Vero-Epirubicin, 50 mg

Pharmacodynamics

Epirubicin is a cytotoxic anthracycline antibiotic. Anthracyclines are known to disrupt various biochemical processes and biological functions of eukaryotic cells, but the exact mechanisms of the cytotoxic and/or antiproliferative effects of epirubicin are not fully established.

Epirubicin forms a complex with DNA through ring intercalation between pairs of nucleotide bases and inhibits the synthesis of nucleic acids (DNA and RNA) and proteins. Intercalation initiates DNA cleavage by topoisomerase II, which determines the cytotoxic effect. Epirubicin also inhibits DNA-helicase activity and thus prevents enzymatic separation of double-stranded DNA and disrupts replication and transcription.

Epirubicin also takes part in oxidation/reduction reactions, causing the formation of cytotoxic free radicals. The antiproliferative and cytotoxic effects of epirubicin are thought to result from these and other possible mechanisms.

Pharmacokinetics

The pharmacokinetic parameters of epirubicin are linear over a dose range of 60 to 150 mg/m² . Plasma clearance of the drug is independent of infusion duration or route of administration. T_1/2 is 30-40 hours.

After intravenous administration, epirubicin is rapidly and actively distributed in the tissues.

The degree of binding of epirubicin to plasma proteins, mainly to albumin, is about 77% and is independent of the drug concentration. Epirubicin accumulates in erythrocytes; its concentration in whole blood is approximately twice that in plasma.

Epirubicin is rapidly and actively metabolized in the liver as well as in other organs and cells, including red blood cells. Four major metabolic pathways have been identified:

1. reduction of the C-13 keto group to form the 13(S)-dihydro derivative epirubicinol;
2. conjugation of the unchanged drug and epirubicinol with glucuronic acid;
3. Lociation of the amino-sugar component by hydrolysis and formation of aglycones of doxorubicin and doxorubicinol;
4. Lociation of the amino-sugar component by redox process and formation of aglycones of 7-deoxydoxorubicin and 7-deoxydoxorubicinol.

The cytotoxic activity of epirubicinol in vitro is 1/10 of that of epirubicin. Since plasma concentrations of epirubicinol are lower compared to the unchanged drug, they are unlikely to be sufficient to exhibit cytotoxic effects in vivo. There is no evidence of significant activity or toxicity of other metabolites.

Epirubicin and its major metabolites are excreted primarily in the bile (34%) and, to a lesser extent, in the urine (27%).

Pharmacokinetics in special groups

Hepatic impairment

The clearance of epirubicin is decreased in patients with hepatic impairment.

Renal dysfunction

In patients with a serum creatinine level of 5 mg/dL, a 50% decrease in plasma clearance has been noted. In patients on dialysis, pharmacokinetics have not been studied.

Indications

Active ingredient

Composition

Active ingredients:

Epirubicin hydrochloride 10 mg.

Auxiliary substances:

mannitol,

methylhydroxybenzoate.

How to take, the dosage

Intravenously, intraarterially, intravesically.

Vero-epirubicin can be used both in monotherapy and in combination with other antitumor drugs, and therefore, doses and mode of administration of the drug should be guided by the literature.

Intravenous administration

As monotherapy, the recommended standard dose per cycle is 60-90 mg/m2 every three to four weeks. The total dose of the drug per cycle can be administered either at one time or divided into multiple injections, over 2 to 3 consecutive days.

If Vero-epirubicin is used in combination with other antitumor drugs, the recommended dose per cycle should be reduced accordingly. In individual cases, high doses of Vero-epirubicin 90-120 mg/m2 once at 3-4 week intervals may be used.

Repeated administration of the drug is possible only when all signs of toxicity (especially gastrointestinal and hematological) have disappeared.

Renal dysfunction. In patients with severe renal dysfunction (serum creatinine level > 5 mg/dL) lower doses of Vero-epirubicin should be used.

Hepatic impairment: If serum bilirubin levels are 1.2-3 mg/dL or ACT values are 2-4 times the upper limit of normal, the administered dose of Vero-epirubicin should be reduced by 50% of the recommended dose. If the serum bilirubin level is greater than 3 mg/dL or the ACT value is more than 4 times the upper limit of normal, the administered dose should be reduced by 75% of the recommended dose.

Other special patient groups. Lower doses or longer intervals between cycles are recommended in patients who have previously received massive antitumor therapy, as well as in patients with tumor infiltration of the bone marrow.

In elderly patients, standard doses and regimens may be used for initial therapy.

Injection into the bladder

. To prevent recurrence after transurethral resection of superficial bladder tumors, a single installation of 80-100 mg of Vero-epirubicin immediately after transurethral resection or eight weekly installations of 50 mg of Vero-epirubicin (in 25-50 ml of 0.9% sodium chloride solution) starting 2-7 days after transurethral resection are recommended. If local toxicity develops (chemical cystitis), the dose should be reduced to 30 mg. Four weekly instillations of 50 mg and then 11 monthly instillations at the same dose are possible.

