Epilem (Lyophilisate) Instructions for Use

ATC Code

L01DB03 (Epirubicin)

Active Substance

Epirubicin

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

An antineoplastic agent from the group of anthracycline antibiotics. Anthracyclines disrupt various biochemical processes and biological functions in eukaryotic cells, with the leading role of the following mechanisms suggested: at the molecular level, Epirubicin is capable of forming a complex with DNA through intercalation between nucleotide base pairs, which leads to disruption of nucleic acid (DNA, RNA) and protein synthesis.

It causes serious disturbances in the tertiary structure of DNA; Epirubicin inhibits the activity of DNA helicase, which prevents the enzymatic separation of double-stranded DNA and disrupts replication and transcription; Epirubicin participates in oxidation/reduction reactions with the formation of highly active cytotoxic free radicals.

Pharmacokinetics

The pharmacokinetic parameters of epirubicin are linear in the dose range from 60 to 150 mg/m². Plasma clearance is independent of the infusion duration or administration schedule. Binding to plasma proteins (primarily albumin) is 77%.

After IV administration, Epirubicin is rapidly and extensively distributed into tissues. Epirubicin accumulates in erythrocytes; its concentration in whole blood is approximately 2 times higher than in plasma. It does not cross the blood-brain barrier. It is rapidly and extensively metabolized in the liver, as well as in other organs and cells, including erythrocytes.

Epirubicin and its main metabolites are excreted primarily through the intestine and, to a lesser extent, through the kidneys. Elimination from the body is triphasic with a slow terminal phase lasting from 30 to 40 hours. After 72 hours, approximately 43% of epirubicin is found in bile and approximately 16% in urine.

Indications

Breast cancer, ovarian cancer, non-small cell and small cell lung cancer, stomach and esophageal cancer, primary hepatocellular carcinoma, transitional cell bladder cancer, soft tissue sarcoma, osteosarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, acute leukemia, multiple myeloma, pancreatic cancer, rectal cancer, head and neck cancer, hormone-resistant prostate cancer.

ICD codes

Dosage Regimen

Administer intravenously, intra-arterially, or intravesically as directed by the specific treatment protocol.

Determine the dose individually based on the type and stage of malignancy, the patient’s hematological status, and the chosen combination chemotherapy regimen.

For intravenous use, calculate the dose based on body surface area (mg/m²). The standard single-agent dose for previously untreated patients is 60-90 mg/m² administered as a slow intravenous push or brief infusion.

Repeat the intravenous administration every 21 days. Adjust the dose and interval based on the nadir of myelosuppression observed in the previous cycle.

Reduce the dose by approximately 50% if the platelet count falls below 50,000/mm³, the absolute neutrophil count (ANC) falls below 250/mm³, or if severe mucositis occurs.

For patients with impaired hepatic function, reduce the dose as follows: for serum bilirubin 1.2-3 mg/dL, use 50% of the recommended dose; for serum bilirubin greater than 3 mg/dL, use 25% of the recommended dose.

For patients with renal impairment (serum creatinine greater than 5 mg/dL), consider a dose reduction.

Do not exceed the lifetime cumulative dose of 900 mg/m² to minimize the risk of irreversible cardiotoxicity. A lower cumulative dose is recommended for patients with prior mediastinal irradiation or concurrent cardiotoxic therapy.

For intravesical administration, instill 50 mg dissolved in 25-50 mL of 0.9% Sodium Chloride solution into the bladder once weekly for 8 weeks. Retain the instillation for 1 hour.

Reconstitute the lyophilisate strictly according to the manufacturer’s instructions using the appropriate sterile diluent. Do not mix with incompatible solutions such as heparin.

Inspect the parenteral product visually for particulate matter and discoloration prior to administration. Discard any unused solution appropriately.

Adverse Reactions

Infections and infestations septic shock, sepsis, pneumonia.

Blood and lymphatic system disorders bone marrow suppression, thrombocytopenia, tissue hypoxia as a result of myelosuppression.

Coagulation disorders: bleeding, thromboembolism, including pulmonary embolism (in some cases with fatal outcome).

Nervous system disorders: dizziness.

Eye disorders: conjunctivitis, keratitis.

Cardiac disorders cardiotoxicity.

Gastrointestinal disorders anorexia, nausea, vomiting, stomatitis, mucositis, esophagitis, diarrhea, increased concentration of total bilirubin and activity of hepatic transaminases in plasma, hyperpigmentation, erosions or ulcerations of the oral mucosa, pain and bleeding from the oral cavity, pain or burning sensation in the abdominal area, erosions of the gastric mucosa, gastrointestinal bleeding, colitis.

Renal and urinary disorders: red discoloration of urine for 1-2 days after epirubicin administration.

Reproductive system and breast disorders: amenorrhea, azoospermia.

Skin and subcutaneous tissue disorders: alopecia, urticaria, rash, itching, skin redness, erythema, hyperpigmentation of the skin and nails, photosensitivity and hypersensitivity of irradiated skin areas (recall reaction to radiation).

