EPIRUBICIN TEVA 2 mg/ml INJECTABLE SOLUTION AND PERFUSION SOLUTION

2. What you need to know before you use Epirubicin Teva 2 mg/ml

Do not use Epirubicin Teva 2mg/ml

• if you are allergicto epirubicin, to similar medicines (called anthracyclines or anthracenediones, see below) or to any of the other ingredients of this medicine (listed in section 6);
• if you are breast-feeding

Depending on the route of administration, Epirubicin Teva 2 mg/ml should not be administered in the following situations:

Intravenous route (in a vein):

• if you have been treated previously with high doses of other cancer medicines, including doxorubicin and daunorubicin, which belong to the same group of medicines as Epirubicin Teva 2 mg/ml (called anthracyclines). These medicines have similar side effects (including effects on the heart);
• if you have or have had heart problems;
• if you have a low blood cell count;
• if you have severe liver disorder;
• if you have a severe acute infection.

Intravesical route (directly into the bladder):

• if the cancer has penetrated the bladder wall;
• if you have an infection in the urinary tract;
• if you have pain or inflammation in the bladder;
• if your doctor has difficulty inserting the catheter (tube) into your bladder;
• if there is a large amount of residual urine in your bladder after trying to empty it;
  • if there is blood in your urine;
  • if you have a contracted bladder.

Warnings and precautions

Tell your doctor or pharmacist before starting treatment with Epirubicin Teva 2 mg/ml:

• if you are an elderlyperson or a child, because there is a greater risk of serious heart side effects. Your heart function will be checked before and after treatment with epirubicin.
• if you have had heart problemsin the past or if you are currently suffering from them. You must inform your doctor. The dose of epirubicin will need to be adjusted. Your doctor will regularly check if your heart is working properly.
• if you have been previously treatedwith cancer medicines (anthracyclines (such as doxorubicin or daunorubicin), anthracenediones or trastuzumab) or if you have received radiation to the chest area, due to the increased risk of serious heart side effects. Inform your doctor as this will affect the determination of the total dose of epirubicin to be administered to you.
• if you have kidney or liver problems. This may lead to an increased risk of side effects. Both kidney and liver function will be regularly checked and the dose adjusted if necessary.
• if you are planning to have children. Both men and women should use effective contraceptive methods during treatment and for 6.5 months (women) or 3.5 months (men) after treatment. It is recommended that both seek genetic counseling (see “Pregnancy, breast-feeding and fertility”).
• if you suffer from infections or bleeding. Epirubicin can affect the bone marrow. The number of white blood cells in the blood may decrease, making you more susceptible to infections (leukopenia). Bleeding may occur more easily (thrombocytopenia). These side effects are temporary. The decrease in the number of white blood cells is greater after 10-14 days after administration and usually returns to normal 21 days after administration. Your doctor will regularly perform blood tests.
• if you have recently received or want to receive any vaccine.

Be careful during treatment with Epirubicin Teva 2 mg/ml:

• check your uric acid level in the blood. Your doctor will check it.
• if blood clots form in your blood vessels (thromboembolism) that can lead to inflammation of the vein (thrombophlebitis) or blockage of the pulmonary artery (pulmonary embolism).
• if you experience severe inflammation or ulcers in the mouth.
• if you notice a burning sensationat the injection site. This may indicate that the epirubicin has leaked out of the vein. Inform your doctor about this.

Children and adolescents

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

Using Epirubicin Teva 2 mg/ml with other medicines

Tell your doctor or pharmacist if you are taking/using, have recently taken/used or might take/use any other medicines.

An interaction means that the medicines you use together may influence the effect of the other and/or their side effects. An interaction may occur with the concomitant use of this solution and:

