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

Active substanceEpirubicinEpirubicin

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Dosage form: & nbsplyophilizate for the preparation of solution for intravascular and intravesical administration

Composition:

Each vial contains

Active substance

Epirubicin hydrochloride 10 mg or 50 mg

Excipients

Lactose Monohydrate 50 mg or 250 mg

Sodium hydroxide q.s. to pH 4.5-6.5

Description:

Lyophilized mass of red-orange color.

Pharmacotherapeutic group:antitumor agent - antibiotic

ATX: & nbsp

L.01.D.B.03 Epirubicin

Pharmacodynamics:

Epirubicin is a cytotoxic anthracycline antibiotic. It is known that anthracyclines disrupt various biochemical processes and biological functions of eukaryotic cells, but precise mechanisms of cytotoxic and / or antiproliferative 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 of the infusion or the regimen.

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

4) cleavage of the aminosugar component as a result of the oxidation-reduction process and the formation of aglycones of 7-deoxydoxorubicin and 7-deoxydoxorubicinol. The 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 main metabolites are excreted mainly with bile and, to a lesser extent, with urine. In a study of 1 patient, about 60% of the total radioactive dose was found in stool (34%) and urine (27%). The data obtained correlate with the results of examination of 3 patients with extrahepatic bile duct obstruction and subcutaneous drainage, in which about 35% and 20% of the dose were detected in the form of epirubicin and its main metabolites in bile and urine, respectively, for 4 days.

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:

Transitional cell cancer of the bladder, breast cancer, stomach and esophagus cancer, head and neck cancer, primary hepatocellular carcinoma, acute leukemia,non-small cell and small cell lung cancer, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, ovarian cancer, pancreatic cancer, hormone-resistant prostate cancer, rectal cancer, soft tissue sarcoma and bones.

Contraindications:

Hypersensitivity to epirubicin or other components of the drug, as well as to other anthracyclines and anthracenedions.

Pregnancy and lactation

Intravenous administration is contraindicated when persistent myelosuppression, severe liver function abnormalities, severe heart failure and severe arrhythmias, recent myocardial infarction, prior therapy with epirubicin and / or other anthracyclines and anthracenedones in the limiting total doses.

Introduction to urinary bubble 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 (it may be necessary to reduce starting doses or increase intervals between doses, use as part of combined antitumor therapy, as well as in combination with radiation or other antitumor therapy.

Dosing and Administration:

Intravenous, intravesical or intra-arterial.

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 literature.

Intravenous administration

As a monotherapy, the recommended standard dose per cycle for adults 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 Epirubicin applied in combination with other antitumor drugs, the recommended dose per cycle should be appropriately reduced.

In some cases, high doses of 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 impairment (serum creatinine> 5 mg / dl), lower doses of Epirubicin Impaired liver function:

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

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

Other special population 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.

To reduce the risk of thrombosis and extravasation Epirubicin it is recommended to enter through the tube system for intravenous infusion, during the infusion of 0.9% solution of sodium chloride or 5% solution of dextrose. Duration of infusion should be from 3 to 20 minutes, depending on the dose of the drug and the volume of the infusion solution.

Introduction to the bladder

To prevent recurrence after transurethral resection of superficial bladder tumors, a single instillation of 80-100 mg is recommended immediately after transurethral resection or eight weekly instillations of 50 mg of 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 epirubicin is instillated 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, the patient should be rotated from side to side during instillation. 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.

Side effects:

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

From the side of the cardiovascular system: manifestations of early (acute) cardiotoxicity of epirubicin are mainly sinus tachycardia and / or anomalies on the ECG (nonspecific wave changes ST-T). There may also be tachyarrhythmias (including ventricular extrasystole and ventricular tachycardia), bradycardia, atrioventricular blockade, and blockade of the bundle's legs. 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 Epirubicin. Possible the appearance of hyperuricemia due to rapid lysis of tumor cells.

From the side of the organs of sight: 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. Also, phlebosclerosis may develop, especially if Epirubicin is reentered 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 can be observed,as well as widespread necrosis of perfused tissue. 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:

Epirubicin 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.When epirubicin is used in combination with other potentially cardiotoxic chemotherapeutic agents, as well as with cardiovascular drugs (eg, 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 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 should 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:

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 using high doses of 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. Prior to the start of treatment, it is recommended to evaluate cardiac function with ECG, radioisotope or echocardiography, especially in patients with risk factors for increased cardiotoxicity (an obvious or latent cardiovascular disease, previous or concomitant mediastinal / pericardial radiotherapy, previous therapy with other anthracyclines or anthracendones and concomitant therapy with drugs that reduce the contractile ability 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 with extreme caution. However, it should be borne in mind that cardiotoxicity may develop with lower cumulative doses of epirubicin, regardless of the presence of risk factors.

In the process of treatment with Epirubicin, especially when high doses are used, 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 function tests (in particular bilirubin level and ACT) and serum creatinine level (patients with a creatinine level of more than 5 mg / dL should reduce the dose of 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 extravasation of epirubicin (burning or soreness at the injection site) appear, the infusion should be stopped immediately and then resumed infusion into another vein until the full dose is given. Local activities to eliminate the consequences of extravasation. It is advisable to use ice packs.

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

Whenever epirubicin is administered to the bladder, special attention should be paid to conditions that interfere with catheterization (for example, obstruction of the urethra due to massive tumors of the bladder).

Men and women receiving Epirubicin should use reliable contraceptive methods.

When working with 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; if caught in the eye - pull back the eyelids and rinse the eye (eye) with plenty of water for at least 15 minutes.

Effect on the ability to drive transp. cf. and fur:

During the treatment period, care must be taken when driving and potentially dangerous mechanisms due to possible dizziness, drowsiness, stiffness and visual disturbances, which can lead to a slowing of the speed of psychomotor reactions and a decrease in the ability to concentrate.

Form release / dosage:

Lyophilizate for the preparation of solution for intravascular and intravesical administration of 10 mg and 50 mg.

Packaging:

The amount of the drug, corresponding to 10 or 50 mg of epirubicin hydrochloride, into a bottle of type I glass (F.USA), sealed with rubber stopper and cap type "flip-off".

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

List B.

In the dark place at a temperature of no higher than 25 ° C.

Shelf life:

2 years.

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 should be stored in a place protected from light. Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000478

Date of registration:01.03.2011 / 23.06.2015

Expiration Date:01.03.2016

The owner of the registration certificate:ARS, LLC ARS, LLC Russia

Manufacturer: & nbsp

VMG Pharmaceuticals, Private Ltd. India

Representation: & nbspARS, LLCARS, LLC

Information update date: & nbsp19.11.2015

Illustrated instructions

Instructions

Epirubicin (Epirubicin)