Installation is carried out using a catheter and the drug should remain in the bladder for 1 hour. The patient should turn from side to side during installation to ensure even exposure of the drug to the bladder mucosa. To avoid excessive dilution of the drug with urine, patients should be warned to refrain from taking liquids for 12 hours before installation. At the end of the instillations, the patient should empty the bladder.

Intra-arterial administration

Patients with hepatocellular cancer may be given the drug as an infusion into the main hepatic artery at a dose of 60-90 mg/msup>2 at intervals of 3 weeks to 3 months or at a dose of 40-60 mg/m2 at intervals of 4 weeks.

Regulations for preparation and administration of the solution

Vero-epirubicin should be dissolved in water for injection to a concentration of at least 2 mg/ml. After adding water for injection, the bottle is shaken until the drug is completely dissolved. The prepared solution is stable for 24 hours at room temperature and 48 hours at 4 to 10 °С. The solution shall be stored in a place protected from light.

In order to reduce the risk of thrombosis and extravasation, it is recommended that Vero-epirubicin be administered slowly (3 to 20 minutes, depending on the drug dose and volume of the infusion solution) through a tube of an intravenous infusion system, during infusion of 0.9% sodium chloride solution or 5% dextrose solution.

Interaction

Epirubicin is mainly used in combination with other cytotoxic agents. In this regard, additive toxicity is possible, especially in relation to the hematopoietic system and the gastrointestinal tract.

Myelotoxic drugs increase the manifestation of hematotoxicity of the drug.

When using epirubicin in combination with other potentially cardiotoxic chemotherapeutic agents as well as with cardiovascular drugs (such as slow calcium channel blockers) cardiac function should be monitored.

Epirubicin is actively metabolized in the liver. Changes in liver function caused by concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity of epirubicin.

Cimetidine causes a 50% increase in the area under the concentration-time curve (AUC) of epirubicin, so it should be stopped before starting treatment with epirubicin.

The administration of paclitaxel prior to epirubicin may result in increased plasma concentrations of unchanged epirubicin and its metabolites. No changes in epirubicin pharmacokinetics have been observed when using taxanes (paclitaxel or docetaxel) after epirubicin.

Epirubicin should not be mixed with other drugs. Contact with alkaline solutions should be avoided as this may lead to hydrolysis of epirubicin. Because of chemical incompatibility, epirubicin should not be mixed with heparin (a precipitate will form when mixed).

Special Instructions

Vero-Epirubicin should only be used under the supervision of physicians experienced in the use of cytotoxic drugs.

The patient must recover from the acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia and systemic infections) before starting treatment.

When using high doses of Vero-epirubicin ( > 90 mg/m2 every 3-4 weeks), adverse events were generally similar to those with standard doses ( < 90 mg/m2 every 3-4 weeks), but the severity of neutropenia and stomatitis/mucositis may be increased. Because of possible clinical complications resulting from myelosuppression, patients receiving high-dose epirubicin should be closely monitored.

In therapy with anthracyclines, there is a risk of early (i.e., acute) or late (delayed) cardiotoxicity. Delayed cardiotoxicity usually develops late in the course of therapy or within 2-3 months after discontinuation, but more delayed side effects are possible (several months or even years after therapy ends).

Before and during therapy with the drug, heart function should be monitored to minimize the risk of severe heart damage. For this purpose, the left ventricular ejection fraction should be determined regularly and treatment should be stopped immediately at the first signs of worsening of heart function. Adequate methods of quantifying cardiac function (measuring ejection fraction) include radioisotopic angiography (MUGA) and echocardiography.

. Prior to initiation of treatment, it is recommended that cardiac function be assessed by ECG, radioisotope study, or echocardiography, especially in patients with risk factors for increased cardiotoxicity (overt or occult cardiovascular disease, prior or concomitant mediastinal/pericardial radiation therapy, prior therapy with other anthracyclines or anthracenedion, and concomitant therapy with drugs that reduce the contractility of the heart). Left ventricular ejection fraction should be measured dynamically, especially with increasing cumulative anthracycline doses. It is advisable to use the same method at all times.

The risk of congestive heart failure increases rapidly when the cumulative cumulative dose of epirubicin exceeds 900 mg/m2; the drug should be used with extreme caution at these doses. However, it should be considered that cardiotoxicity may also develop with lower cumulative doses of epirubicin regardless of the presence of risk factors.

. During treatment with Vero-epirubicin, especially with high doses, hematologic parameters should be assessed before and during each cycle of therapy, including determination of leukocytes, platelets, hemoglobin, blood cells, liver function tests (particularly bilirubin and ACT levels) and serum creatinine levels (patients with creatinine levels greater than 5 mg/dL should reduce the Vero-epirubicin dose).

In patients receiving anthracyclines, including epirubicin, cases of secondary leukemia with or without preleukemic phase have been described. Secondary leukemia is more common when these drugs are used in combination with other antitumor agents that cause DNA damage, radiation therapy, and in patients who previously received intensive cytotoxic therapy or high-dose anthracyclines. Secondary leukemia may have a latency period of 1-3 years.