• previous or concomitant administration of other products related to epirubicin (also called anthracyclines; (e.g. cancer medicines such as mitomycin-C, dacarbazine, dactinomycin andcyclophosphamide)), other medicines thatcan affect the heart(e.g. cancer medicines such as 5-fluorouracil, cyclophosphamide, cisplatin, taxanes, trastuzumab) or calcium channel blockers(used to treat high blood pressure or certain heart diseases); heart damage may increase. In these cases, more intense monitoring of heart function is necessary.
• epirubicin may increase the effect of radiation and even some time after it (epirubicin) it may cause serious side effects in the irradiated area.
• paclitaxel and docetaxel(medicines used against some types of cancer); when paclitaxel is administered before epirubicin or when docetaxel is administered immediately after epirubicin, the amount of epirubicin in the blood increases, which may lead to an increase in side effects.
• dexverapamil(medicine used to treat certain heart problems); if used with epirubicin, it may have negative effects on the bone marrow.
• interferon alfa-2b(medicine used against some types of cancer and lymphomas and in certain forms of hepatitis).
• quinine(medicine used to treat malaria and leg cramps); may increase the distribution rate of epirubicin in the body, which may negatively affect red blood cells.
• dexrazoxane(medicine sometimes used with doxorubicin to reduce the risk of heart problems); the time epirubicin stays in the body may decrease, which may reduce the effect of epirubicin.
• cimetidine(medicine used to treat stomach ulcers); increases the amount of epirubicin in the blood, which may lead to an increase in side effects.
• previous or concomitant treatment with other medicines that may affect the bone marrow (e.g. other cancer medicines, sulfonamides and chloramphenicol(antibiotics), phenytoin(antiepileptic),amidopyrine derivatives(analgesics),antiviral medicines); blood cell formation may be affected.
• medicines that cause heart failure.
• medicines that affect liver function; the hepatic degradation of epirubicin may be altered, which may reduce the effect of epirubicin or increase side effects.
• live or attenuated live vaccines; there is a risk of developing a fatal disease, so this combination is not recommended.

Using Epirubicin Teva 2mg/ml with food and drinks

Do not drink during the 12 hours before administration if epirubicin is administered in the bladder.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Pregnancy and fertility

Epirubicin may cause harm to the fetus if used during pregnancy. Animal studies have shown that epirubicin is harmful to the fetus and may cause malformations.

It is very important that you inform your doctor if you are pregnant or become pregnant during treatment. Epirubicin hydrochloride 2 mg/ml should not be used during pregnancy, unless your doctor considers it absolutely necessary to start treatment with epirubicin immediately.

If you become pregnant during treatment with epirubicin, genetic counseling is recommended. Some reports referring to pregnant women indicate that epirubicin was associated with heart problems in newborns and fetuses, including fetal death.

Women of childbearing age should use effective contraceptive methods during treatment and for at least 6.5 months after the last dose. Men undergoing treatment with epirubicin should use effective contraceptive methods during treatment and for at least 3.5 months after the last dose.

Treatment with epirubicin may cause infertility. Both men and women should seek advice on fertility preservation before treatment.

Epirubicin may cause absence of menstruation or premature menopause in premenopausal women.

Breast-feeding

It is not known whether epirubicin is excreted in breast milk. You should interrupt breast-feeding during treatment with Epirubicin Teva 2 mg/ml and for at least 7 days after the last dose.

Driving and using machines

Driving and use of machines are not recommended since many patients have had nausea or vomiting during treatment.

Epirubicin Teva 2mg/ml contains sodium

This medicine contains 18 mg of sodium (main component of cooking/table salt) in each 5 ml vial. This is equivalent to 0.9% of the maximum recommended daily intake of sodium for an adult.

This medicine contains 35 mg of sodium (main component of cooking/table salt) in each 10 ml vial. This is equivalent to 1.8% of the maximum recommended daily intake of sodium for an adult.

This medicine contains 89 mg of sodium (main component of cooking/table salt) in each 25 ml vial. This is equivalent to 4.4% of the maximum recommended daily intake of sodium for an adult.

This medicine contains 266 mg of sodium (main component of cooking/table salt) in each 75 ml vial. This is equivalent to 13.3% of the maximum recommended daily intake of sodium for an adult.

This medicine contains 354 mg of sodium (main component of cooking/table salt) in each 100 ml vial. This is equivalent to 17.7% of the maximum recommended daily intake of sodium for an adult.

3. How to use Epirubicin Teva 2 mg/ml

Epirubicin Teva 2 mg/ml should only be administered under the supervision of a doctor with experience in the use of this type of treatment. Ask your doctor or pharmacist if you have any questions.

Your doctor will perform blood tests while you are being treated with epirubicin. This is done to measure the effect of the medicine. Your doctor will also perform tests to check your heart function. Blood tests and heart function checks will be performed before and during treatment with epirubicin.

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

Intravenous administration (in a vein)

The dose is determined based on your general state of health and any previous treatments, taking into account your height and weight. The dose is expressed as milligrams per square meter of body surface area.

This medicine is administered as an injection into a vein over 3-5 minutes or as an infusion into a vein over a maximum of 30 minutes.

When only epirubicin hydrochloride is administered, i.e. 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 divided over 2-3 consecutive days. This is repeated every 21 days. In combination with other cancer medicines, the doses are reduced.

