Package leaflet: Information for the patient

Epirubicin HCl 2 mg/ml injection solution or infusion

Generic medicine
The name of the medicine is “Epirubicin HCl 2 mg/ml solution for injection or infusion” but throughout
the rest of this leaflet it will be referred to as “Epirubicin HCl”.
Please read this leaflet carefully before you are given this medicine, as it
contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor, pharmacist, or nurse.
If you get any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

What Epirubicin HCl is and what it is used for
What you need to know before you are given Epirubicin HCl
How Epirubicin HCl is given
Possible side effects
How to store Epirubicin HCl
Contents of the pack and other information

1. What Epirubicina AHCL is and what it is used for

The name of your medicine is 'Epirubicina AHCL 2 mg/ml concentrate for solution for infusion', but
in the rest of this leaflet it will be referred to as 'Epirubicina AHCL'.
What Epirubicina AHCL is
Epirubicina AHCL is an antineoplastic medicine. Treatment with an anticancer drug is sometimes
called anticancer chemotherapy. Epirubicina AHCL belongs to a group of medicines
called anthracyclines, which act on actively growing cells to slow down or stop their
growth and increase the likelihood of cell death.
What Epirubicina AHCL is used for
Epirubicina AHCL is used to treat a variety of tumours, either alone or in combination with other
medicines. The way it is used depends on the type of cancer being treated.
Epirubicina AHCL is used in the treatment of breast, lung, ovarian and stomach cancers.
When injected into the bladder through a catheter, Epirubicina AHCL is used to
treat abnormal cells or tumours of the bladder wall. It may also be used after other
treatments to prevent the regrowth of these cells.
Talk to your doctor if you do not feel better or if you feel worse.

2. What you need to know before you are given Epirubicin AHCL

Do not use Epirubicin AHCL
If you are allergic to epirubicin or to any of the other ingredients of this medicine (listed in
section 6) or to similar chemotherapeutic medicines (anthracyclines or anthracenediones)
If you are breastfeeding
If you have a reduced ability to produce blood cells leading to a low number of red blood cells, as this may be further reduced
If you have severe liver disease
If you have recently suffered a heart attack, impaired heart muscle function, severe irregular heartbeat, sudden chest pain, non-inflammatory heart muscle disease, or have had other serious heart problems in the past, or are currently receiving treatment for such conditions
If you have previously been treated with epirubicin hydrochloride injection or similar chemotherapeutic medicines, as prior treatment with these medicines may increase the risk of adverse effects
If you have infections affecting multiple organs
If you have a urinary tract infection
If you have bladder inflammation
If you have invasive tumours penetrating into the bladder
If you have difficulties with catheterization (your doctor has problems inserting the catheter (tube) into your bladder)
If you have blood in your urine

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Epirubicin AHCL if:

your liver or kidneys are not functioning properly
you have had or are scheduled to receive a vaccine
you currently suffer from acute toxicity such as:
- acute mouth inflammation
- low white blood cell count
- low platelet count
- or infections in general
you are currently taking or have recently taken trastuzumab (a medicine used to treat certain types of cancer). Trastuzumab can remain in the body for up to 7 months. Since trastuzumab can affect the heart, Epirubicin AHCL must not be administered until 7 months after stopping trastuzumab. If Epirubicin AHCL is administered within this time frame, cardiac function must be closely monitored.

This will help your doctor determine whether this medicine is suitable for you.
Inform your doctor or nurse if any of the following conditions appear or worsen DURING treatment with Epirubicin AHCL (see also section 4 “Possible side effects”):

