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

Epirubicin is an antitumor agent from the group of synthetic anthracycline antibiotics. Anthracyclines disrupt various biochemical processes and biological functions in eukaryotic cells, including the leading role of the following mechanisms:

- at the molecular level epirubicin is able to form a complex with DNA by inserting (intercalating) between pairs of nucleotide bases, which leads to a disruption in the synthesis of nucleic acids (DNA and RNA) and proteins;

- intercalation in DNA initiates the cleavage of DNA under the action of topoisomerase II, which leads to 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 takes part in oxidation / reduction reactions with the formation of highly active cytotoxic free radicals. However, in epirubicin, to a lesser degree than doxorubicin, systemic (general) and cardiotoxicity is expressed.

Pharmacokinetics:

Pharmacokinetic parameters of epirubicin are linear in the dose range from 60 to 150 mg / m2. The clearance of the drug from the blood plasma does not depend on the duration of the infusion or the regimen.The connection with blood plasma proteins (mainly with albumin) is 77%.

After intravenous administration it is quickly distributed in tissues, accumulates in erythrocytes (the concentration of the drug in whole blood is approximately twice as high as in plasma). Does not penetrate the blood-brain barrier.

Rapidly and actively metabolized in the liver, as well as in other organs and cells, including red blood cells. There are four main ways of metabolism:

1. Reduction of the C-13 keto group to form 13 (S) -dihydro derivative - epirubicinol (13-hydroxyepirubicin). Cytotoxic activity of epirubicinol in vitro is 1/10 of the activity of epirubicin. Since the concentration of this metabolite in the blood plasma is lower than that of unchanged epirubicin, they can hardly be sufficient for the development of a cytotoxic effect in vivo.

2. Conjugation of unchanged drug and epirubicinol with glucuronic acid. 4'-O-glucuronation is the main difference between epirubicin and doxorubicin and may be the reason for the faster excretion of epirubicin and, consequently, its lower toxicity.

3. Cleavage of the aminosugar component as a result of hydrolysis and the formation of aglucones of doxorubicin and doxorubicinol.

4. Cleavage of the aminosaccharide component as a result of the oxidation-reduction process and the formation of aglycones of 7-deoxydoxorubicin and 7-deoxydoxorubicinol.

Epirubicin and its major metabolites are excreted mainly through the intestine (with bile) and, to a lesser extent, kidneys. Removal of the drug from the body is of a three-phase nature with a slow end phase lasting from 30 to 40 hours. After 72 hours, approximately 43% of the drug is detected in bile and approximately 16% in the urine.

When one patient was examined, about 60% of the total radioactive dose was excreted through the intestine (34%) and kidneys (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 received was found in the form of epirubicin and its main metabolites in bile and urine, respectively, for 4 days. Pharmacokinetics in special groups:

Liver failure: Epirubicin clearance in patients with impaired liver function is reduced.

Renal insufficiency: in patients with a creatinine concentration in the blood plasma <5 mg / dL, no significant changes in the pharmacokinetics of epirubicin (and epirubicinol) were detected.When creatinine concentration in plasma> 5 mg / dl was observed in some cases, the plasma clearance of the drug decreased by 50%. The pharmacokinetics of epirubicin in patients on hemodialysis have not been studied

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

Contraindications:

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

- pregnancy and the period of breastfeeding;

- children under 18 years of age (efficacy and safety not established);

- Intravenous administration is contraindicated when: severe myelosuppression, severe hepatic insufficiency, severe heart failure and severe arrhythmias, recently transferred myocardial infarction,previous therapy with other anthracyclines or anthracenedions in the maximum total doses, unstable angina, cardiomyopathy, acute systemic infections;

- Introduction to the bladder is contraindicated when: invasive tumors with penetration into the wall of the bladder, infections of the urinary tract, inflammation of the bladder, hematuria, obstructive diseases of the urinary tract, impossibility to perform catarrhization.

Carefully:

Risk factors for cardiotoxicity, previous intensive chemotherapy, bone marrow infiltration, liver and kidney dysfunction (lowering starting doses or increasing intervals between doses may be required), use in combination antitumor therapy, and in combination with radiotherapy or other types of antitumor therapy.

Pregnancy and lactation:

The use of the drug Epirubicin-Ebove during pregnancy can cause serious malformations of the fetus, therefore the use of the drug Epirubicin-Ebwee is contraindicated during pregnancy.

