Farmorubicin instant - instructions for use, dose, 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 the DNA of tumor cells 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 epirubicin from the blood plasma does not depend on the duration of the infusion or the regimen of application.

Distribution

After intravenous administration epirubicin quickly and actively distributed in tissues. The degree of binding of epirubicin to blood plasma proteins, mainly albumin, is about 77% and does not depend on the concentration of epirubicin. Epirubicin accumulates in erythrocytes; its concentration in whole blood is approximately twice that in blood plasma.

Metabolism

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 13 (S) -digadroduct - 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; P N013796/01-080213

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 blood plasma is lower compared to unchanged epirubicin, 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.

Excretion

Epirubicin and its major metabolites are excreted mainly with bile and, to a lesser extent, through the kidneys. 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 detected in the form of epirubicin and its main metabolites in bile and urine, respectively, for 4 days.

Farmakokinetics in special groups Impaired liver function

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

Impaired renal function

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

Indications:

Transitional cell carcinoma of the bladder, breast cancer (including early stages of cancer and metastatic / cancer), gastric and esophageal cancer, head and neck cancer, primary hepatocellular carcinoma, 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 anthracyclamps and anthracenedions; pregnancy and the period of breastfeeding.

Intravenous administration is contraindicated when persistent myelosuppression, severe liver function abnormalities, myocardiopathy and severe arrhythmias, recent myocardial infarction, prior therapy with epirubicin, and / or other anthracyclamps and anthracenedones in the limiting 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 bone marrow tumor infiltration, as well as patients with impaired liver and kidney function (lower initial doses or longer intervals between doses may be required); use in combination antitumor therapy, as well as in combination with radiation or other antitumor therapy.

Pregnancy and lactation:

Epirubicin can induce a process of damage to the chromosomes of spermatozoa. Men who are receiving epirubicin therapy are recommended to use reliable methods of contraception.

Epirubicin can also lead to amenorrhea or premature menopause in premenopausal women.

Women of reproductive age are recommended to use reliable methods of contraception. A woman should be warned about the potential negative effect of epirubicin on the fetus.

Studies in animals have shown that epirubicin can lead to damage to the fetus in pregnant women.

Studies of the use of epirubicin in pregnant women have not been conducted. The use of epirubicin in pregnant women is contraindicated.

It is not known whether epirubicin in breast milk. Since many drugs, including other anthracyclines, can be secreted into breast milk and because of the potential risk of developing serious adverse events in the newborn, breastfeeding should be terminated before therapy with epirubicin.

Dosing and Administration:

Intravenous, intravesical or intra-arterial.

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

Safety and efficacy of epirubicin in children have not been established. Intravenous administration

As a monotherapy, the recommended standard dose per cycle for adults is 60-120 mg / m². With the use of the drug, Pharmorubicin, instantly soluble as a component of adjuvant therapy in patients with breast cancer with axillary lymph node involvement, an initial dose of 100-120 mg / m².

When using combination therapy, the initial high dose (up to 120 mg / m²) should be administered on the first day every 3-4 weeks.

The total dose of the drug per cycle (every 3-4 weeks) can also be administered either simultaneously or divided into several administrations, for 2-3 consecutive days.

If Pharmorubicin® is instantly used in combination with other antitumor drugs, the recommended dose per cycle should be appropriately reduced.

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

High initial doses of the drug Farmorubicin can be used in the treatment of breast cancer and lung cancer. When used in monotherapy, the recommended initial high dose of the drug (up to 135 mg / m² per cycle) should be administered on the first day or divided into several administrations on the first, second, third day every 3-4 weeks. To reduce the risk of thrombosis and extravasation of Pharmorubicin®, it is recommended to inject a system for intravenous infusion through the tube, during the infusion of 0.9% sodium chloride solution or 5 % solution of dextrose. Also, it is not recommended to administer Pharmorubicin® by intravenous injection due to the risk of extravasation.Duration of infusion should be from 3 to 20 minutes, depending on the dose of the drug and the volume of the infusion solution.

