Epirubicin-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Epirubicin-Teva (Epirubicin-Teva)

Composition:

active substance: epirubicin hydrochloride;

1 ml of injection solution contains epirubicin hydrochloride 2 mg;

excipients: sodium chloride, hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear red-colored solution.

Pharmacotherapeutic group. Antineoplastic agents. Cytotoxic antibiotics and related substances. Anthracyclines and related compounds. ATC code L01D B03.

Pharmacological properties.

Pharmacodynamics.

Epirubicin hydrochloride acts against a broad spectrum of experimental tumors, including leukemias (L1210 and P388), sarcomas (solid and ascitic forms of SA180), melanoma (B16), mammary carcinoma, Lewis lung carcinoma, and colon carcinoma (38), as well as human tumors transplanted into thymectomized mice (melanoma, mammary, lung, prostate, and ovarian carcinomas).

Pharmacokinetics.

In patients with normal hepatic and renal function, plasma levels of epirubicin hydrochloride after intravenous administration of 60–150 mg/m² exhibit a triphasic exponential decline, with the first phase being very rapid, and the mean elimination half-life in the terminal phase being approximately 40 hours. These doses fall within the range of pharmacokinetic linearity with respect to both plasma clearance parameters and metabolic profile.

Plasma levels of the main metabolite – the 13-OH derivative – are consistently lower and practically parallel to those of the unchanged drug. The drug is primarily eliminated via the liver; elevated plasma "clearance" values (0.9 L/min) indicate slow elimination due to extensive tissue distribution. Epirubicin hydrochloride does not cross the blood-brain barrier.

Clinical characteristics.

Indications.

For the treatment of a broad spectrum of neoplasms, including:

• breast cancer;
• malignant lymphomas;
• soft tissue sarcomas;
• gastric cancer;
• liver cancer;
• pancreatic cancer;
• rectal cancer;
• head and neck cancer;
• lung cancer;
• ovarian cancer;
• leukemia.

Intravesical administration of epirubicin is indicated for the treatment of superficial bladder cancer (transitional cell carcinoma, in situ carcinoma) and for prevention of recurrences following transurethral resection.

Contraindications.

• Hypersensitivity to epirubicin or to any excipient of the medicinal product, as well as to other anthracyclines and anthracenediones;
• breastfeeding period.

Intravenous administration is contraindicated in:

• persistent myelosuppression;
• severe hepatic impairment;
• cardiomyopathy;
• recent myocardial infarction;
• severe arrhythmia;
• prior treatment with maximum cumulative doses of epirubicin hydrochloride and/or other anthracyclines and anthracenediones (see section "Special precautions");
• acute systemic infections;
• unstable angina.

Intravesical administration is contraindicated in:

• urinary tract infection;
• bladder inflammation;
• hematuria;
• invasive bladder tumors;
• difficulties with catheterization.

Special safety precautions.

The following precautionary measures applicable to handling all antineoplastic agents are recommended:

• personnel should be well trained and proficient in the appropriate techniques;
• procedures should not be performed by pregnant workers;
• personnel handling this medicinal product should use protective equipment: goggles, gowns, masks, and disposable gloves;
• all items used for administration, cleaning, and decontamination, including gloves, should be placed in containers designated for toxicological waste and incinerated at high temperatures;
• in case of accidental contact of the medicinal product with skin or eyes, the skin should be immediately washed thoroughly with plenty of water and soap, and the eyes should be irrigated with sodium bicarbonate solution, followed by careful monitoring by a specialist;
• in case of accidental contamination of surfaces, they should be immersed in a 1% hypochlorite solution, then thoroughly rinsed with large amounts of water;
• cleaning and decontamination materials should be disposed of as described above;
• unused medicinal product and its waste should be disposed of in accordance with current local regulatory requirements.

For more detailed information, see section "Dosage and administration".

Interaction with other medicinal products and other types of interactions.

Epirubicin hydrochloride may also be used in combination with other chemotherapeutic antineoplastic agents. Cumulative toxicity affecting bone marrow/hematological parameters and gastrointestinal tract may occur (see section "Special precautions").

When epirubicin hydrochloride is used as part of combination chemotherapy with other potentially cardiotoxic agents, or when co-administered with other cardioactive drugs (e.g., calcium channel blockers), cardiac function should be monitored throughout the treatment period.

Epirubicin hydrochloride is extensively metabolized in the liver. Changes in liver function induced by concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity of epirubicin hydrochloride (see section "Special precautions").