Heart problems, which may include:
- Acute (occurring shortly after starting treatment): increased or decreased heart rate and disturbances in heart rhythm (arrhythmias). These conditions are easily detectable by electrocardiogram (ECG) and are usually not serious enough to require discontinuation of treatment.
- Delayed (appearing long after treatment has started, sometimes 2–3 months later, or even months or years after treatment ends). The most common manifestations of delayed toxicity are:
  - inability of the heart to pump sufficient blood to meet the body’s needs (heart failure). Common symptoms include: difficulty breathing (dyspnea), fluid accumulation in the lungs (pulmonary edema), swelling in other parts of the body, especially in the legs and ankles (dependent edema), enlargement of the heart (cardiomegaly) and liver (hepatomegaly), reduced urine output (oliguria), fluid accumulation in the abdomen (ascites) and in the space between the lungs and chest wall (pleural effusion), and abnormal heart rhythm (gallop rhythm). Sometimes heart failure can be severe and lead to death.
- Decreased levels in the blood of total white blood cells (leucopenia) or of a specific type of white blood cells called neutrophils (neutropenia), or of platelets (thrombocytopenia), or of red blood cells (anaemia). Typically, the lowest white blood cell count occurs 10–14 days after starting treatment and returns to normal by day 21. Sometimes, the consequences of low blood cell counts can be severe, including fever, infections in various organs and in the blood, shock, bleeding, reduced oxygen supply to the brain, and death.
- Blood cancer (leukaemia) not present before starting epirubicin treatment (secondary leukaemia). Leukaemia may develop 1–3 years after completing epirubicin treatment and is more likely if this medicine is given at high doses or in combination with other anticancer medicines or radiotherapy.
- Nausea, vomiting, and inflammation of the mouth lining (stomatitis). In severe cases, mouth ulcers may also occur. Typically, these lesions resolve within three weeks of treatment.
- Liver problems, as this increases the risk of systemic toxic effects from this medicine. Your doctor will adjust the dose of epirubicin based on your condition.
- Inflammation of the vein where repeated injections of epirubicin have been given (phlebitis), inflammation and blockage of the vein (thrombophlebitis), or leakage of the medicine from the vein (extravasation). In case of extravasation, local pain, blistering, redness of the skin may occur, and in more severe cases, necrosis. Therefore, administration of epirubicin must be immediately stopped. Necrosis may appear several weeks after extravasation. These risks can be avoided by strictly following the instructions for intravenous administration of epirubicin (see section 3 “How to take Epirubicin AHCL”).
Excessive increase in the amount of uric acid in the blood.
Inflammation and blood clot formation in veins, mainly in the legs and pelvis (thrombophlebitis) and in the lungs (pulmonary embolism). In some cases, pulmonary embolism can be fatal.

Inform your doctor or nurse if any of the following conditions appear or worsen DURING administration of Epirubicin AHCL directly into the bladder (intravesical administration) (see also section 4 “Possible side effects”):

Difficulty urinating (dysuria), frequent passage of small amounts of urine without increased fluid intake (pollakiuria), frequent need to urinate at night (nocturia), painful, slow, and intermittent urination, often drop by drop (stranguria), presence of blood in the urine (haematuria), bladder discomfort, necrosis of the inner bladder wall, bladder compression.

During treatment with Epirubicin AHCL, you must not receive vaccinations with live or attenuated vaccines, as severe or fatal infections may occur due to weakened immune defences. However, you may receive killed or inactivated vaccines, although their effectiveness may be reduced.

This medicine may cause irreversible damage that could affect future children. Therefore, women of childbearing potential must be informed about the need to use an effective contraceptive method during treatment with Epirubicin AHCL. If you wish to have children after stopping treatment, consult a specialist doctor. Before and during treatment with Epirubicin AHCL, your doctor will perform frequent and regular laboratory tests to assess your condition and the effectiveness of this medicine.

Other medicines and Epirubicin AHCL
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription. In particular, the following:

Cimetidine (a medicine used to treat stomach ulcers and heartburn). Cimetidine increases the effects of Epirubicin AHCL.
Calcium channel blockers (used for heart conditions).
Interferon alfa-2b (used to treat tumours).
Quinine (an antimalarial medicine).
Antibiotics such as sulfonamides and chloramphenicol.
Antiretrovirals (medicines used to treat HIV infection).
Phenytoin (a medicine used to treat epilepsy).
Painkillers such as amidopyrine derivatives.
Dexverapamil (used to treat certain heart diseases).
Trastuzumab (a therapy used to treat cancer). Your doctor should avoid using Epirubicin AHCL for up to 7 months after stopping trastuzumab, if possible. If Epirubicin AHCL is used within this period, careful monitoring of heart function is recommended.
Dexrazoxane (used to prevent chronic cumulative cardiotoxicity caused by epirubicin).
Vaccinations with live vaccines must be avoided in patients receiving epirubicin.
Paclitaxel or docetaxel (medicines used to treat cancer). When paclitaxel is administered before epirubicin, it may increase epirubicin blood concentration. However, when paclitaxel and docetaxel are administered together and after epirubicin, they do not affect epirubicin concentration.

Pregnancy, breastfeeding, and fertility
Pregnancy
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before taking this medicine. Avoid becoming pregnant while you or your partner are undergoing treatment with this medicine. Whether you are male or female, if you are sexually active, it is recommended to use effective contraceptive methods to prevent pregnancy during treatment. This medicine may cause birth defects, so it is important to inform your doctor if you suspect you are pregnant.

Breastfeeding
You must stop breastfeeding before starting treatment with this medicine, as some medicines may pass into breast milk and possibly harm your baby.