Cooking method vacmeova for intravenous administration

Dissolve the lyophilizate in a 0.9% solution of sodium chloride or in water for injection. Please note that the contents of the vial are under negative pressure.

To avoid aerosol formation, special care should be taken when inserting the needle into the bottle. Avoid inhalation of aerosol that occurs during solution preparation.

Impaired renal function: In patients with severe renal dysfunction (serum creatinine concentration> 5 mg / dL), lower doses of the drug should be used.

Impaired liver function:

- at a serum bilirubin concentration of 1.2-3 mg / dl or if the activity of aspartate aminotransferase (ACT) in 2-4 times exceeds the upper limit of the norm, the administered dose should be reduced by 50% of the recommended dose;

- at a serum bilirubin concentration of more than 3 mg / dL, or if activity 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: correction of the dose of epirubicin in the development of hematological and non-hematological toxicity is necessary with the smallest number of platelets <50000 / mm³, the absolute number of neutrophils (ACHN) <250 / mm³, the presence of neutropenic fever, or the development of non-hematological toxicity of 3 or 4 degrees of severity. It is necessary to reduce the dose of epirubicin on the first day of therapy of the next cycle to 75% of the initial dose of the current cycle. It should be postponed taking the drug on the first day of subsequent courses of therapy until the platelet count is restored to> 100,000 / mm³, ACHN> 1500 / mm³ and reducing the degree of nonhematological toxicity to <1 degree.

Disturbance of bone marrow function

Consideration should be given to the possibility of using a lower initial dose (75-90 mg / m) in patients who previously received massive therapy, in patients with an existing bone marrow depression or in the presence of tumor infiltration of the bone marrow. In patients receiving epirubicin in two doses (on the first and eighth day of therapy), on the eighth day, the dose of the drug should be reduced to 75% of the dose taken on the first day of the cycle if the platelet count is 75000-100000 / mm³ and АЧН from 1000 to 1499 / mm³. Dose intake should be skipped on the eighth day if the platelet count is <75,000 / mm by this time³, АЧН <1000 / mm³ or marked development of non-hematologic toxicity of 3 or 4 severity.

When used in elderly patients with initial therapy, dose adjustment and dosing regimen are not required.

Introduction to the bladder

Superficial tumors of the bladder

Single instillation of 80-100 mg immediately after transurethral resection or eight weekly instillations of 50 mg of epirubicin (in 25-50 ml of 0.9% sodium chloride solution). Treatment should be started 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.

Introduction to the bladder is not suitable for the treatment of invasive tumors with germination in the muscular layer of the bladder wall.

Intraarterial administration

For patients with hepatocellular carcinoma, the drug can be administered as a bolus 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: anemia, thrombocytopenia, febrile neutropenia, neutropenia, leukopenia.

From the side of the cardiovascular system: chronic heart failure (CHF), blood flushes to the skin of the face, ventricular tachycardia, atrioventricular blockade, bundle branch blockade, bradycardia, arterial thromboembolism, phlebitis, tromoofleoit, shock, ostiomythromic left ventricular frac- tion (LVEF), bleeding.

With anthracycline therapy, we have the risk of developing cardiotoxicity - early (ie acute) or late (delayed).

Manifestations early cardiotoxicity 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 delayed cardiotoxicity, are rarely clinically significant, and usually do not require withdrawal of the drug.

Late Cardiotoxicity usually develops in the late stages of a course of therapy or within 2-3 months after its termination, however, later side effects may develop (several months or even years after the end of therapy). Late cardiotoxicity is manifested by a decrease in LVEF and / or symptoms of CHF, such as dyspnea, pulmonary edema, orthostatic edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy and gallop rhythm, tachycardia.

The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is life-threatening CHF.

With the use of epirubicin, as well as other cytotoxic agents, thrombophlebitis and thromboembolism have sometimes been observed, including pulmonary embolism (in some cases fatal).