Anthracyclines, including epirubicin, should not be administered in combination with other cardiotoxic agents without careful monitoring of cardiac function.

Patients receiving anthracyclines after discontinuation of other cardiotoxic medicinal products, particularly those with a long half-life such as trastuzumab, may also have an increased risk of developing cardiotoxicity. Trastuzumab has a variable half-life and may remain in the circulatory system for up to 7 months. Therefore, whenever possible, physicians should avoid administering anthracycline-based therapy within 7 months after discontinuation of trastuzumab. If anthracyclines are administered earlier, careful monitoring of cardiac function is recommended.

Live vaccines should be avoided in patients receiving epirubicin hydrochloride. Inactivated and killed vaccines may be administered, although their effectiveness may be reduced.

Cimetidine increases the AUC of epirubicin hydrochloride by 50%; therefore, its use should be discontinued during epirubicin hydrochloride therapy.

Paclitaxel, when administered prior to epirubicin hydrochloride, may increase plasma concentrations of unchanged epirubicin hydrochloride and its metabolites; however, these metabolites are neither toxic nor active. When epirubicin hydrochloride is administered before taxanes, concurrent administration of paclitaxel or docetaxel does not alter the pharmacokinetics of epirubicin hydrochloride. This combination may be beneficial when alternating administration of the two drugs. Epirubicin hydrochloride and paclitaxel should be administered with an interval of at least 24 hours between infusions of the two medicinal products.

Dexverapamil may alter the pharmacokinetics of epirubicin hydrochloride and potentially enhance its myelosuppressive effects.

In one study, docetaxel was found to increase plasma concentrations of epirubicin hydrochloride metabolites when administered immediately after epirubicin hydrochloride.

Quinine may accelerate the initial distribution of epirubicin hydrochloride from blood into tissues and may also affect its distribution into erythrocytes.

Concomitant use with interferon-α2b may reduce the terminal half-life, as well as the total and partial clearance of epirubicin hydrochloride.

Potential for severe hematological toxicity should be considered in patients who have undergone (prior) therapy with agents affecting bone marrow function (e.g., cytostatics, sulfonamides, chloramphenicol, phenytoin, aminopyrine derivatives, antiretroviral agents). Enhanced myelosuppression is possible in patients receiving combination therapy with an anthracycline derivative and dexrazoxane.

Special precautions for use.

General information. Epirubicin hydrochloride should be administered under the supervision of a physician experienced in the use of cytotoxic therapy.

Prior to initiation of treatment with epirubicin hydrochloride, patients should have recovered from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) caused by previous cytotoxic therapy.

High-dose epirubicin hydrochloride treatment (e.g., ≥ 90 mg/m² every 3 or 4 weeks) generally causes the same types of adverse effects as standard-dose regimens (< 90 mg/m² every 3 or 4 weeks), but the severity of neutropenia and stomatitis/mucositis may be increased. High-dose epirubicin hydrochloride therapy requires special caution due to the potential for clinical complications arising from severe myelosuppression.

Cardiac function. Anthracycline therapy is associated with the risk of cardiotoxicity, which may manifest as both acute and delayed effects.

Acute toxicity. Early manifestations of epirubicin hydrochloride cardiotoxicity primarily include sinus tachycardia and/or ECG changes such as non-specific ST-T segment alterations. Cases of tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, bradycardia, atrioventricular block, and bundle branch block, have been reported. These manifestations usually do not indicate subsequent development of delayed cardiotoxicity, are rarely of clinical significance, and generally do not warrant discontinuation of epirubicin hydrochloride therapy.

Delayed toxicity. Delayed cardiotoxicity typically develops at the end of the treatment course or within 2–3 months after therapy cessation, although cases have been reported later (months or years after treatment completion). Manifestations of delayed cardiomyopathy include reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF), such as dyspnea, pulmonary edema, dependent edema, cardiomegaly, and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening heart failure is the most severe form of anthracycline-induced cardiomyopathy, reflecting cumulative dose-limiting toxicity of the drug.

The risk of developing congestive heart failure increases rapidly with cumulative epirubicin hydrochloride doses exceeding 900 mg/m². This cumulative dose should only be exceeded with extreme caution.

Cardiac function should be assessed prior to initiating epirubicin hydrochloride therapy and monitored throughout treatment to minimize the risk of severe cardiac effects.

