Episondan - instructions for use, doses, side effects, contraindications

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:

After intravenous administration epirubicin quickly distributed in tissues, as indicated by a very short half-life. Wherein epirubicin does not penetrate the blood-brain barrier in detectable amounts.

Epirubicin undergoes intensive metabolism, mainly in the liver. The main identified metabolites are epirubicinol (13-OH epirubicin), which has a certain degree of antitumor activity, and epirubicin and epirubicinol glucuronides. 4'-O-glucuronation is distinguished epirubicin from doxorubicin and may cause its lower toxicity.

In patients with normal liver and kidney function, plasma epirubicin concentrations after intravenous administration (60-150 mg / m²) decrease three-exponentially with a slow final phase lasting from 30 to 40 hours. The final half-life of epirubicinol is similar to that of epirubicin. Epirubicin is excreted mainly through the liver: about 38% of the administered dose is detected within 24 hours in bile in the form of epirubicin (about 19%), epirubicinol and other metabolites. Only 9-12% of the dose is excreted by the kidneys, also in the form of unchanged drug and metabolites.After 72 approximately 43% of the drug is found in the bile and about 16% in the urine.

Pharmacokinetics the special patient 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 esophageal cancer, head and neck cancer, primary hepatocellular cancer, acute leukemia, non-small cell and small cell lung cancer, non-Hodgkin's lymphoma, lymphogranulomatosis, 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.

Children under 18 years.

Intravenous administration is contraindicated at 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 treated previously intensive chemotherapy, patients with tumor infiltration of the bone marrow, as well as patients with impaired liver and kidney function (may require reduction in starting doses or longer intervals between doses, the application of combination antineoplastic therapy, as well as in combination with radiation or other antitumor therapy).

Dosing and Administration:

Intravenously, into the bladder cavity or intra-arterially.

Epibendan 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 special literature.

Intravenous administration

As a monotherapy, the recommended standard dose per cycle for adults is 60-90 mg / m 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.

The total exchange dose should not exceed 900 mg / m² surface of the body.

Preparation of the solution

The lyophilizate can be diluted with 0.9% solution of sodium chloride for injection or water for injection to a concentration of 2 mg / ml (5 ml of solvent for the 10 mg bottle and 25 ml for the 50 mg bottle).

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 used² once 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 concentration> 5 mg / dL) lower doses of Epsilandan should be used.

Impaired liver function:

- If serum bilirubin concentration is 1.2-3 mg / dl or aspartate aminotransferase (ACT) in 2-4 times exceeds the upper limit of the norm, the injected dose of Epiphyldan should be reduced by 50% of the recommended dose.

- If the serum bilirubin concentration 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 dose.

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.

To reduce the risk of thrombosis and extravasation, it is recommended to inject Epiphanes through the tube of the intravenous infusion system, during the infusion of 0.9% sodium chloride solution or 5% dextrose solution.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 uric bubble

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 Epsilandan (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 of Egisandan 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.

Side effects:

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

From the cardiovascular system: manifestations of early (acute) cardiotoxicity of epirubicin are mainly 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), 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 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; an increase in the concentration of total bilirubin and an increase in the activity of "hepatic" transaminases in the blood 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.

On the part 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, 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:

Symptoms: 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.

Treatment: 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 using epirubicin in combination with other potentially cardiotoxic chemotherapeutic agents, as well as with cardiovascular drugs (for example, blockers of "slow" calcium channels), it is necessary to monitor the function of the heart.

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 increases AUC epirubicin by 50%, so it should be discontinued before starting treatment with epirubicin.

Myelotoxic drugs increase the manifestation of hematotoxicity of the drug. 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:

Epigenandan should be used only under the supervision of a physician 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 3-4 weeks), adverse events were generally similar to those in 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 in the late stages of a course of therapy or within 2-3 months after its termination, however,It is possible to develop more delayed side effects (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 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.

During treatment with Epsiland, especially when high doses are used, it is necessary to evaluate hematological parameters before and during each cycle of therapy, including determining the content of leukocytes, platelets, hemoglobin, blood elements, hepatic functional tests (in particular bilirubin concentration 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.

After intravenous drip, a "washing" of the vein is necessary.

With the use of epirubicin due to the rapid lysis of tumor cells, hyperuricemia can be observed, and therefore, it is recommended that patients determine the concentration 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.

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 who receive therapy with Epiphanes should use reliable contraceptive methods.

When working with Ehksindandom 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:

The ability of epirubicin to influence the management of vehicles and mechanisms has not been studied. Care should be taken when driving vehicles and engaging in other potentially hazardous activities in the event of the development of adverse reactions that affect the concentration of attention and the speed of psychomotor reactions.

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

Packaging:

For 10 mg and 50 mg of active substance in glass bottles, hermetically sealed with bromobutyl rubber stoppers with a silicate filler and rolled with an aluminum cap with a polypropylene disc. 1 bottle with instructions for use in a cardboard pack.

Storage conditions:

At a temperature of no higher than 25 ° C. Keep out of the reach of children!

Shelf life:

3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-002669

Date of registration:29.12.2011

The owner of the registration certificate:AKTAVIS GROUP, AO AKTAVIS GROUP, AO Iceland

Manufacturer: & nbsp

S.C. SINDAN-PHARMA S.R.L. Romania

Representation: & nbspAktavis, Open Company Aktavis, Open Company

Information update date: & nbsp21.11.2015

Illustrated instructions

Instructions

Episyndan (Episindan)