Vero-Epirubicin - instructions for use, dose, side effects, contraindications

Epirubicin is a cytotoxic anthracycline antibiotic. It is known that anthracyclines disrupt the various biochemical processes and biological functions of eukaryotic cells, but the exact mechanisms of cytotoxic and / or anti-proliferative effects of epirubicin are not fully established. Epirubicin forms a complex with DNA through intercalation of rings between pairs of nucleotide bases and inhibits the synthesis of nucleic acids (DNA and RNA) and proteins. Intercalation initiates the cleavage of DNA under the action of topoisomerase II, which determines the cytotoxic effect. Epirubicin also inhibits the activity of DNA-helicase and thereby prevents the 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. It is believed that the antiproliferative and cytotoxic effects of epirubicin are the result of these and other possible mechanisms.

Pharmacokinetics:

Pharmacokinetic parameters of epirubicin are linear in the dose range from 60 to 150 mg / m². The clearance of the drug from the plasma does not depend on the duration infusion or route of application. The half-life is 30-40 hours.

After intravenous administration epirubicin quickly and actively distributed in tissues.The degree of binding of epirubicin to plasma proteins, mainly albumin, is about 77% and does not depend on the concentration of the drug. 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 erythrocytes. There are four main ways of metabolism:

1) reduction of the C-13 keto group to form the 13 (S) -dihydro derivative-epirubicinol;

2) conjugation of unchanged drug and epirubicinol with glucuronic acid;

3) elimination of the aminosugar component as a result of hydrolysis and the formation of aglucones of doxorubicin and doxorubicinol;

4) the elimination of the aminosugar component as a result of the oxidation-reduction process and the formation of aglycones of 7-deoxydoxorubicin and 7-deoxydoxorubicinol.

Cytotoxic activity of epirubicinol in vitro is 1/10 of that of epirubicin. Since the concentration of epirubicinol in the plasma is lower compared to the unchanged drug, they are unlikely to be sufficient for the development of a cytotoxic effect in vivo. Signs of severe activity or toxicity of other metabolites have not been identified.

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

Pharmacokinetics in special groups

Impaired liver function

The clearance of epirubicin in patients with impaired liver function is reduced.

Impaired renal function

In patients with serum creatinine <5 mg / dL, no significant changes in the pharmacokinetics of epirubicin or its main metabolite, epirubicinol, were detected. At a serum creatinine level ≥5 mg / dl, a decrease in plasma clearance by 50% was noted. In patients on dialysis, pharmacokinetics have not been studied.

Indications:

Epirubicin is effective in the treatment of the following diseases:

- mammary cancer;

- cancer of the stomach and esophagus;

- pancreas cancer;

- rectal cancer;

- non-small cell and small cell lung cancer;

- ovarian cancer;

- transitional cell carcinoma of the bladder;

- sarcoma of soft tissues and bones;

- cancer of the head and neck;

- primary hepatocellular carcinoma;

- non-Hodgkin's lymphoma;

- Hodgkin's disease;

- hormone-resistant prostate cancer;

- multiple myeloma;

- - acute leukemia.

Contraindications:

- hypersensitivity to epirubicin or other components of the drug, as well as to other anthracyclines and anthracenedions;

- Pregnancy and the period of breastfeeding.

Intravenous administration is contraindicated when persistent myelosuppression, severe liver function abnormalities, severe heart failure and severe arrhythmias, recent myocardial infarction, previous epirubicin therapy and / or other anthracyclines and anthracenedions, and at the maximum total doses.

Introduction to the bladder is contraindicated when infections of the urinary tract, inflammation of the bladder, hematuria, invasive tumors with penetration into the wall of the bladder.

Carefully:

Patients with risk factors for cardiotoxicity; patients who received previously intensive chemotherapy; patients with tumor infiltration of the bone marrow, as well as patients with impaired liver and kidney function (may need to reduce starting doses or increase the intervals between doses); use in combination antitumor therapy, as well as in combination with radiation or other antitumor therapy.Safety and effectiveness in children are not well understood. Cardiotoxicity in patients of childhood can be increased.