In case of the first signs of extravasation of Vero-epirubicin (burning or soreness at the injection site), the infusion should be stopped immediately, and then the infusion should be resumed in another vein until the full dose is administered. Carry out local remedial measures to eliminate the effects of extravasation. The use of ice packs is appropriate.

Hyperuricemia may occur with Vero-epirubicin due to rapid lysis of tumor cells; therefore, patients should have their uric acid, potassium, calcium and creatinine levels determined during therapy. Interventions such as hydration, alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia can minimize the risk of complications associated with tumor lysis syndrome.

When injecting Vero-epirubicin into the bladder, special attention should be paid to conditions that create obstacles to catheterization (e.g., urethral obstruction due to massive bladder tumors).

Men and women receiving Vero-epirubicin therapy should use reliable methods of contraception.

The rules for handling cytotoxic substances must be followed when handling Vero-epirubicin. It is recommended to treat the surface contaminated by the drug with diluted solution of sodium hypochlorite (containing 1% chlorine). In case of contact of the drug on the skin – immediately rinse the skin with soap and water or sodium bicarbonate solution; in case of contact with eyes – pull back the eyelids and rinse the eye (eyes) with plenty of water for at least 15 minutes.

Contraindications

Intravenous administration is contraindicated in persistent myelosuppression, severe hepatic dysfunction, severe heart failure and severe arrhythmias, recent myocardial infarction, prior therapy with epirubicin and/or other anthracyclines and anthracenedion at maximum total doses.

Injection into the bladder is contraindicated in cases of urinary tract infections, bladder inflammation, hematuria, invasive tumors with penetration into the bladder wall.

With caution: patients with risk factors of cardiotoxicity; patients who received earlier intensive chemotherapy; patients with tumor infiltration of bone marrow as well as patients with liver and kidney function disorders (reduction of starting doses or increase of intervals between doses may be required); use in combination antitumor therapy and also in combination with radiotherapy or other antitumor therapy.

Safety and efficacy in children have not been adequately studied. Cardiotoxicity may be increased in pediatric patients.

Side effects

Blood system disorders: leukopenia, neutropenia, anemia, thrombocytopenia.

Cardiovascular system: manifestations of early (acute) cardiotoxicity of epirubicin are mainly sinus tachycardia and/or abnormalities on ECG (non-specific ST-T wave changes). Tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, AV block, and Gis bundle branch block may also be noted. These effects are not always predictive of later delayed cardiotoxicity, are rarely clinically significant, and usually do not require withdrawal of therapy with the drug.

Late (delayed) cardiotoxicity is manifested by decreased left ventricular ejection fraction (LVEF) and/or symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary edema, orthostatic edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, galloping rhythm. Subacute phenomena such as pericarditis/myocarditis may also be noted. The most severe form of anthracycline-induced cardiomyopathy is life-threatening ZSN, which is a toxicity that limits the cumulative dose of the drug.

In addition, thromboembolic complications, including pulmonary embolism (in some cases fatal), hot flashes to the face may occur.

Digestive system disorders: anorexia, nausea, vomiting, stomatitis, oral mucosa hyperpigmentation, esophagitis, abdominal pain or burning sensation, gastric erosions, bleeding from the stomach, diarrhea, colitis; increased serum levels of total bilirubin and transaminases.

Urinary system disorders: urine staining red for 1-2 days after administration of Vero-epirubicin. Hyperuricemia may occur due to rapid lysis of tumor cells.

An organ of vision: conjunctivitis, keratitis.

Skin and skin appendages: alopecia, rash, itching, sudden skin redness, hyperpigmentation of skin and nails, photosensitivity, hypersensitivity of irritated skin (anamnestic reaction to irradiation), urticaria.

Endocrine system disorders: amenorrhea (at the end of therapy ovulation is restored, but premature menopause may occur); oligospermia, azoospermia (in some cases sperm count is restored to normal levels; this may occur several years after therapy ends).

Local reactions. Erythematous striations along the course of the vein into which the infusion was made are not uncommon, followed by local phlebitis or thrombophlebitis. Phlebosclerosis may also develop, especially if Vero-epirubicin is re-injected into a small vein. Local soreness, severe inflammation of the subcutaneous tissue and tissue necrosis may occur if the drug enters the surrounding tissue.

In addition to systemic toxicity, gastric and duodenal ulceration (possibly due to reflux of the drug into the gastric artery) and narrowing of the biliary tract due to drug-induced sclerosing cholangitis and widespread necrosis of perfused tissue may be observed during intra-arterial administration.

Intravesical use of epirubicin may result in symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction.

Others: malaise, asthenia, fever, chills, accession of secondary infections, anaphylaxis, dehydration, development of acute lympholeukemia or myeloleukemia.

Overdose

Acute overdose of epirubicin can lead to severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and cause acute cardiac complications.

The antidote to epirubicin is not known. In case of overdose, symptomatic therapy is recommended.

Pregnancy use

The drug is contraindicated in pregnancy and during lactation (breast-feeding).