Administration is via a catheter or by infusion with a saline or glucose solution (sugar solution).

Higher doses are used for the treatment of breast cancer (100-120 mg/m2) of body surface area).

Intravesical administration (directly into the bladder)

The medicine can be administered directly into the bladder (for the treatment of bladder cancer) via a catheter. If this method is used, you should not drink any fluid in the 12 hours before treatment to avoid diluting the medicine too much.

After administration, the medicine solution should be kept in the bladder for 1-2 hours. Occasionally, you will need to change your position to ensure that the medicine reaches the entire bladder.

When urinating after administration of the medicine, be careful not to let the urine come into contact with the skin. If it does come into contact, wash the affected area well with water and soap, but do not rub.

If you use more Epirubicin Teva 2mg/ml than you should

This medicine will be administered to you in the hospital, so the risk of an overdose is unlikely. This may affect your heart, decrease your blood cell count, and cause gastrointestinal toxic effects (mainly mucositis). You may notice ulcers in the mouth. If you think you have been given too much Epirubicin Teva 2 mg/ml, contact your doctor immediately.

In case of overdose or accidental ingestion, consult the Toxicology Information Service (91) 562 04 20.

If you forget to use Epirubicin Teva 2mg/ml

This medicine will be administered to you in the hospital, so the risk of forgetting a dose is unlikely.

Consult your doctor if you have any questions.

If you stop using Epirubicin Teva 2mg/ml

Consult your doctor.

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

It can be expected that more than 10% of treated patients may develop adverse effects. The most frequent adverse effects are a decrease in blood cell production (myelosuppression), gastrointestinal adverse effects, loss of appetite (anorexia), hair loss (alopecia), and infection.

The following adverse effects may occur, among others:

Very Common: may affect more than 1 in 10 people

• Infection
• Eye inflammation (conjunctivitis or keratitis)
• Decreased blood cell production (bone marrow depression; resulting in a decrease in white blood cells, red blood cells, platelets), which implies an increased sensitivity to infections and fever, anemia, bruising, and bleeding when injured
• Hot flashes, redness along the vein (phlebitis)
• Nausea and vomiting (often occur within the first 24 hours in almost all patients), inflammation of the mucous membrane of the mouth (stomatitis), inflammation of the mucous membrane (mucositis; may occur 5 to 10 days after the start of treatment), diarrhea that may result in dehydration.
• Hair loss (alopecia, in 60-90% of treated cases. This implies poor beard growth in men. Hair loss is dose-dependent and reversible in most cases)
• Skin injury
• Red coloration of urine for 1 or 2 days after administration
• Absence of menstruation (amenorrhea)
• Feeling of general discomfort, fever
• Changes in the levels of some enzymes (transaminases)
• Inflammation of the bladder (cystitis), sometimes with bleeding, after direct administration into the bladder

Common: may affect up to 1 in 10 people

• Loss of appetite (anorexia), dehydration
• Reduced heart function with resulting blood congestion (congestive heart failure), heart failure (shortness of breath, fluid accumulation throughout the body (edema), liver enlargement, fluid accumulation in the abdominal cavity (ascites), fluid accumulation in the lungs (pulmonary edema), pleural effusions, abnormal heart rhythm (galloping rhythm)), increased frequency of heartbeats arising from the lower chambers of the heart (ventricular tachycardia), slow heart rate (bradycardia), cessation of impulse transmission in the heart (AV block, branch block)
• Decreased fraction of blood pumped from a ventricle with each heartbeat (decreased ejection fraction)
• Bleeding (hemorrhage), skin redness (flushing)
• Inflammation of the mucous membrane of the esophagus (esophagitis), abdominal pain, erosion, and ulcers in the gastrointestinal tract
• Skin rash, intense itching (pruritus), skin disorder
• Increased pigmentation (hyperpigmentation) of the skin and nails
• Redness at the infusion site, chills
• Local reactions such as a burning sensation and frequent urge to urinate have been observed after administration into the bladder

Uncommon: may affect up to 1 in 100 people

• Blood poisoning (sepsis), lung infection (pneumonia)
• Certain forms of blood cancer (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML))
• Vascular inflammation with the formation of a blood clot, often felt as a pain of some kind with a hard core and red skin around (thrombophlebitis)
• Formation of blood clots (embolism, arterial embolism), including the formation of blood clots in the lungs (pulmonary embolism, in isolated cases with a fatal outcome)
• Bleeding in the gastrointestinal tract
• Skin rash with the formation of small bumps (urticaria), skin redness (erythema)
• Feeling of weakness (asthenia)