On the part of the digestive system: anorexia, nausea / vomiting, mucositis / stomatitis, diarrhea, erosion and ulceration of the gastrointestinal tract (GI tract), pain or burning sensation in the abdomen, bleeding from the gastrointestinal tract, hyperpigmentation of the oral mucosa, dehydration, change in the activity of transaminases.

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

From the side of the organ of vision: conjunctivitis, keratitis.

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

On the part of the reproductive system: amenorrhea.

Local reactions: extravasation during intravenous infusion of epirubicin may lead to the appearance ofpain, severe tissue damage (blistering, marked inflammation of the subcutaneous tissue) and necrosis. When the drug is injected into a small vein or when it is repeated in the same vein, the development of phlebosclerosis is possible.

Other: malaise, asthenia, fever, chills, attachment of secondary infections, anaphylaxis, development of acute lymphocytic leukemia or acute myelogenous leukemia, sepsis, pneumonia.

Introduction to urinary bubble 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.

Intraarterial administration epirubicin may cause, 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 (drug sclerosing cholangitis), as well as widespread necrosis of perfused tissue.

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:

When epirubicin is used in combination with other cytotoxic agents, additive toxicity is possible, especially with regard to the hematopoiesis and gastrointestinal system. When epirubicin is used in combination with other potentially cardiotoxic chemotherapeutic agents, as well as with cardiovascular drugs (eg blockers of "slow" calcium channels), cardiac function

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 canceled before the treatment with enirubicin.

The introduction of epirubicin directly before or after paclitaxel can lead to an increase in plasma concentrations of unchanged epirubicin and its metabolites.The use of epirubicin directly before or after docetaxel does not affect plasma concentrations of epirubicin, but may lead to an increase in the plasma concentrations of its metabolites.

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).

There are limited data on the simultaneous use of epirubicin and radiation therapy. 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.

Special instructions:

Pharmorubicin®, a quick-dissolving drug, should be used only under the supervision of physicians experienced in the use of cytotoxic drugs. Before the start of treatment, acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia and systemic infections) should be stopped in the patient.Before the start of treatment and against the background of epirubicin therapy in patients, it is necessary to monitor the liver function (concentration of total serum bilirubin and activity ALT and ACT) and kidneys (serum creatinine concentration and creatinine clearance.

When applying high doses epirubicin (> 90 mg / m² every 3-4 weeks), adverse events were generally similar to those in standard dose (<90 mg / m²every 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.

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 LVEF should be determined on a regular basis and immediately discontinued treatment with the appearance of the first signs of cardiac dysfunction. Adequate methods of quantitative analysis of heart function (LVEF measurement) include radioisotope angiography 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 (eg, obvious or latent cardiovascular disease, previous or concomitant Radiation therapy in the mediastinum / pericardium, preceding therapy with the use of other anthracyclines or anthracendones and concomitant therapy with drugs that reduce the contractility of the heart or cardiotoxic drugs with a long half-life (eg trastuzumab)). LVEF should be measured in dynamics, especially at higher cumulative doses of anthracycline. It is advisable to constantly use the same method.

The risk of CHF development increases rapidly with an increase in the cumulative dose of epirubicin of more than 900 mg / m; In such doses, the drug should be used with extreme caution. However, it should be borne in mind that cardiotoxicity may also develop with the use of lower cumulative doses of epirubicin, regardless of the presence of risk factors.

Do not use anthracyclines, including epirubicin, concomitantly with other cardiotoxic drugs, until an examination of the patient's cardiac function is performed. The use of anthracyclines in patients who have recently been treated with other cardiotoxic drugs, especially with drugs with a long half-life (such as trastuzumab), the risk of cardiotoxicity may also be increased. The half-life of trastuzumab is approximately 28-38 days, it can be present in the bloodstream for 27 weeks. In this regard, it is recommended to avoid anthracycline therapy whenever possible within 27 weeks after the abolition of trastuzumab. If anthracyclines are required before the end of this period, the function of the heart should be carefully monitored. The toxicity of epirubicin and other anthracyclines or anthracendones is probably additive.