Epirubicin is able to induce the process of damage to chromosomes of spermatozoa.Men receiving epirubicin therapy should use effective methods of contraception. In connection with the likelihood of irreversible toxic effects on the reproductive system, if possible and willing, cryopreservation of seminal fluid should be used.

Women of reproductive age should be informed about the possible negative effects of epirubicin on the fetus. Women of reproductive age are recommended to use reliable methods of contraception during therapy with the drug Epirubicin-Ebove. If pregnancy occurred during the treatment with Epirubicin-Ebeva, it is necessary to consult with specialists regarding the risk of adverse effects of epirubicin on the fetus.

Patients receiving epirubicin therapy and planning to have a baby are advised to get a geneticist consultation.

The drug Epirubicin-Ebwee can also lead to amenorrhea or premature menopause.

It is not known whether the epirubicin in breast milk. Since many drugs, including other anthracyclines, are able to penetrate into breast milk,in connection with the potential risk of serious adverse events in the newborn during the period of treatment with the drug Epirubicin-Ebove, breastfeeding should be discontinued.

Dosing and Administration:

Intravenous, intraarterial and intravesical.

The reconstituted solution of the preparation is recommended to be used immediately after preparation.

The drug Epirubicin-Ebwee can be used both in monotherapy and in combination with other antitumor drugs in various doses depending on the regimen of therapy. For individual dose selection, reference should be made to the literature.

Intravenous administration (IV)

In monotherapy, the recommended standard dose per cycle for adults is 60-90 mg / m2 every three to four weeks.

If Epirubicin-Ebweve is used in combination with other antitumor drugs, the recommended dose per cycle should be appropriately reduced, however, in some cases, using a combination therapy, a high initial dose of the drug (up to 120 mg / m2) is used. it should be administered on the first day of the cycle, every 3-4 weeks.

The total dose of the drug per cycle can be administered either simultaneously or divided into several administrations, for 2-3 consecutive days. The drug Epirubicin-Ebwee is recommended to be administered concomitantly with infusion of 0.9% sodium chloride solution or 5% dextrose solution into the total lumen of the venous catheter, making sure that the needle / catheter is properly inserted into the vein. This method allows you to reduce the risk of extravasation of the drug and allows you to ensure that the vein is washed with physiological solution after the drug is injected. Extravasation of epirubicin can lead to serious damage to nearby tissues, up to their necrosis. It is not recommended to administer Epirubicin-Ebewe by intravenous injection. The introduction of the drug into small vessels or repeated injections into the same vein can cause the development of phlebosclerosis.

Duration of infusion should be from 3 to 20 minutes, depending on the dose of the drug and the volume of the infusion solution.

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

In some cases, high doses of Epirubicin-Ebove can be used:

Lungs' cancer

- Small cell lung cancer (previously baked): 120 mg / m2 on the first day of the cycle, every 3 weeks.

- Non-small cell lung cancer (previously untreated, large cell carcinoma or adenocarcinoma): 135 mg / m2 on the first day of the cycle or 45 mg / m2 on days 1,2 and 3, every 3 weeks.

Breast Cancer (BC)

When conducting adjuvant therapy for breast cancer with lymph node involvement (N +) the recommended dose of epirubicin in combination therapy is 100 mg / m2 (on the first day of the cycle) to 120 mg / m (divided into two doses administered on the first and the 8th day of the cycle.) For more information on combination therapy for breast cancer see the corresponding diagrams.

Special categories of patients:

Impaired renal function

In patients with severe renal dysfunction (creatinine concentration in the blood plasma> 5 mg / dl), lower doses of Epirubicin-Ebweve should be used.

Impaired liver function

TAs the removal of epirubicin from the body is mainly carried out through the hepatobiliary system, in order to avoid an increase in the risk and severity of toxic phenomena, in patients with hepatic insufficiency should use reduced doses of the drug:

- at a concentration of total bilirubin in the blood plasma in the range of 1.4-3 mg / dL or concentration ACT, in 2-4 times higher than the upper limit of the norm (VGN), the administered dose of Epirubicin-Ebweve should be reduced by 50% of the recommended dose.

- in severe hepatic insufficiency (concentration of total bilirubin in blood plasma> 3 mg / dL or concentration ACT more than 4 UGN) the dose of Epirubicin-Ebweve should be reduced by 75% of the recommended dose.