Fertility
Men: There is a risk of infertility caused by epirubicin therapy, and male patients should consider sperm preservation before treatment. Male patients treated with epirubicin are advised not to father children during treatment and for at least 4 months after treatment.

Women: Epirubicin may cause absence of menstrual periods or premature menopause in premenopausal women. Female patients treated with epirubicin are advised not to become pregnant during treatment and for at least 7 months after treatment.

Driving and use of machines
No special precautions are required, provided you feel completely well after hospital treatment. However, you should discuss your health status with your doctor.

Epirubicin AHCL contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per ml, i.e., essentially ‘sodium-free’.

3. How to take Epirubicin HCl

If you have been prescribed Epirubicin HCl, it will be administered to you only by a doctor or nurses specialized in chemotherapy administration.
This medicine is normally given by a doctor or nurse as an intravenous infusion (a drip) into a vein. Your doctor will decide the dose and the number of treatment days you will receive, based on your condition.
The dose is determined according to your condition, height, and body weight. From your height and weight, your doctor will calculate your body surface area, which is used to determine your dose. Epirubicin HCl may also be instilled directly into the bladder to treat bladder cancer or to help prevent its recurrence. The dose depends on the type of bladder cancer you have. When this medicine is administered directly into the bladder, you will be instructed not to drink any fluids during the 12 hours before treatment, to avoid diluting the medicine with urine in your bladder.
While one treatment cycle may sometimes be sufficient, your doctor will often recommend additional cycles every three or four weeks. Several cycles may be needed before your disease is under control and you start to feel better.

Regular checks performed by your doctor during treatment with Epirubicin HCl
During treatment, your doctor will carry out regular checks of:
Blood – to monitor low blood cell counts, which may require treatment
Heart function – heart damage may occur when high doses of Epirubicin HCl are administered. This damage may not become evident for several weeks; therefore, regular tests may be required during this period
Liver – blood tests are used to check that this medicine is not adversely affecting liver function
Blood uric acid levels – Epirubicin HCl may increase blood uric acid levels, which could lead to gout. If your uric acid levels are too high, you may be given another medicine.

If you receive more Epirubicin HCl than you should:
You may notice the development of mouth ulcers. However, since this medicine is administered in a hospital setting, it is unlikely that you will receive too high or too low a dose. If you have any further questions about the use of this medicine, please ask your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

More serious side effects
If you experience any of the following side effects, inform your doctor as soon as possible, as you may require urgent medical treatment or hospitalisation:

Very common (may affect more than 1 in 10 people):

Decrease in white blood cell count (which fight infections), increasing the risk of infections and fever (leucopenia)
Reduction in platelets (blood platelets that help blood clotting), which may lead to easier bruising or bleeding when injured (thrombocytopenia)
Reduction in certain types of white blood cells – granulocytes and neutrophils (granulocytopenia and neutropenia)
A reduction in certain types of white blood cells accompanied by fever (febrile neutropenia)
Reduction in the number of red blood cells (anaemia), which may make you feel tired and lethargic
Inflammation of the veins (phlebitis)

Common (may affect up to 1 in 10 people):

Reduced heart function (heart failure) (see section 2 “Warnings and precautions”). Heart problems may manifest as difficulty breathing (dyspnoea), swelling in various parts of the body due to fluid accumulation, especially in the feet, ankles, legs and arms, liver enlargement, fluid accumulation and swelling in the abdomen (ascites), fluid in the space between the lung and chest wall (pleural effusion)
Severe heart rhythm disorder (ventricular arrhythmia)
Certain types of heart rhythm disturbances (atrioventricular block, bundle branch block)
Slow heart rate (bradycardia)
Bleeding from blood vessels (haemorrhage)
Pain or burning in the gastrointestinal tract
Ulcers in the gastrointestinal tract
Inflammation of the mucous lining of the gastrointestinal tract

Uncommon (may affect up to 1 in 100 people):

Certain types of blood cancer (acute lymphocytic leukaemia, acute myeloid leukaemia)
High fever, chills, general malaise, possible sensation of cold arms and legs due to blood infections
Blockage of blood vessels (embolism)
Obstruction of an artery (arterial embolism)
Swelling and pain in the arms or legs due to inflammation of a blood vessel, possibly including blood clotting
Blood clots in the lungs causing chest pain and shortness of breath (pulmonary embolism)
Bleeding from the gastrointestinal tract (gastrointestinal haemorrhage)