The risk of severe cardiac dysfunction can be reduced by regular monitoring of LVEF during the treatment course and prompt discontinuation of therapy at the first signs of cardiac dysfunction. The preferred methods for repeated cardiac assessment are evaluation of LVEF by multigated radionuclide angiography (MUGA) or echocardiography (ECHO). Baseline cardiac function should be evaluated by ECG, MUGA scan, or ECHO, especially in patients with risk factors for increased cardiotoxicity. LVEF should be reassessed by MUGA scan or ECHO, particularly when high cumulative doses of anthracyclines are used. The same assessment method should be used throughout follow-up monitoring. Due to the risk of cardiomyopathy, exceeding a cumulative epirubicin dose of 900 mg/m² should be done with extreme caution.

Risk factors for the development of cardiotoxicity include active or latent cardiovascular disease, previous or concurrent mediastinal/pericardial radiotherapy, prior therapy with other anthracyclines or anthracenediones, concomitant use of other drugs that may depress myocardial contractility or are cardiotoxic (e.g., trastuzumab), and advanced age (see section "Interaction with other medicinal products and other forms of interaction").

Congestive heart failure (NYHA class II–IV) has been observed in patients receiving trastuzumab as monotherapy or in combination with anthracyclines such as epirubicin. Moderate to severe heart failure, including fatal cases, may occur.

Trastuzumab and anthracyclines such as epirubicin should not be used in combination except in properly controlled clinical trials with cardiac function monitoring. Patients previously treated with anthracyclines also have an increased risk of cardiotoxicity when receiving trastuzumab, although this risk is lower than with concurrent use of trastuzumab and anthracyclines.

Due to the variable half-life of trastuzumab, it may remain in circulation for up to 7 months after discontinuation of treatment. Patients receiving anthracyclines such as epirubicin after stopping trastuzumab may have an increased risk of cardiotoxicity. If possible, physicians should avoid prescribing anthracycline-based therapy within 7 months after stopping trastuzumab. When using anthracycline derivatives, particularly epirubicin, careful monitoring of cardiac function is required.

If symptoms of heart failure occur during treatment with epirubicin while receiving trastuzumab, standard medical therapy for heart failure should be initiated.

Particular attention to cardiac monitoring is required for patients receiving high cumulative doses and those with risk factors. However, epirubicin hydrochloride-related cardiotoxicity may occur at lower cumulative doses regardless of the presence or absence of risk factors.

Spontaneous cases of fetal/neonatal cardiotoxic effects, including fetal death, have been reported following in utero exposure to epirubicin (see section "Use in pregnancy or lactation"). Epirubicin and other anthracyclines or anthracenediones are likely to have additive toxicity.

Hematological toxicity. Like other cytotoxic agents, epirubicin may cause myelosuppression. Hematological parameters, including differential leukocyte count, should be closely monitored before and during each treatment cycle with epirubicin. Dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the predominant manifestations of epirubicin hematological toxicity and the most common dose-limiting acute toxicity of the drug.

Leukopenia and neutropenia are generally more severe with higher doses, with nadir values typically occurring between days 10 and 14 after drug administration. These effects are usually transient, and leukocyte/neutrophil counts return to normal within 21 days. Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary leukemia. Cases of secondary leukemia, with or without a preleukemic phase, have been reported in patients treated with anthracyclines, including epirubicin. Secondary leukemia occurs more frequently when these agents are used in combination with DNA-damaging antineoplastic agents, radiation therapy, following prior intensive cytotoxic therapy, or with increased anthracycline doses. Secondary leukemia may have a latent period of 1 to 3 years.

Gastrointestinal tract. Epirubicin hydrochloride has emetogenic effects. Mucositis/stomatitis usually occurs early in treatment and, in severe cases, may progress within a few days to mucosal ulceration. In most patients, these adverse effects resolve by the third week of therapy.

Liver function. Epirubicin hydrochloride is primarily eliminated via the liver. Total bilirubin and serum AST levels should be monitored before and during treatment. In patients with elevated bilirubin and AST levels, drug clearance may be reduced and overall toxicity increased. Lower doses are recommended for such patients (see sections "Pharmacological properties" and "Dosage and administration"). Epirubicin hydrochloride should not be administered to patients with severe hepatic impairment (see section "Contraindications").

Kidney function. Serum creatinine levels should be regularly checked before and during treatment. Dose adjustment is recommended for patients with elevated serum creatinine (> 5 mg/dL) (see section "Dosage and administration").