Correction of the dose against the background of toxicity of the drug

With the development of hematological and non-hematological toxicity, against the background of therapy with the drug, namely: with a decrease in the number of platelets <50000 / mm \ of the absolute number of neutrophils (ACHN) <250 / mm³, the appearance of neutropenic fever, or the development of hematological toxicity of grade 3 or 4 severity, the dose of epirubicin should be reduced to 75% on the first day of the next cycle of cytotoxic therapy. The subsequent course of chemotherapy should be postponed until the platelet count is restored> 100,000 / mm, ACHN> 1500 mm / m and the manifestations of nonhematological toxicity to <1 degree decrease.

Disturbance of bone marrow function

It is recommended the appointment of lower doses of the drug (75-90 mg / m²) or increased intervals between cycles in patients who previously received massive antitumor therapy, as well as in patients with bone marrow tumor infiltration.

In patients receiving epirubicin in two doses (on the first and on the 8th day of therapy), in the case of a decrease in the number of platelets after the first injection to 75,000- 100,000 / mm³ and / or ACHN 1000-1499 / mm³, the dose for 8 days should be reduced up to 75%. If the number platelets by the 8 day of the cycle is <75,000 / mm³ and / or ACHN <1000 / mm \ or marked the phenomenon of non-hematologic toxicity 3 or 4 degrees of dosing on the 8th day of therapy should be skipped.

In elderly patients with initial therapy, dose adjustment and dosage regimen is not required.

Introduction to the bladder

Intravesical administration of epirubicin is contraindicated in tumors that grow into the wall of the bladder (muscle layer). In these cases, preference should be given to surgical and systemic methods of treatment. Epirubicin-Ebweve is injected into the bladder via a catheter, and the drug must remain inside the bladder for 1 hour. The patient should be warned that he should refrain from taking liquid for 12 hours before instillation.To ensure a uniform effect of the drug on the mucosa of the bladder, the patient (after instillation) should turn from side to side. At the end of instillation, the patient should empty the bladder.

When symptoms of local toxic effects (chemical cystitis) appear, the dose of epirubicin should be reduced to 30 mg.

Superficial tumors of the bladder

For therapy superficial tumors of the urinary bladder it is recommended that a single instillation of 80-100 mg be administered immediately after transurethral resection (TUR) or eight weekly instillations of 50 mg epirubicin (in 25-50 ml 0.9% sodium chloride solution) starting 2-7 days after TUR.

In the treatment cancer of the bladder in situ, depending on the individual tolerability, the dose of the drug can be increased to 80 mg.

For prevention of recurrence after transurethral resection of superficial tumors it is recommended that four weekly instillations of 50 mg followed by 11 monthly instillations in the same dose.

Intraarterial administration

Patients with hepatocellular carcinoma to ensure an intensive effect on the tumorThe simultaneous decrease in the total toxic effect of Epirubicin-Ebove can be administered intraarterially to the main hepatic artery at a dose of 60-90 mg / m2 at intervals of 3 weeks to 3 months or in doses of 40-60 mg / m2 at intervals of 4 weeks.

Side effects:

According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100 to <1/10), infrequently (>> 1/1000 to <1/100), rarely (from> 1/10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Infectious and parasitic diseases often: infection;

frequency is unknown: septic shock, sepsis, pneumonia.

On the part of the organs of hematopoiesis

Often: oppression of bone marrow hematopoiesis (leukopenia, neutropenia and granulocytopenia, anemia, febrile neutropenia). Cytopenia usually reaches its lowest value 10-14 days after the administration of the drug, the restoration of the blood picture is usually observed on day 21. infrequently: thrombocytopenia; frequency is unknown: bleeding, tissue hypoxia as a result of myelosuppression.

From the central and peripheral nervous system rarely: dizziness.

From the sense organs

frequency is unknown: conjunctivitis, keratitis.

From the side of the cardiovascular system often: "tides" of blood to the face;

infrequently: phlebitis, thrombophlebitis;

rarely: early (acute) cardiotoxicity of epirubicin is manifested mainly by sinus tachycardia and / or anomalies on the ECG (nonspecific changes in the waves ST-T). There may also be tachyarrhythmias, including ventricular extrasystole and ventricular tachycardia, as well as bradycardia, atrioventricular blockade, and blockade of the bundle of the bundle. The emergence of these phenomena is not always a predictor of the subsequent development of delayed cardiotoxicity, they are rarely clinically significant and usually do not require the abolition of epirubicin therapy. Late (deferred) Cardiotoxicity usually develops late in the course of therapy with epirubicin, or within 2-3 months after its termination, and later manifestations were noted (several months later or after the end of therapy). Late (delayed) cardiotoxicity is manifested by a decrease in the left ventricular ejection fraction (LVEF) and / or symptoms of congestive heart failure (ACE), such as dyspnea,pulmonary edema, orthostatic edema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, gallop rhythm. There may also be subacute phenomena, such as pericarditis / myocarditis. The most severe form of anthracycline-induced cardiomyopathy is a life-threatening CHF, which is a toxicity that limits the total (cumulative) dose of the drug.

frequency unknown: shock, thromboembolism, including pulmonary embolism (in some cases with fatal outcome).