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

Sudden, life-threatening allergic reaction. Symptoms include sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other body parts, difficulty breathing, wheezing or breathing problems
Absence of sperm in semen
Allergic reactions following administration of Epirubicin HCl directly into the bladder

Not known (frequency cannot be estimated from available data):

Life-threatening condition occurring when blood pressure is too low due to blood poisoning (shock)
Abdominal disorder
Septic shock
Lack of oxygen to tissues
Tissue death (tissue necrosis) following leakage of the medicine from the vein where the needle was inserted. In this case, administration of Epirubicin HCl will be immediately stopped (see section 2 “Warnings and precautions”)

Other side effects:

Very common (may affect more than 1 in 10 people):

Infections
Eye inflammation with red, watery eyes (conjunctivitis)
Inflammation of the transparent part of the eye called the cornea (keratitis)
Hot flushes
Nausea
Vomiting
Inflammation of the mucous lining in the mouth (stomatitis)
Fever
Diarrhoea
Hair loss (alopecia)
Skin lesion
Red-coloured urine for 1–2 days after administration of epirubicin
Absence of menstruation (amenorrhoea)
Painful inflammation and ulceration of the mucous membranes lining the digestive tract
General feeling of being unwell
Changes in levels of certain liver enzymes (transaminases)
Following direct administration of epirubicin into the bladder, inflammation (cystitis) may occur. Symptoms may include: difficulty urinating (dysuria), frequent passage of small amounts of urine without concurrent fluid intake (pollakiuria), frequent need to urinate at night (nocturia), painful, slow and intermittent urination, often drop by drop (stranguria), presence of blood in the urine (haematuria), bladder discomfort, necrosis of the inner bladder wall (see section 2 “Warnings and precautions”)

Common (may affect up to 1 in 10 people):

Reduced appetite/loss of appetite
Loss of water or body fluids from the body (dehydration)
Severe heart rhythm disorder (ventricular arrhythmia)
Conduction disturbances of cardiac impulses
Certain types of heart rhythm disturbances (AV block, bundle branch block)
Slow heartbeat (bradycardia)
Inadequate pumping of blood through the body (left ventricular ejection fraction)
Skin redness (flushing)
Pain or burning in the gastrointestinal tract
Inflammation of the mucous membrane of the oesophagus (oesophagitis)
Ulcers in the gastrointestinal tract
Skin rash, itching
Abnormal change in nail colour
Skin changes
Abnormal change in skin colour
Frequent urination
Chills
Irritation at the injection site
Local reactions such as burning sensation following administration of Epirubicin HCl directly into the bladder
Reduced heart function

Uncommon (may affect up to 1 in 100 people):

Lung infection (pneumonia)
Urticaria
Erythema
Feeling of weakness

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

Increased level of uric acid in the blood
Abnormalities in the electrocardiogram (ECG) due to disturbances in heart function
Sensation of light-headedness

Not known (frequency cannot be estimated from available data):

Mucosal damage in the mouth, pain and burning sensation in the mucosa, bleeding from the mouth and appearance of dark spots inside the mouth
Abdominal discomfort
Skin redness or other reactions similar to sunburn when exposed to sunlight or ultraviolet rays
Changes in the skin where you previously received radiation therapy
Pain at the injection site
Cellulitis
Thickening of blood vessel walls (phlebosclerosis)

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Epirubicin HCl

Store in a refrigerator (2°C-8°C). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
Always store Epirubicin HCl in a safe place out of the sight and reach of children.
Do not use Epirubicin HCl after the expiry date stated on the label and carton after "Exp". The expiry date refers to the last day of that month.
Do not use Epirubicin HCl if there are any visible signs of deterioration.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Epirubicin AHCL contains:
The active substance in Epirubicin Injection is epirubicin hydrochloride. Each ml contains 2 mg of
epirubicin hydrochloride.
Other excipients include sodium chloride, hydrochloric acid, and water for injections.

Description of the appearance of Epirubicin AHCL and package contents:
Epirubicin AHCL is a clear red solution.
Package sizes:
1 vial of 5 ml (10 mg/5 ml)
1 vial of 10 ml (20 mg/10 ml)
1 vial of 25 ml (50 mg/25 ml)
1 vial of 50 ml (100 mg/50 ml)
1 vial of 100 ml (200 mg/100 ml)

Vials of 5 and 10 ml: tubular glass vial (type I), with a 20 mm chlorobutyl rubber stopper RTS and a white flip-off aluminum cap
Vial of 25 ml: tubular glass vial (type I), with a 20 mm chlorobutyl rubber stopper RTS and a white/royal blue flip-off aluminum cap
Vial of 50 ml: molded colorless glass vial (type I), with a 20 mm chlorobutyl rubber stopper RTS and a royal blue flip-off aluminum cap
Vial of 100 ml: molded colorless glass vial (type I), with a 20 mm chlorobutyl rubber stopper RTS and a white/royal blue flip-off aluminum cap
Pack size: 1 vial.
Not all pack sizes may be marketed.