Dosing and Administration:

Intravenously, intraarterially, intravesically.

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

Intravenous administration

As a 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 simultaneously or divided into several administrations, for 2-3 consecutive days.

If Vero-epirubicin is used in combination with other antitumor drugs, the recommended dose per cycle should be appropriately reduced. In some cases, high doses of Vero-epirubicin 90-120 mg / m can be used²once with an interval of 3-4 weeks.

Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (especially gastrointestinal and hematological).

Impaired renal function.

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

Impaired liver function:

If the serum bilirubin level is 1.2-3 mg / dl or the value of aspartate aminotransferase (ACT) in 2-4 times the upper limit of the norm, the dose of Vero-epirubicin administered should be reduced by 50% of the recommended dose.

If the serum bilirubin level exceeds 3 mg / dl or the value ACT more than 4 times the upper limit of the norm, the administered dose should be reduced by 75% of the recommended.

Other special patient groups.

It is recommended that lower doses be given or longer intervals between cycles in patients who previously received massive antitumor therapy, as well as in patients with bone marrow tumor infiltration. In elderly patients with initial therapy, standard doses and regimens can be used.

Introduction to the bladder

For prevention of recurrence after transurethral resection of superficial tumors a single instillation of 80-100 mg is recommendedVerobepropicin immediately after transurethral resection or eight weekly instillations of 50 mg of Vero-epirubicin (in 25-50 ml of 0.9% sodium chloride solution), starting 2-7 days after transurethral resection. If the local toxicity (chemical cystitis) develops, the dose should be reduced to 30 mg. It is possible to conduct 4 weekly instillations of 50 mg and then 11 monthly instillations at the same dose.

The instillation is carried out with a catheter, and the drug should remain in the bladder for 1 hour. To ensure a uniform effect of the drug on the bladder mucosa during the instillation, one should turn from side to side. To avoid excessive dilution of the drug with urine, patients should be warned that they should refrain from taking liquid for 12 hours before instillation. At the end of instillation, the patient should empty the bladder.

Intraarterial administration

For patients with hepatocellular carcinoma, the drug can be administered as an infusion into the main hepatic artery at a dose of 60-90 mg / m² with an interval of 3 weeks to 3 months or in a dose of 40-60 mg / m² with an interval of 4 weeks.

Rules for the preparation and administration of a 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 vial is shaken until the drug is completely dissolved. The prepared solution is stable for 24 hours at room temperature and for 48 hours at a temperature of 4 to 10 ° C. The solution is stored in a place protected from light.

To reduce the risk of thrombosis and extravasation, Vero-epirubicin is recommended to be injected slowly (from 3 to 20 minutes, depending on the dose of the drug and the volume of the infusion solution) through the tube of the system for intravenous infusion, during the infusion of 0.9% sodium chloride solution or 5% solution of dextrose.

Side effects:

On the part of the hematopoiesis system: leukopenia, neutropenia, anemia, thrombocytopenia.

From the cardiovascular system: manifestations of early (acute) cardiotoxicity of epirubicin are mainly sinus tachycardia and / or anomalies on the ECG (nonspecific changes in ST-T waves). There may also be tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, atrioventricular blockade, and blockade of Tysa's leg arms.These effects are not always a prognostic factor in the development of subsequently delayed cardiotoxicity, are rarely clinically significant, and usually do not require withdrawal of drug therapy. Late (deferred) cardiotoxicity is manifested by a decrease in the 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, gallop rhythm. There may also be subacute phenomena, such as pericarditis / myocarditis. The most severe form of anthracycline-induced cardiomyopathy is the life-threatening CHF, which is a toxicity that limits the cumulative dose of the drug. In addition, there may be thromboembolic complications, including pulmonary embolism (in some cases fatal), hot flashes to the face.