From the digestive system

often: anorexia, nausea, vomiting, stomatitis, mucositis, esophagitis, diarrhea;

rarely: an increase in the concentration of total bilirubin and the activity of "hepatic" transaminases in blood plasma;

frequency unknown: hyperpigmentation, erosion or ulceration, oral mucosa, pain and bleeding from the oral cavity, oral bleeding, pain or burning sensation in the abdomen, erosion of the gastric mucosa, bleeding from the gastrointestinal tract, colitis.

From the genitourinary system

Often: staining the urine in red for 1-2 days after the administration of epirubicin;

rarely: amenorrhea (after the termination of therapy, as a rule, ovulation recovers, but premature menopause may occur), azoospermia (in some cases, the number of spermatozoa is restored to normal levels, which can happen several years after the end of therapy).

From the skin and subcutaneous fat Often: alopecia; rarely: hives;

frequency is unknown: rash, itching, reddening of the skin, erythema, hyperpigmentation of the skin and nails, photosensitivity and hypersensitivity of irradiated skin areas (anamnestic reaction to irradiation), other skin changes.

Local Reactions

With intravenous administration

often: erythematous striae along the vein in which the infusion was made, local phlebitis or thrombophlebitis, phlebosclerosis (more often with repeated injections into veins of small diameter). When the drug gets into the surrounding tissue - soreness, pronounced cellulite and necrosis of surrounding tissues.

With intra-arterial administration

often: in addition to systemic toxicity, gastric and duodenal ulcers can be observed (probably,due to reflux of the drug in the gastric artery); narrowing of the bile ducts due to drug-induced sclerosing cholangitis, as well as widespread necrosis of perfused tissue.

When inserted into the bladder

often: development of chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder area), necrosis of the walls and constriction of the bladder, hemorrhagic cystitis.

Other

often: joining of secondary infections;

rarely: hyperuricemia (due to massive lysis of tumor cells), general malaise, asthenia, fever, chills, anaphylaxis, dehydration, development of secondary acute lymphocytic leukemia or myeloid leukemia.

Overdose:

Symptoms: pronounced myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects from the gastrointestinal tract (mainly mucositis), as well as acute complications from the heart.

Treatment: symptomatic therapy is performed. Antidote to epirubicin is not known. Hemodialysis is not effective.

Interaction:

Epirubicin can increase the toxicity of other antitumour agents, especially myelotoxicity and toxic effects on the gastrointestinal tract.

The possibility of pronounced oppression of hematopoiesis should also be considered in patients receiving other drugs that are able to exert a myelosuppressive effect (for example, sulfonylamides, chloramphenicol, diphenylhydantoin (phenytoin), amidopyrine derivatives, antiretroviral agents).

When epirubicin is used in combination chemotherapy in combination with other potentially cardiotoxic drugs, especially with a long half-life, such as trastuzumab, as well as when used together with other cardioactive drugs (for example, blockers of "slow" calcium channels), it is necessary to monitor cardiac activity during the entire treatment period.

In patients receiving a combination of trastuzumab and anthracyclines (including epirubicin), the development of heart failure was described (II-IV functional class according to the classification of the New York Association of Cardiology (NYHA)), including deaths. The sharing of anthracyclines and trastuzumab is not recommended outside well-controlled clinical trials.

Cimetidine increases the area under the concentration-time curve (AUC) epirubicin by 50%, therefore it is necessary to cancel the time of epirubicin therapy.

Epirubicin can not be mixed with other drugs, with alkaline solutions (possible hydrolysis of epirubicin), with heparin (a precipitate is formed).

Pakligoxel administered before epirubicin can increase the concentration of epirubicin and its metabolites in blood plasma. Pakligoxel or docetaxel do not affect the pharmacokinetic parameters of epirubicin if epirubicin introduced before the application of taxanes. However, one study showed that if docetaxel is introduced immediately after the application of epirubicin, it is possible to increase the concentration of epirubicin and its metabolites in blood plasma. If combined therapy is necessary, it is recommended that epirubicin 24 hours before Taxanes. Dexverapamil may alter the pharmacokinetics of epirubicin, and possibly enhance oppression of bone marrow function.

