/ml.

3. RECOMMENDATIONS FOR THE SAFE HANDLING

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

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

People working with Epirubicin hydrochloride 2 mg/ml are required to wear protective gloves, safety goggles and a mask.

Epirubicin hydrochloride 2 mg/ml can be diluted in NaCl 0.9% or Glucose 5% and be administered intravenously. The solution must be prepared immediately prior to use.

For intravesical administration the product must be diluted with NaCl 0.9% or sterile water. The concentration of the dilution has to be 0.6-1.6 mg/ml.

Epirubicin hydrochloride 2 mg/ml contains no preservatives and is therefore only suitable for single use. After use the unused remainder should be destroyed according to the regulations for cytostatic agents. See also “Disposal".

Inactivation of spilled or leaked medicinal product can be obtained with a 1% sodium hypochlorite solution or simply with a phosphate buffering agent (pH >8) until the solution is decolourised. All cleaning materials are disposed of as mentioned under “Disposal".

Pregnant women must avoid contact with cytostatic agents.

Excreta and vomit should be cleaned up with care.

A damaged vial must be treated with the same precautions and must be considered as contaminated waste. Contaminated waste must be stored in appropriate specially marked waste containers. See under “Disposal".

4. PREPARATION OF THE SOLUTION

Epirubicin is only intended for intravenous or intravesical use.

4.1    PREPARATION FOR THE INTRAVENOUS ADMINISTRATION

Epirubicin hydrochloride 2 mg/ml can be diluted in NaCl 0.9% or Glucose 5% and be administered intravenously. The solution must be prepared immediately prior to use.

The concentration of the dilution has to be 0.6-1.6 mg/ml.

It is advisable that the red solution, which should be clear and transparent, is injected via the catheter of a free running intravenous infusion of a physiological salt solution or glucose 5% over a period of up to a duration of 30 minutes (depending on the dose and the volume of the infusion). The needle should be properly placed in the vein. This method reduces the risk of thrombosis and extravasation that could lead to severe cellulitis and necrosis. In case of extravasation, administration should be stopped immediately. Injection in small veins and repeated injection in the same vein can lead to venous sclerosis.

For the treatment with a high dose epirubicin can be administered as an intravenous bolus over 3-5 minutes or as an infusion up to 30 minutes duration.

4.2    PREPARATION FOR THE INTRAVESICAL ADMINISTRATION

For intravesical administration Epirubicin hydrochloride 2 mg/ml must be diluted with NaCl 0.9% or sterile water. The concentration of the dilution has to be 0.6-1.6 mg/ml.

DILUTION TABLE FOR BLADDER INSTILLATION SOLUTIONS

5. DISPOSAL

Any unused product, all materials used in the preparation and administration, or which have come in contact with epirubicin hydrochloride in any way, must be destroyed in accordance with local requirements.

87028-P

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HOSPITALS

PACKAGE LEAFLET: INFORMATION FOR THE USER

EPIRUBICIN HYDROCHLORIDE 2 mg/ml, SOLUTION FOR INJECTION OR INFUSION

Read all of this leaflet carefully before you start using this medicine.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, please ask your doctor or pharmacist.

•    This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

•    If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

IN THIS LEAFLET:

1.    What Epirubicin hydrochloride 2 mg/ml is and what it is used for

2.    Before you use Epirubicin hydrochloride 2 mg/ml

3.    How to use Epirubicin hydrochloride 2 mg/ml

4.    Possible side effects

5.    How to store Epirubicin hydrochloride 2 mg/ml

6.    Further information

OWHAT EPIRUBICIN HYDROCHLORIDE 2 mg/ml IS AND WHAT IT IS USED FOR

Medicinal product group

Epirubicin belongs to the group of cytostatics (products to fight cancer). Epirubicin makes sure that cancer cells cannot grow any more, which eventually kills them.

Use for

Epirubicin is administered for the treatment of:

• breast cancer • stomach cancer

• Epirubicin hydrochloride is also used intravesically (directly into the bladder) to treat early (superficial) urinary bladder cancer and to help prevent recurrence of bladder cancer after surgery.

Epirubicin is often used concomitantly with other cancer fighting medicinal products (in so-called polychemotherapy schedules).

©BEFORE YOU USE EPIRUBICIN HYDROCHLORIDE 2 mg/ml

Do not use Epirubicin hydrochloride 2 mg/ml

• if you are allergic (hypersensitive) to epirubicin, similar medicines (called anthracyclines or anthracenediones, see below) or any of the other ingredients of Epirubicin hydrochloride 2 mg/ml • if you have been treated before with high doses of some other anti-cancer medicines including doxorubicin and daunorubicin which belong to the same group of drugs as epirubicin hydrochloride 2 mg/ml (called anthracyclines). They have similar side effects (including those effects on the heart).