On the part of the digestive system: anorexia, nausea, vomiting, stomatitis, hyperpigmentation of the oral mucosa, esophagitis, pain or burning sensation in the abdomen, erosion of the stomach, bleeding from the gastrointestinal tract, diarrhea,colitis; increased levels of total bilirubin and transaminases in serum.

From the urinary system: staining the urine in red for 1-2 days after the administration of Vero-epirubicin. Possible the appearance of hyperuricemia due to rapid lysis of tumor cells.

On the part of the organs of vision: conjunctivitis, keratitis.

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

From the endocrine system: amenorrhea (at the end of therapy, ovulation recovers, but premature menopause may occur); oligospermia, azoospermia (in a number of cases the number of spermatozoa is restored to normal level, this can happen several years after the end of therapy).

Local reactions. Often there is erythematous striation along the vein into which the infusion was made, then local phlebitis or thrombophlebitis may occur. Phlebosclerosis may also develop, especially if Vero-epirubicin is injected repeatedly into a small vein.In the event of a drug falling into the surrounding tissues, local soreness, severe inflammation of the subcutaneous tissue and necrosis of the tissues may occur.

With intra-arterial administration in addition to systemic toxicity, ulceration of the stomach and duodenum (possibly due to reflux of the drug in the gastric artery) and narrowing of the bile ducts due to drug-induced sclerosing cholangitis, as well as widespread necrosis of perfused tissue can be observed.

Intravesical application epirubicin can lead to the appearance of symptoms of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall) and constriction of the bladder.

Other: malaise, asthenia, fever, chills, attachment of secondary infections, anaphylaxis, dehydration, development of acute lymphocytic leukemia or myeloid leukemia.

Overdose:

Acute overdose of epirubicin can lead to severe myelosuppression (mainly to leukopenia and thrombocytopenia), to toxic effects from the gastrointestinal tract (mainly mucositis), to cause acute complications from the heart. Antidote to epirubicin is not known.In case of overdose, symptomatic therapy is recommended.

Interaction:

Epirubucin is generally used in combination with other cytotoxic agents. In this regard, the manifestation of additive toxicity, especially with regard to the system of hematopoiesis and gastrointestinal tract.

Myelotoxic drugs increase the manifestation of hematotoxicity of the drug.

When epirubicin is used in combination with other potentially cardiotoxic chemotherapeutic agents, as well as with cardiovascular drugs (eg, slow calcium channel blockers), heart function must be monitored. Epirubicin is actively metabolized in the liver. Changes in liver function caused by concomitant therapy may affect metabolism, pharmacokinetics, therapeutic efficacy, and / or toxicity of epirubicin. Cimetidine causes an increase in the area under the "concentration-time" curve (AUC) epirubicin by 50%, so it should be discontinued before starting treatment with epirubicin. The introduction of paclitaxel to epirubicin can lead to an increase in plasma concentrations of unchanged epirubicin and its metabolites. When applying taxanes (paclitaxel.or docetaxel). after epirubicin no changes were observed in the pharmacokinetics of epirubicin. Epirubicin can not be mixed with other drugs. Do not allow contact with alkaline solutions, as this can lead to the hydrolysis of epirubicin. Because of chemical incompatibility epirubicin Do not mix with heparin (a precipitate forms when mixed).

Special instructions:

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

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

When applying high doses. Vero-epirubicin (≥90 mg / m² every 3 to 4 weeks), adverse events were generally similar to those observed 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 epirubicin in high doses, should be carefully monitored.

With anthracycline therapy, there is a risk of developing cardiotoxicity - early (ie acute) or late (delayed). Delayed cardiotoxicity usually develops at late stages of the course of therapy or within 2-3 months after its termination, however, more delayed side effects may develop (several months or even years after the end of therapy).