Rare: may affect up to 1 in 1,000 people

• Severe, immediate allergic reaction (anaphylactic/anaphylactoid reaction) with or without shock, including skin rash and itching, fever, and chills.
• Increased level of uric acid in the blood (hyperuricemia)
• Dizziness
• Cardiotoxicity (e.g., ECG abnormalities, arrhythmias, heart muscle disease (cardiomyopathy))
• Lack of sperm in the semen (azoospermia)
• High fever (extremely high)

Unknown: frequency cannot be estimated from available data

• Blood poisoning and shock (septic shock) as a result of decreased blood cell production (myelosuppression)
• Bleeding, lack of oxygen in tissues
• Certain nerve disorders (peripheral neuropathy), headache
• Shock
• Abdominal discomfort, erosion of the oral mucous membrane, mouth ulcers, mouth pain, burning sensation in the mucous membrane, mouth bleeding (oral hemorrhage), oral cavity discoloration (oral pigmentation)
• Sensitivity to light (photosensitivity) or allergic reaction in the case of radiation (radiation-recall reaction)
• Increased amount of protein in the urine (proteinuria) in patients who were treated with a high dose
• Local pain, severe inflammation of the tissue (cellulitis), tissue death (necrosis), thickening or hardening of the walls of the veins (phlebosclerosis) after accidental injection outside the vein

Intravesical Route (in the Bladder):Serious adverse reactions affecting the whole body as well as allergic reactions are rare when Epirubicina Teva 2 mg/ml is administered in the bladder.

Reporting of Adverse Effects

If you experience any kind of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Website: www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Epirubicina Teva 2 mg/ml

Keep out of sight and reach of children.

Do not use this medicine after the expiration date that appears on the label/package after CAD. The expiration date is the last day of the month indicated.

Store in a refrigerator (between 2°C and 8°C).

Refrigerated storage and transport.

Do not freeze.

After the first opening, the medicine must be used immediately.

The chemical and physical stability is as follows:

From a microbiological point of view, the medicine must be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2-8°C.

Storage of the injection solution in cold conditions may lead to the formation of a gel-like product. This gel-like product will change from slightly viscous to a mobile solution after 2 hours and a maximum of 4 hours at controlled temperature (15-25°C).

Medicines should not be disposed of through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Epirubicina Teva 2 mg/ml

-The active ingredient is epirubicin hydrochloride; 1 ml of solution contains 2 mg of epirubicin hydrochloride.

-The other components are sodium chloride, hydrochloric acid, and water for injection.

Appearance of the Product and Package Contents

Epirubicina Teva 2 mg/ml is a medicine in the form of a transparent, red, injectable, and infusion solution. It is marketed in glass vials for injection with 5 ml (10 mg), 10 ml (20 mg), 25 ml (50 mg), 75 ml (150 mg), or 100 ml (200 mg) of injectable and infusion solution.

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Holder

Teva Pharma S.L.U.

C/ Anabel Segura, 11. Edificio Albatros B, 1ª planta

Alcobendas, 28108 Madrid (Spain)

Manufacturer

Pharmachemie B.V.

Swensweg 5

PO Box 552

2003 RN Haarlem, Netherlands

This medicine is authorized in the Member States of the European Economic Area and in the United Kingdom (Northern Ireland) with the following names:

Belgium: EPIRUBICINE TEVA 2 mg/ml

Denmark: Epirubicin Teva solution for injection or infusion

France: EPIRUBICINE TEVA CLASSICS 2 mg/ml, solution injectable ou pour perfusion

Germany: Epi Teva 2 mg/ml Injektionslösung oder Infusionslösung

Greece: Epirubicin HCL / PCH, ευ?σιμο δι?λυμα ? δι?λυμα για ?γχυση 2 mg/ml

Hungary: Epirubicin- Teva 2 mg/ml oldatos injekció vagy infúzió

Italy: Epirubicina Teva 2 mg/ml soluzione iniettabile o per infusione

Luxembourg: EPIRUBICINE TEVA 2 mg/ml

Netherlands: Epirubicine HCL Pharmachemie 2 mg/ml oplossing voor injectie of intraveneuze infusie