When combined with ipterferonom-a2b, the half-life of epirubicin in the terminal phase and the overall clearance of epirubicin may decrease.

There are limited data on the simultaneous use of epirubicin and radial tarepia. Probably, the use of epirubicin can increase the sensitivity of tissues to the cytotoxic effect of radiation therapy. The use of epirubicin after radiotherapy can induce inflammatory reactions caused by radiation therapy.

Quinine can accelerate the distribution of epirubicin from blood to tissues, and also affect the distribution of epirubicin in erythrocytes.

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

Special instructions:

Treatment with the drug Epirubicin-Ebwee should be conducted under the supervision of physicians with experience in the use of antitumor drugs.

Before the start of treatment, the patient should resolve acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia and generalized infections).

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

A heart

To reduce the risk of severe cardiotoxicity, it is recommended that cardiac monitoring be performed regularly, including the LVEF assessment based on echocardiography (Echo-CG) or multichannel radioisotope angiography (ICPA), and ECG monitoring, especially in patients before and during therapy with Epirubicin-Ebweze. with risk factors for increased cardiotoxicity (cardiovascular disease, previous or concomitant radiotherapy in the mediastinum / pericardium, the use of other cardiotoxic drugs, see t "Interaction with other medicines"). LVEF should be measured in dynamics, especially with an increase in cumulative doses of anthracyclines, it is advisable to use the same method for assessing LVEF. An early clinical diagnosis of heart failure due to the use of the drug is very important for successful treatment. Acute (early) cardiotoxicity in most cases is transient (reversible), and it is usually not considered as an indication for the abolition of therapy with Epirubicin-Ebove.Symptoms are sinus tachycardia and / or nonspecific changes on ECG waves ST-T. There are also reports of the occurrence of tachyarrhythmias, ventricular tachycardia, bradycardia (reduction in heart rate), atrioventricular blockade, blockade of the bundle of the bundle. These effects usually do not lead to delayed cardiotoxicity.

Late (delayed) cardiotoxicity depends on the total dose, in connection with which the recommended cumulative dose of epirubicin (900 mg / m²) can only be exceeded in exceptional cases. Risk factors for cardiotoxicity include: cardiovascular disease (active or latent), previous or concomitant radiotherapy to the mediastinal / pericardial region, previous therapy with other anthracyclines or anthracene diodes, and simultaneous administration of other drugs that suppress the contractile function myocardium. Epirubicin-induced cardiotoxicity develops primarily on the background of treatment or within two months after its termination, however, delayed side effects may occur (several months or even years after the end of therapy).Symptoms of late cardiotoxicity include decreased left ventricular myocardial contractility and / or congestive heart failure symptoms such as dyspnea, pulmonary edema, orthostatic edema, cardio- and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. There may also be subacute phenomena, such as pericarditis / myocarditis. To prevent the development of cardiotoxicity, it is recommended that cardiac examinations be performed regularly (echocardiography, positron emission tomography, etc.).

Patients who previously received anthracyclines are also at high risk for trastuzumab, although the risk is lower than when they are used together. In connection with the long period of excretion (T1/2 trastuzumab is 4-5 weeks, trastuzumab may persist in the bloodstream for 20-27 weeks), patients who previously received this drug are also at increased risk of developing cardiotoxicity. If possible, epirubicin should be avoided in such patients for at least 27 weeks after discontinuing trastuzumab therapy.

If signs of late cardiotoxicity are found, treatment with Epirubicin-Ebewe is immediately stopped.

Hematological toxicity

Like other cytotoxic agents, epirubicin can cause myelosuppression. In the process of treatment with the drug Epirubicin-Ebove, especially when using high doses, before and during each cycle of therapy it is necessary to assess the hematological parameters (counting of leukocytes, platelets, hemoglobin, blood elements) and the leukocyte formula. Leukopenia and neutropenia are dose-dependent and reach the lowest value (nadir) on average 10-14 days after drug administration, the restoration of the blood picture is usually observed by day 21. Thrombocytopenia and anemia are also possible. Clinically, it can be manifested by fever, infection, sepsis / septicemia, septic shock, hemorrhages, tissue hypoxia and death.

In patients receiving anthracyclines, including epirubicin, it is possible to develop secondary leukemia. Secondary leukemias can develop 1-3 years after therapy, with or without the preleukemic phase.This complication of anthracycline therapy is most common in patients treated in combination with other DNA-damaging drugs, radiation therapy, pre-therapy with cytotoxic drugs, and with the use of high doses of anthracyclines.