Local reactions: with IV administration – erythematous streaking along the vein into which the infusion was performed, local phlebitis or thrombophlebitis, phlebosclerosis; if epirubicin enters the surrounding tissues – pain, severe cellulitis and necrosis of surrounding tissues. With intra-arterial administration – in addition to systemic toxicity, gastric and duodenal ulcers may be observed (probably due to reflux of epirubicin into the gastric artery); narrowing of the bile ducts due to epirubicin-induced sclerosing cholangitis, as well as extensive necrosis of the perfused tissue. With intravesical administration – development of chemical cystitis, necrosis of the walls and constriction of the bladder, hemorrhagic cystitis.

Other secondary infections, hyperuricemia (due to massive tumor cell lysis), general malaise, asthenia, fever, chills, anaphylaxis, dehydration, development of secondary acute lymphocytic leukemia or myelogenous leukemia.

Contraindications

General: hypersensitivity to epirubicin, as well as to other anthracyclines or anthracenediones; pregnancy, breastfeeding period; children and adolescents under 18 years of age.

For IV administration: severe myelosuppression, severe hepatic insufficiency, unstable angina, cardiomyopathy, severe heart failure and arrhythmias, recent myocardial infarction, acute systemic infections; previous therapy with other anthracyclines or anthracenediones at the maximum cumulative doses.

For intravesical administration: urinary tract infections, bladder inflammation, hematuria, invasive tumors with penetration into the bladder wall; obstructive diseases of the urinary tract and inability to perform catheterization.

Use with caution

Risk factors for the development of cardiotoxicity, previously conducted intensive chemotherapy, tumor infiltration of the bone marrow, impaired liver and/or kidney function, use as part of combined anticancer therapy, as well as in combination with radiation therapy or other types of anticancer therapy.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy. If it is necessary to use during lactation, breastfeeding should be discontinued.

Women of childbearing potential should use reliable methods of contraception during therapy with epirubicin.

In experimental studies, teratogenic and embryotoxic effects of epirubicin have been established.

Use in Hepatic Impairment

IV administration is contraindicated in severe hepatic insufficiency. Use with caution in case of impaired liver function (a reduction in starting doses or an increase in the intervals between doses may be required).

Use in Renal Impairment

Use with caution in case of impaired renal function (a reduction in starting doses or an increase in the intervals between doses may be required).

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Before starting treatment, the patient’s acute toxic effects from previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) must have resolved.

During treatment, monitoring of peripheral blood counts, liver function, ECG, cardiac ultrasound, and plasma uric acid concentration is necessary.

The risk of developing cardiotoxic side effects increases if the cumulative dose of epirubicin exceeds 900 mg/m².

It should be taken into account that heart failure associated with the cardiotoxic effect of epirubicin can occur several weeks after the cessation of therapy.

Vaccination with live vaccines during therapy with epirubicin is not recommended, as superinfection may develop. Administration of inactivated or killed vaccines is allowed, but the response to such vaccines may be reduced.

In experimental studies, carcinogenic and mutagenic effects of epirubicin have been established.

Men and women receiving therapy with epirubicin should use reliable methods of contraception. Women of reproductive age should be informed about the possible negative effect of epirubicin on the fetus. If pregnancy occurs during treatment, it is necessary to consult with specialists regarding the risk of adverse effects of epirubicin on the fetus.

The use of epirubicin can lead to amenorrhea or premature menopause.

Effect on ability to drive and operate machinery

During the use of epirubicin, patients should exercise caution when driving vehicles and operating machinery, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use of epirubicin with other antineoplastic agents, the toxic effect of the latter is enhanced, especially myelotoxicity and effects on the gastrointestinal tract; with cardiotropic drugs and drugs with potential cardiotoxicity – the risk of cardiotoxic effects increases.

The possibility of pronounced suppression of hematopoiesis should also be considered in patients who have received other drugs capable of exerting a myelosuppressive effect (for example, sulfonamides, chloramphenicol, diphenylhydantoin (phenytoin), amidopyrine derivatives, antiretroviral agents).

With simultaneous use with cimetidine, prolongation of the T_1/2 of epirubicin is observed.

In patients receiving a combination of trastuzumab and anthracyclines (including Epirubicin), the development of heart failure (NYHA functional class II-IV), including fatal cases, has been described.

With combined use with interferon-α2b, the T_1/2 of epirubicin in the terminal phase and the total clearance of epirubicin may decrease.

There are limited data on the simultaneous use of epirubicin and radiation therapy. It is likely that the use of epirubicin may increase the sensitivity of tissues to the cytotoxic effect of radiation therapy. The use of epirubicin after radiation therapy may induce inflammatory reactions caused by radiation therapy.

With simultaneous use, quinine may accelerate the distribution of epirubicin from the blood into tissues and also affect the distribution of epirubicin in erythrocytes.

With simultaneous use of anthracyclines with dexrazoxane, the degree of myelosuppression increases.

Epirubicin should not be administered in the same solution with heparin or other antineoplastic drugs, as precipitation occurs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.