• if you suffered or currently have heart problems • if you are breast-feeding • if you have a low blood count • if you have a severe liver function disorder • if you suffer from an acute severe infection.

When administered intravesically (directly into the bladder), epirubicin hydrochloride 2 mg/ml should not be used if:

• the cancer has penetrated the bladder wall • you have an infection in your urine tract • you have pain or inflammation in your bladder • your doctor has problems inserting a catheter (tube) into your bladder

• there is a large volume of urine left in your bladder after you attempt to empty it • if your urine contains blood • if you have a contracted bladder.

Take special care with Epirubicin hydrochloride 2 mg/ml

• if you are elderly or a child, because of the higher risk of severe cardiac side effects. Your cardiac function will be checked before and after the treatment with epirubicin.

• if you have had problems with your heart in the past or if you are currently experiencing such problems. You should inform your doctor. The dose of epirubicin will have to be adjusted. Your doctor will regularly check if your heart is working properly.

• if you have previously been treated with products to fight cancer (such as with doxorubicin or daunorubicin, anthracenedion derivatives or trastuzumab) or if you have had radiation, because the risk of severe cardiac side effects is greater. Inform your doctor because this is included in determining the total dose of epirubicin you will be administered.

• if you have a liver or kidney disorder. This may cause an increase in side effects. Both the kidney function and the liver function will be checked regularly and if needed the dose will be adjusted.

• if you desire to have children. Both men and women should use effective contraceptive measures both during and for 6 months after the treatment. Men are advised to request information about the possibility of storing sperm by means of freezing before the treatment.

• if you suffer from infections or bleedings. Epirubicin may affect the bone marrow. The number of white blood cells in your blood will be reduced, which makes you more susceptible to infections (leukopenia). Bleedings can occur more easily (thrombocytopenia). These side effects are temporary in nature. The reduction of the number of white blood cells is greatest 10-14 days after the administration and usually returns to normal 21 days after the administration.

• if you have recently received or want to receive any vaccination • to check the level of uric acid in your blood. Your doctor will check this.

• to ensure the number of cells in your blood does not drop too low.

Your doctor will regularly check this.

• if you are experiencing severe inflammation or ulcers in your mouth • if you have received or are receiving radiotherapy to the chest area • if you get a burning feeling at the site of the administration. This could indicate that epirubicin is leaking outside the blood vessel. Warn your doctor about this.

Please consult your doctor if one of the above mentioned warnings is applicable to you, or has been applicable to you in the past.

Using other medicines

Attention: the following remarks may also be applicable to the recent use of medicinal products or their use in the near future.

The medicines mentioned in this section may be known to you under a different name, often the brand name. In this section only the active ingredient(s) of the medicinal product is mentioned, not the brand name! Therefore always carefully read on the package or in the patient leaflet what the active ingredient is of the medicines you are using.

An interaction means that (medicinal) products that are used together can influence each other's effect and/or side effect. An interaction can occur with the concomitant use of this solution and:

•    prior or concomitant administration of other products related to epirubicin (so-called anthracyclines; (for instance the cancer fighting medicines mitomycin-C, dacarbazine, dactinomycin and cyclophosphamide);), other medicines that may affect the heart (for instance the cancer fighting medicines 5-fluorouracil, cyclophosphamide, cisplatin, taxanes, trastuzumab); the harmfulness to the heart can increase. Extra monitoring of the heart is then necessary.

•    epirubicin can increase the effect of radiation and even after quite some time after the radiation it can cause serious side effects in the irradiated area

•    rifampicin (product used for the treatment of tuberculosis) and barbiturates (products that are used for insomnia or epilepsy, such as for instance phenobarbital); these products decrease the amount of epirubicin in the blood, which could lead to a reduced effect of epirubicin

•    paclitaxel and docetaxel (products that are used for some cancers); when paclitaxel is administered before epirubicin or docetaxel is administered immediately after epirubicin, the amount of epirubicin in the blood is increased, which could lead to an increase of the side effects

•    dexverapamil (a product that is used to treat some cardiac disorders); when used together with epirubicin it may have a negative effect on bone marrow

•    interferon a2b (a product used in some cancers and lymphomas and some forms of hepatitis)

•    quinine (a product used for treatment of malaria and for leg cramps); quinine may speed up the distribution of epirubicin into the body, which may have a negative effect on the red blood cells

•    dexrazoxane (a product sometimes used with doxorubicin to reduce the risk of heart problems); the time that epirubicin is present in the body may be decreased, which could lead to decreased effect of epirubicin

•    cimetidine (a product to reduce the acid in your stomach); the amount of epirubicin in the blood is increased, which could lead to an increase of the side effects

•    previous or concomitant treatment with other products which influence the bone marrow (for instance other products to treat cancer, sulfonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, products against certain virus); the formation of blood cells can be disturbed

•    products that cause heart failure

•    products that influence the liver function; the degradation of epirubicin by the liver may be influenced, which may cause a reduced effect of epirubicin or an increase of the side effects

•    live vaccines; there is risk of fatal disease therefore this combination is not recommended

•    cyclosporine (a product that suppresses the immune system); the immune system may be suppressed too much.