Before and during therapy with the drug, it is necessary to monitor the function of the heart to minimize the risk of its severe damage. To do this, the left ventricular ejection fraction should be regularly determined and immediately discontinued if the first signs of worsening of heart function appear. Adequate methods of quantitative analysis of heart function (measurement of ejection fraction) include radioisotope angiography (MUGA) and echocardiography. Before starting treatment, it is recommended to evaluate cardiac function with ECG, radioisotope or echocardiography, especially in patients with risk factors for increased cardiotoxicity (obvious or latent cardiovascular disease, prior or concomitant mediastinal / pericardial radiation therapy,previous therapy with other anthracyclines or anthracendones and concomitant therapy with drugs that reduce the contractility of the heart). The left ventricular ejection fraction should be measured in dynamics, especially with an increase in cumulative doses of anthracycline. It is advisable to constantly use the same method. The risk of developing congestive heart failure increases rapidly with an increase in the cumulative dose of epirubicin of more than 900 mg / m²; in such doses, the drug

wall / pen and carda, previous therapy with other anthracyclines or anthracendones, and concomitant therapy with drugs that reduce the contractility of the heart). The left ventricular ejection fraction should be measured in dynamics, especially with an increase in cumulative doses of anthracycline. It is advisable to constantly use the same method. The risk of developing congestive heart failure increases rapidly with an increase in the cumulative dose of epirubicin of more than 900 mg / m²; in such doses, the drug should be used very carefully.However, it should be borne in mind that cardiotoxicity may develop with lower cumulative doses of epirubicin, regardless of the presence of risk factors.

During the treatment with Vero-epirubicin, especially when using high doses, it is necessary to assess the hematological parameters before and during each cycle of therapy, including the determination of the white blood cell count, platelets, hemoglobin, blood elements, liver functional tests (in particular bilirubin level and ACT) and serum creatinine levels (patients with a creatinine level of more than 5 mg / dL should reduce the dose of Vero-epirubicin).

In patients receiving anthracyclines, including epirubicin, cases of secondary leukemia with or without preleukemic phase are described. Secondary leukemia occurs more frequently when these drugs are used in combination with other antitumour agents that cause DNA damage, radiation therapy, as well as in patients who have previously received intensive cytotoxic therapy or anthracyclines in high doses. Secondary leukemia can have a latent period of 1-3 years.

When the first signs of extraversion of Vero-epirubicin (burning or soreness at the injection site) appear, the infusion should be stopped immediately, and then the infusion is resumed to another vein before the full dose is administered. Local activities to eliminate the consequences of extravasation. It is advisable to use ice packs.

With the use of Vero-epirubicin due to the rapid lysis of tumor cells, hyperuricemia can occur, and therefore, it is recommended that patients determine the level of uric acid, potassium, calcium and creatinine during therapy. Such activities as hydration, alkalization and prevention with allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome.

When Vero-epirubicin is injected into the bladder, special attention should be paid to conditions that interfere with catheterization (for example, obstruction of the urethra caused by massive tumors of the bladder).

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

When working with Vero-epirubicin, it is necessary to observe the rules for handling cytotoxic substances.It is recommended to treat the contaminated surface with a dilute solution of sodium hypochlorite (containing 1% chlorine). If the product gets on the skin, immediately flush the skin with soap and water or a solution of sodium bicarbonate; In case of contact with eyes, pull eyelids and rinse eyes (eyes) with plenty of water for at least 15 minutes.

Form release / dosage:Lyophilizate for the preparation of a solution for intravascular and intravesical administration of 10 mg and 50 mg

Packaging:

In the bottles of neutral glass. 1 bottle with instructions for use in a pack of cardboard. For 25 or 35 bottles with instructions for use, based on one instruction for 10 bottles, in a box of cardboard (for hospitals).

Storage conditions:

List B. In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date shown on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N002208 / 01

Date of registration:31.03.2008 / 12.08.2016

Expiration Date:Unlimited

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp02.02.2017

Illustrated instructions

Instructions

Vero-Epirubicin (Vero-Epirubicin)