Vero-epirubicin (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Veropharm, LLC (Russia)

ATC Code

L01DB03 (Epirubicin)

Active Substance

Epirubicin (Rec.INN registered by WHO)

Dosage Forms

	Vero-Epirubicin	Lyophilisate for preparation of solution for intravascular and intravesical administration 10 mg: vial 1 pc.
		Lyophilisate for preparation of solution for intravascular and intravesical administration 50 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravascular and intravesical administration as a porous amorphous mass of red or orange-red color.

Excipients: methylparahydroxybenzoate (nipagin) – 2 mg, mannitol (mannite) – 40 mg.

Colorless glass vials (1) – cardboard packs.

Lyophilisate for preparation of solution for intravascular and intravesical administration as a porous amorphous mass of red or orange-red color.

Excipients: methylparahydroxybenzoate (nipagin) – 10 mg, mannitol (mannite) – 200 mg.

Colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

Antineoplastic agent from the group of anthracycline antibiotics. Anthracyclines disrupt various biochemical processes and biological functions in eukaryotic cells, including the proposed leading role of the following mechanisms: 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 (mainly albumin) is 77%.

After IV administration, Epirubicin is rapidly and actively distributed in 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 actively metabolized in the liver, as well as in other organs and cells, including erythrocytes.

Epirubicin and its main metabolites are excreted primarily through the intestines 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 detected 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. Determine the regimen individually based on the specific malignancy, disease stage, and patient’s hematological status.

Calculate the dose based on body surface area (mg/m²). Adjust the initial dose for patients with impaired hepatic or renal function. Do not exceed the cumulative dose of 900 mg/m² to minimize the risk of cardiotoxicity.

For intravenous administration, administer slowly as an intravenous push or a short infusion over 3-5 minutes into the tubing of a freely running intravenous infusion of 0.9% sodium chloride or 5% dextrose solution. Avoid rapid injection. Do not administer intramuscularly or subcutaneously.

For intravesical administration, instill the solution into the bladder via a catheter. Retain the solution in the bladder for 1 to 2 hours. Rotate the patient’s position every 15 minutes to ensure contact with all areas of the bladder mucosa.

Reconstitute the lyophilisate immediately before use. Use only 0.9% sodium chloride injection or sterile water for injection as a diluent. Do not use other solvents. Shake the vial gently until the contents completely dissolve. The resulting solution concentration is 2 mg/mL.

Inspect the reconstituted solution visually for particulate matter and discoloration. Discard the solution if it is unclear or contains a precipitate. Protect the solution from light. Discard any unused solution appropriately.

Monitor complete blood count, liver function tests, and renal function before each course of therapy. Assess cardiac function (e.g., ECG, echocardiogram) regularly, especially as the cumulative dose approaches the maximum limit.

Delay administration if the neutrophil count is below 1,500/mm³ or if severe stomatitis is present. Reduce subsequent doses in case of severe hematological or non-hematological toxicity, excluding alopecia and nausea/vomiting.

Adverse Reactions

Infections septic shock, sepsis, pneumonia.

From the hematopoietic system bone marrow suppression, thrombocytopenia, tissue hypoxia as a result of myelosuppression.

From the blood coagulation system: bleeding, thromboembolism, including pulmonary embolism (in some cases with fatal outcome).

From the nervous system: dizziness.

From the organ of vision: conjunctivitis, keratitis.

From the cardiovascular system cardiotoxicity.

From the digestive system anorexia, nausea, vomiting, stomatitis, mucositis, esophagitis, diarrhea, increased concentration of total bilirubin and activity of hepatic transaminases in blood 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.

From the urinary system: red coloration of urine for 1-2 days after epirubicin administration.

From the reproductive system: amenorrhea, azoospermia.

From the skin and subcutaneous tissues: alopecia, urticaria, rash, itching, skin redness, erythema, hyperpigmentation of the skin and nails, photosensitivity and hypersensitivity of irradiated skin areas (anamnestic reaction to radiation).

Local reactions: with IV administration – erythematous striation 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 widespread necrosis of the perfused tissue. With administration into the urinary bladder – 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 myelocytic 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; prior 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.

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 epirubicin therapy.

Experimental studies have established teratogenic and embryotoxic effects of epirubicin.

Use in Hepatic Impairment

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

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated.

Special Precautions

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

During treatment, monitoring of peripheral blood count, 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 epirubicin therapy is not recommended, as superinfection may develop. Administration of inactivated or killed vaccines is allowed, but the response to such vaccines may be reduced.

Experimental studies have established carcinogenic and mutagenic effects of epirubicin.

Men and women receiving epirubicin therapy 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 may lead to amenorrhea or premature menopause.

Effect on ability to drive vehicles 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 medicinal products with potential cardiotoxicity – the risk of cardiotoxic action 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 T½ of epirubicin is observed.

In patients receiving the 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 terminal half-life and 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 tissue sensitivity 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 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.