Injection site reactions. Phlebosclerosis may occur with administration into small vessels or repeated injections into the same vein. The risk of phlebitis/thrombophlebitis at the injection site can be minimized by following the recommended administration technique (see section "Dosage and administration").

Extravasation. Extravasation of epirubicin hydrochloride during intravenous administration may cause local pain, severe tissue damage (blistering, severe cellulitis), and necrosis. If signs or symptoms of extravasation occur during intravenous infusion of epirubicin, the infusion should be immediately stopped. The occurrence and severity of adverse effects due to anthracycline extravasation can be prevented or reduced by immediate use of specific agents, such as dexrazoxane (see appropriate instructions for medical use). Patient discomfort may be alleviated by cooling and maintaining the injection site in a cooled state, and by using hyaluronidase and dimethyl sulfoxide (DMSO). Close monitoring of the patient is required thereafter, as tissue necrosis may develop weeks after extravasation. Surgical consultation regarding possible resection of the affected area should be considered if necessary.

Other. With cytotoxic therapy, including epirubicin hydrochloride, cases of thrombophlebitis and thromboembolic events, including pulmonary embolism (in some cases fatal), have been reported.

Tumor lysis syndrome. Epirubicin hydrochloride may cause hyperuricemia due to extensive purine catabolism associated with rapid tumor cell lysis induced by the drug (tumor lysis syndrome). After initiation of treatment, serum levels of uric acid, potassium, calcium phosphate, and creatinine should be determined. Hydration, urinary alkalinization, and prophylactic use of allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.

Immunosuppressive effect/increased susceptibility to infections. Administration of live or attenuated live vaccines to patients with immunosuppression due to chemotherapy, including epirubicin hydrochloride, may result in severe or fatal infections (see section "Interaction with other medicinal products and other forms of interaction"). Live vaccines should be avoided in patients receiving epirubicin. Inactivated or killed vaccines may be used, although their efficacy may be reduced.

Reproductive system. Epirubicin hydrochloride may cause genotoxic effects. Men and women undergoing treatment with epirubicin hydrochloride should use effective contraception during treatment and for a certain period after completion. Where appropriate and feasible, patients desiring fertility after treatment completion should be offered genetic counseling (see section "Use in pregnancy or lactation").

Intravesical administration. Administration of epirubicin hydrochloride may cause symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, urinary retention, hematuria, bladder discomfort, bladder wall necrosis) and bladder spasms. Special attention is required for issues related to catheterization (e.g., urethral obstruction due to massive intravesical tumors).

Excipients. This medicinal product contains 3.54 mg (or 0.154 mmol) of sodium per 1 mL of injection solution.

One 5 mL vial of this medicinal product contains 18 mg of sodium, equivalent to 0.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

One 25 mL vial of this medicinal product contains 89 mg of sodium, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Caution is advised when administering to patients on a sodium-controlled diet.

Use during pregnancy or lactation.

Pregnancy. Data on the use of epirubicin hydrochloride in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. Epirubicin hydrochloride should not be used during pregnancy except when the woman's clinical condition necessitates treatment with epirubicin.

Epirubicin should be avoided during the first trimester of pregnancy. Human data are insufficient to confirm or exclude severe neonatal defects or miscarriages associated with epirubicin use in the second and third trimesters.

Following in utero exposure to epirubicin in the second and/or third trimester, sporadic cases of transient fetal and/or neonatal ventricular hypokinesia, transient elevation of cardiac enzymes, and fetal death due to suspected anthracycline-induced cardiotoxic effects have been reported (see section "Special precautions for use"). Monitoring of the fetus and/or neonate for cardiotoxicity and appropriate diagnostic evaluation according to local treatment standards should be performed.

Lactation. It is unknown whether epirubicin is excreted in human breast milk. Since many drugs, including other anthracycline derivatives, are excreted in human breast milk and considering the potential for serious adverse reactions in breastfed infants due to epirubicin, breastfeeding should be discontinued during epirubicin treatment and for at least 7 days after the last dose.

Fertility. Epirubicin may induce chromosomal damage in human spermatozoa. Men undergoing treatment with epirubicin should be advised to consider sperm cryopreservation due to the potential for irreversible infertility resulting from treatment. Epirubicin may cause amenorrhea or premature menopause in premenopausal women.

Women of childbearing potential/contraception for men and women.

Due to the genotoxic potential of epirubicin, women of childbearing potential should be advised to avoid pregnancy and use effective contraception during treatment and for at least 7 months after the last dose.