Norway: Epirubicina Teva 2 mg/ml injeksjons/infusjonsvæke, oppløsning

Portugal: Epirrubicina Teva Solução injectável ou para perfusão

Slovenia: Epirubicin Teva 2 mg/ml, raztopina za injiciranje ali infundiranje

Spain: Epirubicina Teva 2 mg/ml solución inyectable y para perfusión EFG

Sweden: Epirubicin Teva 2 mg/ml injektions/infusionsvätska, lösning

United Kingdom: Epirubicin 2 mg/ml solution for injection or infusion

(Northern Ireland):

Date of the last revision of this prospectus: November 2022

Detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es

This information is intended only for healthcare professionals:

GUIDE FOR THE PREPARATION FOR USE OF EPIRUBICINA TEVA 2 MG/ML, SOLUTION FOR INJECTION OR INFUSION

It is essential to read the entire content of this procedure before preparing Epirubicina Teva 2 mg/ml solution for injection or infusion.

1. FORMULATION

Epirubicina Teva 2 mg/ml injectable and infusion solution

Excipients:

Sodium chloride

Hydrochloric acid, for pH adjustment

Water for injection

1. SPECIAL PRECAUTIONS FOR STORAGE

Store in a refrigerator (2°C -8°C)

Refrigerated storage and transport

Do not freeze

The physical and chemical stability is as follows:

From a microbiological point of view, the medicine must be used immediately, and the storage times and conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2-8°C.

Storage of the injection solution in cold conditions may lead to the formation of a gel-like product. This gel-like product will change from slightly viscous to a mobile solution after 2 hours and a maximum of 4 hours at room temperature (15-25°C).

1. NATURE AND CONTENT OF THE PACKAGE

Epirubicina Teva 2 mg/ml is marketed in type I colorless glass vials with a rubber stopper (bromobutyl), aluminum seal, and snap-cap, with 5 ml, 10 ml, 25 ml, 75 ml, and 100 ml, respectively, of injectable and infusion solution

Each package contains a single vial.

Only some package sizes may be marketed.

1. INCOMPATIBILITIES

Long-term contact with alkaline solutions should be avoided as this may lead to hydrolysis. Epirubicina Teva 2 mg/ml should not be mixed with heparin due to possible precipitation.

This medicine should not be mixed with other medicines except Sodium Chloride 0.9%, Glucose 5%, or sterile water.

1. RECOMMENDATIONS FOR USE

If a perfusion solution needs to be prepared, it should be prepared by qualified personnel under aseptic conditions.

Preparation of a perfusion solution should be done in a designated aseptic area.

Personnel working with Epirubicina Teva 2 mg/ml should wear protective gloves, safety glasses, and a mask.

Epirubicina Teva 2 mg/ml does not contain preservatives and is for single use only. After use, the elimination of unused medicine will be carried out according to local regulations for cytostatic agents. See below "Elimination".

Neutralization of spills or leaks of the medicine will be done with a 1% sodium hypochlorite solution or simply with a phosphate buffer agent (pH>8) until the solution discolors. All cleaning materials will be handled as mentioned in "Elimination".

Pregnant women should avoid contact with cytostatic agents.

Vomiting and excretions should be cleaned carefully.

A damaged vial should be treated with the same precautions and should be considered as contaminated material. Contaminated material should be stored in special containers labeled as such. See "Waste Disposal".

1. PREPARATION OF THE SOLUTION

Epirubicin can only be administered intravenously or intravesically.

6.1 Preparation for Intravenous Administration

Epirubicina Teva 2 mg/ml can be diluted in Sodium Chloride 0.9% or Glucose 5% and administered intravenously. The solution should be prepared just before use.

It is recommended that the red-colored solution, which should be clear and transparent, be administered using the catheter of an intravenous perfusion in a uniform flow of saline or glucose 5% solution over a period of up to 30 minutes (depending on the dose and volume of the perfusion). The cannula should be correctly placed in the vein. This method reduces the risk of thrombosis or extravasation that may lead to severe cellulitis and necrosis. In case of extravasation, administration should be stopped immediately. Injections into small veins and repeated injections in the same vein may lead to venous sclerosis.

In high-dose treatment, epirubicin can be administered as an intravenous bolus over 3-5 minutes or as a perfusion over 30 minutes.

6.2 Preparation for Intravesical Administration

For intravesical administration, Epirubicina Teva 2 mg/ml should be diluted in Sodium Chloride 0.9% or sterile water. The concentration of the dilution should be 0.6-1.6 mg/ml.

Table of Dilution for Bladder Instillation Solutions

1. ELIMINATION

The elimination of unused medicine and all materials that have come into contact with it will be carried out according to local regulations.