Gastrointestinal tract and liver

Epirubicin can cause nausea and vomiting. Mucositis and stomatitis are often early side effects of therapy and in severe conditions in a few days can lead to ulceration of the mucous membranes. In most patients this undesirable phenomenon occurs by the third week from the beginning of the cycle.

Because the epirubicin is excreted primarily by the liver, it is necessary to evaluate the liver function before the start of therapy, further it is recommended to regularly monitor the activity of "liver" transaminases and the concentration of total bilirubin in the blood plasma.

Kidneys

Before the start of therapy, you should evaluate the plasma concentration of creatinine and subsequently regularly evaluate it during therapy. At a creatinine concentration> 5 mg / dl, dose adjustment is required.

Tumor lysis syndrome

With the use of the drug Epirubicin-Ebwee due to the rapid lysis of tumor cells, hyperuricemia can be observed, and therefore it is recommended to regularly determine the concentration of uric acid, potassium, calcium and creatinine in the blood plasma during therapy. Adequate hydration, maintenance of alkaline pH of urine and prophylactic appointment of allopurinol allow to minimize the risk of complications associated with tumor lysis syndrome.

Reactions at the site of administration and extravasation of the drug

Consequence of introduction of the drug into a small vessel or with repeated injections of the drug into the same vessel may be the development of phlebosclerosis (see also "Method of administration and dose").

Extravasation of the drug can lead to the development of severe local complications (up to the necrosis of adjacent tissues). At the appearance of the first signs of extravasation of epirubicin (burning or soreness at the injection site), the infusion should be stopped immediately. Local activities to eliminate the effects of extravasation (may be useful introduction of dexrazoxane). It is advisable to cool the injection site using ice packs (within 24 hours).The remaining dose of the drug should be injected into another vein. It is recommended that the injured limb be inspected regularly for 2-3 months, as tissue necrosis may develop within a few weeks. If necessary, consult a surgeon.

Vaccination

Because Epirubicin-Ebweve has immunosuppressive properties, it is not recommended to vaccinate with live vaccines, since it is possible to develop superinfection. Inactivated or killed vaccines are allowed, but the response to administration of such vaccines may be reduced.

Reproductive Toxicity

Men and women receiving Epirubicin-Ebweve should use reliable contraceptive methods. Patients who have received epirubicin and plan to have a baby are advised to get a genetic counseling (see also "Application during pregnancy and during breastfeeding").

Storage and precautions

When the drug is stored in the refrigerator (at a temperature of 2-8 ° C), the concentrate for preparing the solution for intravenous, intraarterial and intravesical administration can acquire a gel-like consistency.In this case, before use, the preparation should be kept at a temperature of 15-25 ° C for 2-4 h until the gel structure disappears.

When working with the drug Epirubicin-Ebove, it is necessary to observe the rules for handling cytotoxic substances:

- To work with the drug should be specially trained personnel; When working with the drug, personal protective equipment should be used (goggles, gown, mask, gloves); preparation of the solution should be carried out in a specially designated place;

- pregnant women should not be in contact with the drug;

- contaminated surface preparation is recommended to be treated 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 wash eyes (-a) with plenty of water for at least 15 minutes;

- After finishing work with the drug, remove gloves and wash your hands.

Special precautions for the destruction of unused medications

The remnants of the preparation, all instruments and materials used to prepare solutions for intravenous, intra-arterial and intraperitoneal administration of the Epirubicin-Ebweve preparation, must be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulations for the destruction of hazardous waste.

Effect on the ability to drive transp. cf. and fur:During the period of treatment with the drug Epirubicin-Ebove, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions

Form release / dosage: Concentrate for solution preparation for solution preparation for intravascular and intravesical administration, 2 mg / ml

Packaging:

For 10 mg / 5 mL, 50 mg / 25 mL, 100 mg / 50 mL in colorless glass bottles. For 1 bottle in a cardboard box with the attached instructions for use.

Storage conditions:

In the dark place at a temperature of +2 to +8 ° C.

During storage, the preparation may acquire a gel-like consistency.In this case, before use, the drug should be kept at a temperature of 15-25 ° C for 2-4 hours until the gel-like consistency disappears.

Keep out of the reach of children. Do not freeze.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N 015975/01

Date of registration:05.10.2009

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp19.11.2015

Illustrated instructions

Instructions

Epirubicin-Ebove (Epirubicin-Ebewe)