Men undergoing treatment with epirubicin should be advised to use effective contraception and avoid fathering a child during treatment and for at least 4 months after the last dose.

Ability to drive and use machines.

No systematic assessment of the effect of epirubicin on the ability to drive or operate machinery has been conducted. Epirubicin may cause nausea and vomiting, which may temporarily impair the ability to drive or operate machinery.

Method of administration and dosage.

Only intravenous or intravesical administration of the drug is permitted. Epirubicin is inactive when taken orally and should not be administered intramuscularly or intrathecally.

Dosage

Intravenous administration

Standard dose regimen

When epirubicin hydrochloride is used as monotherapy, the recommended dose for adults is 60–90 mg/m² body surface area administered by intravenous injection over 5–10 minutes at 21-day intervals depending on hematological status and bone marrow function.

High-dose regimen

Lung cancer

Epirubicin hydrochloride as monotherapy at high doses in lung cancer should be administered according to the following regimens:

• Small cell lung cancer in previously untreated patients: 120 mg/m² on day 1 every 3 weeks;
• Non-small cell lung cancer (epidermoid, squamous, and adenocarcinoma) in previously untreated patients: 135 mg/m² on day 1 or 45 mg/m² on days 1, 2, and 3 every 3 weeks.

Breast cancer

Doses up to 135 mg/m² as monotherapy and up to 120 mg/m² when used in combination, administered every 3–4 weeks, have proven effective and well tolerated in patients with breast cancer.

For adjuvant therapy of early-stage breast cancer with lymph node involvement, recommended doses range from 100 mg/m² to 120 mg/m² administered every 3–4 weeks.

The drug should be administered intravenously as a bolus injection over 5–10 minutes or by intravenous infusion for up to 30 minutes.

Lower doses (60–75 mg/m² or 105–120 mg/m² in high-dose regimens) are recommended for patients with reduced bone marrow reserve due to prior chemotherapy and/or radiotherapy, elderly patients, or those with bone marrow neoplastic infiltration.

The total dose per cycle may be divided over 2–3 consecutive days.

When used in combination with other antineoplastic agents, doses should be appropriately reduced. Since the primary route of drug elimination is the hepatobiliary system, the dose of epirubicin hydrochloride should be reduced in patients with impaired liver function to avoid increased overall toxicity.

In general, when serum bilirubin levels are between 1.4–3 mg/100 mL and bromosulfophthalein (BSP) retention is 9–15%, half the standard dose is recommended. If bilirubin levels and BSP retention are even higher, one-quarter of the standard dose is recommended.

Moderate renal impairment is not a reason to adjust the recommended doses, as renal excretion of epirubicin hydrochloride is minimal.

Intravesical administration

Epirubicin should not be administered intravesically for the treatment of invasive tumors that have penetrated the bladder wall. In such cases, systemic therapy or surgical intervention is more effective.

For the treatment of papillary transitional cell carcinoma, weekly instillations of 50 mg (solvent volume see below) are recommended, repeated for 8 weeks; in case of local toxicity (chemical cystitis), the single dose should be reduced to 30 mg. For the treatment of carcinoma in situ, the dose may be increased up to 80 mg depending on individual tolerance.

The following preparation regimens for epirubicin solutions are recommended for intravesical therapy of superficial bladder cancer.

For prevention of further recurrences following transurethral resection of superficial tumours, weekly instillations of 50 mg are recommended, to be repeated for 4 weeks, after which monthly instillations of the same dose should be administered for a period up to one year.

Intravenous administration

The drug should be administered intravenously over 5–10 minutes using an infusion set with a preceding infusion of physiological saline solution, after confirming that the needle is properly placed within the vein. This technique reduces the risk of extravasation of the drug and ensures venous flushing at the end of administration.

Leakage of epirubicin from the vein during administration may lead to tissue damage and even necrosis.

Intravesical administration

The epirubicin hydrochloride solution, when instilled via catheter, should be retained in the body for one hour, after which the patient should empty the bladder. During instillation, it may be advisable to rotate the patient's pelvis to ensure broad contact of the solution with the bladder mucosa.

To prevent dilution of the solution by urine, the patient should abstain from drinking any fluids for 12 hours prior to instillation.

Children. There are insufficient data on the safety and efficacy of the drug in children.

Overdose.

Acute overdose of epirubicin hydrochloride leads to severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (predominantly mucositis), and acute cardiac complications.

Delayed cardiac failure has been observed following anthracycline administration several months after completion of treatment (see section "Special instructions").