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.

Using Epirubicin hydrochloride with food and drink

You should not drink within 12 hours before application when epirubicin will be administered in the bladder.

Fertility, pregnancy and breast-feeding Fertility and pregnancy

Medicines to fight cancer are only administered during pregnancy in extreme cases. The benefits for the mother must be weighed against the possible danger to the unborn child. In animal studies epirubicin proved to be harmful to the unborn child and can cause deformities. Both men and women should use good contraceptive measures (pill, condom) both during and for 6 months after the use of this medicine to prevent pregnancy.

You should also prevent pregnancy if your partner is treated with epirubicin.

If pregnancy occurs during treatment with epirubicin, genetic counselling is recommended.

Men who wish to father children in the future should seek advice about freezing sperm before treatment with epirubicin is started.

Breast-feeding

It is not known whether epirubicin is excreted in the breast milk. You should discontinue breast-feeding during treatment with Epirubicin hydrochloride 2 mg/ml. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Because many people get very nauseous or have to vomit during the treatment, driving and using machines is not recommended.

Important information about some of the ingredients of Epirubicin hydrochloride 2 mg/ml

This medicinal product contains 3.5 mg sodium per ml solution for injection or infusion. To be taken into consideration by patients on a controlled sodium diet.

©HOW TO USE EPIRUBICIN HYDROCHLORIDE 2 mg/ml

Epirubicin hydrochloride 2 mg/ml will only be given to you under supervision of a doctor specialised in this type of treatment. You should check with your doctor or pharmacist if you are not sure.

The dose you are administered will depend on the type of cancer you have, your health, your age, how well your liver functions are and other medicines you are taking.

The usual dose is

Depending on your general health and possible previous treatments the dose schedule is determined, whereby your length and your weight are taken into account. The amounts in the dose schedule are expressed in numbers of milligrams per square metre of body surface area.

This medicine will be administered as an injection in a vein for 3-5 minutes or as an infusion in a vein for a maximum of 30 minutes.

If only epirubicin is administered, so without other cancer medicines, the recommended dose is 60-90 mg/m² of body surface area. This dose is administered as a single dose or distributed over 2-3 consecutive days. This is repeated every 21 days. In combination with other cancer medicines the dose is reduced.

The administration occurs via a catheter or side line of a free running infusion of a physiological salt solution or glucose (sugar solution). Higher doses might be given for the treatment of breast cancer (100-120 mg/m2 of body surface area).

Administration via the bladder (intravesical administration)

The product can be given directly into the bladder (for the treatment of bladder cancer) by means of a catheter. If this method is used, you must not drink any liquids within 12 hours before the treatment, so your urine will not dilute the medicine too much. The dissolved medicine should be kept in your bladder for 1-2 hours after it has been administered. You will have to change your position occasionally to make sure the medicine reaches all parts of your bladder.

When you empty your bladder after the medicine has been given, make sure that your urine does not get in contact with your skin. In case contact does take place, thoroughly wash the site of contact with water and soap but do not scrub.

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While epirubicin is being administered to you your doctor will perform blood tests. This is to measure the effect of the medicine. Your doctor will also perform tests to see how your heart functions. Both blood test and heart function tests are done before and during treatment with epirubicin.

If you notice that Epirubicin hydrochloride 2 mg/ml is too strong or too weak, consult your doctor or pharmacist.

If more Epirubicin hydrochloride 2 mg/ml was administered than should have been

Because this medicine is administered by medical personnel the risk of an overdose is unlikely. Immediately contact your doctor if you suspect that too much Epirubicin hydrochloride 2 mg/ml has been administered.

If you forget to use Epirubicin hydrochloride 2 mg/ml

Because this medicine is administered by medical personnel it is unlikely that a dose is missed.

You should check with your doctor if you are not sure.

If you stop using Epirubicin hydrochloride 2 mg/ml

Consult your doctor.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

POSSIBLE SIDE EFFECTS

Like all medicines Epirubicin hydrochloride 2 mg/ml can cause side effects, although not everybody gets them.

More than 10% of treated patients can expect to develop undesirable effects. The most common undesirable effects are decrease in the production of blood cells (myelosuppression), gastrointestinal side effects, loss of appetite (anorexia), hair loss (alopecia) and infection.

The following side effects can, amongst others, occur:

Marketing Authorisation Holder and Manufacturer Manufacturer:

Pharmachemie B.V., Swensweg 5, PO Box 552, 2003 RN Haarlem, The Netherlands.

Marketing Authorisation holder:

TEVA UK Limited, Eastbourne, BN22 9AG.

This leaflet was last revised: June 2014

PL 00289/1162