Marketing Authorization Holder:
Accord Healthcare S.L.U.
World Trade Center,
Moll de Barcelona,
s/n, Edifici Est 6ª planta,
08039 Barcelona,
Spain

Manufacturer:
Laboratori FUNDACIO DAU,
C/ De la letra C, 12-14,
Poligono Industrial de la Zona Franca,
08040 Barcelona,
Spain
Accord Healthcare Polska Sp.z o.o.,
ul. Lutomierska 50, 95-200 Pabianice,
Poland
Accord Healthcare Single Member S.A.
64th Km National Road Athens, Lamia, Schimatari, 32009,
Greece

The following information is intended exclusively for physicians or healthcare professionals:

Incompatibilities
Prolonged contact of the medicinal product with any alkaline pH solution (including sodium bicarbonate solutions) must be avoided, as it causes hydrolysis of the active substance (degradation).
Only the diluents listed in the section “Instructions for Use” should be used.
Neither the injection nor any diluted solution should be mixed with other medicinal products. A physical incompatibility with heparin has been reported.
Epirubicin hydrochloride must not be mixed with other medicinal products.

Instructions for Use
Intravenous administration: Epirubicin AHCL is recommended to be administered through the infusion line of a continuous intravenous infusion (0.9% sodium chloride). To minimize the risk of thrombosis or perivenous extravasation, the usual infusion duration is between 5 and 10 minutes, depending on the dose and volume of the infusion solution. Direct injection is not recommended due to the risk of extravasation, which may occur even if adequate blood return is observed during needle aspiration.

Intravesical administration: Epirubicin AHCL must be diluted with sterile water for injections or sterile 0.9% physiological saline before administration. Epirubicin hydrochloride should be instilled via a catheter and retained in the bladder for 1 hour. During instillation, the patient should be rotated to ensure maximum contact of the solution with the pelvic bladder mucosa. To avoid excessive dilution with urine, the patient should not drink any fluids during the 12 hours preceding instillation. The patient should then be instructed to empty the bladder at the end of the instillation.

The injectable solution contains no preservatives, and any unused portion of the vial must be immediately discarded.

Guidelines for Safe Handling and Disposal of Cytotoxic Agents:

Preparation of an infusion solution must be carried out under aseptic conditions by trained personnel.
Preparation of an infusion solution must be carried out in a designated aseptic area.
Personnel must wear disposable gloves, protective eyewear, gown, and protective mask.
Precautions must be taken to avoid accidental contact of the drug with the eyes. In case of eye contact, irrigate thoroughly with copious amounts of water and/or 0.9% sodium chloride solution. Then consult a physician.
In case of skin contact with the drug, wash the affected area thoroughly with water and soap or sodium bicarbonate solution. However, do not abrade the skin with an abrasive brush. Always wash hands after removing gloves.
Spills or leaks should be treated with a diluted solution of sodium hypochlorite (available chlorine 1%), preferably by saturation, followed by rinsing with water. All materials used for cleaning must be disposed of as specified below.
Pregnant personnel must not be involved in the preparation of cytotoxic products.
Appropriate measures and precautions must be taken for the disposal of items (syringes, needles, etc.) used to reconstitute and/or dilute cytotoxic drugs. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.

Storage
Packaged product for sale: Store in a refrigerator (2°C–8°C). Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.

Shelf life after initial opening of the container:
Vials are for single use only; any unused portion must be discarded after use. From a microbiological standpoint, the product should be used immediately after the first puncture of the rubber stopper. If not used immediately, the user is responsible for the storage times and conditions during use.

Shelf life after dilution of the injectable solution:
Epirubicin Hydrochloride 2 mg/ml Injection may be further diluted under aseptic conditions in 5% glucose or 0.9% sodium chloride and administered as an intravenous infusion.
From a microbiological standpoint, the medicine should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at 2–8°C, unless dilution occurs under controlled and validated aseptic conditions.

Disposal
Medicines must not be disposed of via wastewater or household waste. All materials used in the preparation, administration, or otherwise coming into contact with epirubicin hydrochloride must be disposed of in accordance with local regulations governing the handling of cytotoxic compounds.

See the Summary of Product Characteristics for further information on Epirubicin AHCL 2 mg/ml solution for injection or infusion.