Careful monitoring of the patient is required; if signs of cardiac failure appear, treatment should be administered according to standard guidelines.

Symptomatic treatment is indicated in case of overdose. Epirubicin hydrochloride is not eliminated by dialysis.

Adverse Reactions

Adverse reactions may occur in more than 10% of patients receiving treatment with the medicinal product. The most common adverse reactions are myelosuppression, gastrointestinal disorders, anorexia, alopecia, and infections. The following adverse reactions have been reported during epirubicin treatment, observed at the specified frequencies: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown (cannot be estimated from available data).

Infections and infestations. Very common: infection, conjunctivitis. Uncommon: sepsis*, pneumonia*.
Unknown: septic shock, cellulitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps). Uncommon: acute myeloid leukemia, acute lymphoblastic leukemia.

Blood and lymphatic system disorders. Very common: myelosuppression (leukopenia, granulocytopenia and neutropenia, anemia, thrombocytopenia, febrile neutropenia).

Immune system disorders. Rare: hypersensitivity§, anaphylactic reaction*.

Metabolism and nutrition disorders. Common: decreased appetite, dehydration*. Rare: hyperuricemia*.

Nervous system disorders. Common: burning sensation§. Rare: dizziness.

Eye disorders. Very common: keratitis.

Cardiac disorders. Common: congestive heart failure˄, ventricular tachycardia, bradycardia, atrioventricular block, bundle branch block. Rare: cardiotoxicity‖.

Vascular disorders. Very common: flushing, phlebitis*. Common: haemorrhage*, erythema*. Uncommon: embolism*, arterial embolism*, thrombophlebitis*. Unknown: shock*.

Respiratory, thoracic and mediastinal disorders. Uncommon: pulmonary embolism*. Unknown: hypoxiaɷ.

Gastrointestinal disorders. Very common: nausea, vomiting, stomatitis, mucositis, diarrhea. Common: gastrointestinal pain*, gastrointestinal erosions, esophagitis, gastrointestinal ulcer. Uncommon: gastrointestinal haemorrhage. Unknown: abdominal discomfort, oral mucosal erosion, oral ulcers, oral pain, burning sensation of mucous membranes, oral haemorrhage, oral pigmentation*.

Skin and subcutaneous tissue disorders. Very common: alopecia, skin toxicity. Common: rash/itching, nail pigmentation*, skin changes, skin hyperpigmentation*. Uncommon: urticaria*, erythema*. Unknown: photosensitivity*.

Renal and urinary disorders. Very common: chromaturia*†. Common: polyuria§.

Reproductive system and breast disorders. Very common: amenorrhea. Rare: azoospermia.

General disorders and administration site conditions. Very common: malaise, pyrexia*. Common: erythema at infusion site, chills*. Uncommon: asthenia. Unknown: phlebosclerosis, pain, soft tissue necrosisԑ.

Investigations. Very common: abnormal transaminase levels. Common: decreased ejection fraction.

Injury, poisoning and procedural complications. Very common: chemical cystitis*§.
Unknown: recall reaction*Δ.

* Adverse effects reported in the post-marketing period.
˄ Dyspnea, edema, hepatomegaly, ascites, pulmonary edema, pleural effusion, gallop rhythm.
ɷ Myelosuppression-induced.
† Red discoloration of urine on days 1 and 2 after administration.
§ After intravesical administration (see section "Special Warnings and Precautions for Use").
‖ e.g., ECG changes, arrhythmias, cardiomyopathy.
ԑ After accidental paravenous injection.
Δ Skin hypersensitivity in previously irradiated areas.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of efficacy should be reported via: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in a refrigerator (2–8 °C) in the original packaging to protect from light. Keep out of reach of children.

From a microbiological point of view, this medicinal product should be used immediately after opening the vial. If not used immediately, the user is responsible for the storage conditions and duration prior to use.

Incompatibilities.

Prolonged contact with solutions of alkaline pH (including bicarbonate-containing solutions) should be avoided, as this leads to hydrolysis of the drug. Only solvents specified in the section "Special Warnings and Precautions for Use" should be used.

Epirubicin injections and any prepared solutions must not be mixed with other medicinal products. Physical incompatibility with heparin has been reported.

Mixing epirubicin with other medicinal products is prohibited.

Packaging.

5 ml or 25 ml of medicinal product in a glass vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Sindan-Farma S.R.L.

Manufacturer's address and location of operations.

Bulevardul Ion Mihalache 11, Bucharest, 011171, Romania.