Like other cytotoxic agents, epirubicin can cause myelosuppression. A general blood test, including the leukocyte formula, should be performed before and during each epirubicin therapy cycle. Dose-dependent reversible leukopenia and / or granulocytopenia (neutropenia) are the main manifestationhematological toxicity of epirubicin and the most frequent sign of acute toxicity, which limits the dose of the drug. Leukopenia and neutropenia are usually most pronounced with high-dosage regimens and in most cases reach maximum through 10-14 days after drug administration, with the number of white blood cells / neutrophils returning to normal by the 21st day.

Thrombocytopenia and anemia are also possible. Clinical complications of severe myelosuppression include fever, infection. septicemia / septicemia, septic shock, bleeding, tissue hypoxia or death.

In patients receiving anthracyclines, including epirubicin, cases of secondary leukemia with or without preleukemic phase are described.

Secondary leukemia occurs more often 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 had intensive cytotoxic therapy or with an increase in the dose of anthracyclines. Secondary leukemia can have a latent period of 1-3 years.

Mucositis / stomatitis usually develops soon after administration of the drug and in severe cases for several days can lead to ulceration of the mucosa. Most patients recover from these undesirable events by the third week therapy.

At the appearance of the first signs of extravasation of epirubicin (burning or soreness at the injection site), the infusion should be stopped immediately. Accurate compliance with the instructions for use of the drug can minimize the risk of phlebitis / thrombophlebitis at the injection site.

With intravesical application of the drug, special attention should be given to conditions that create barriers to catheterization (for example, urethral obstruction caused by massive tumors of the bladder).

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

In patients who are weakened against the background of cytotoxic therapy (including epirubicin) immunity, the use of live or weakened vaccines can lead to serious infections, in some cases fatal.

The use of live vaccines should be avoided in patients receiving epirubicin. Killed or inactivated vaccines are acceptable, however, the response to administration of these vaccines can be reduced.

Men and women receiving epirubicin therapy should use reliable contraceptive methods. When working with the drug must comply with 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; esl got into the eyes - to pull back the eyelids and to wash the eye (eyes) with a large amount of water for at least 15 minutes.

After IV injection, a "flushing" of the vein is necessary. If possible, avoid veins over the joints or in the extremities with a violation of venous or lymphatic drainage.Extravasation can occur without causing pain. Hyperemia of the facial skin, and also hyperemia of the skin along the vein can evidence of an overly rapid introduction. This may precede phlebitis or thrombophlebitis. Taking anti-emetic drugs can reduce nausea and vomiting. Should consider applying antiemetic drugs before epirubicin, especially in case of taking other drugs, which can cause nausea or vomiting.

As with the application of other cytotoxic drugs, with epirubicin was reported cases of thrombophlebitis and thromboembolic complications in pulmonary thromboembolism arteries (in some cases with lethal outcome).

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

Studies of the effect of the drug Farmorubicin® on the ability to drive and engage in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, not were conducted.

Form release / dosage:Lyophilizate for solution preparation for intravascular and intravesical administration

Packaging:

For 10 mg of epirubicin hydrochloride in a colorless glass bottle of type P1, sealed with a rubber stopper and sealed with an aluminum cap with an insert in the form of a polypropylene disk; solvent (water for injection): 5 ml in a colorless glass ampoule type I. 1 bottle with lyophilizate and 1 ampoule with a solvent, along with instructions for use, is placed in a cardboard box.

50 mg of epirubicin hydrochloride in a colorless glass vial of type I, capped with a rubber stopper and sealed with an aluminum cap with an insert in the form of a polypropylene disk. One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

At temperatures from +15 ° С to +25 ° С.

Keep out of the reach of children.

Shelf life:

Liofilizate - 4 years Solvent - 5 years

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N013796 / 01

Date of registration:19.11.2007

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

ACTAVIS ITALY, S.p.A. Italy

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp22.11.2015

Illustrated instructions

Instructions

Farmorubicin® instantly soluble (Farmorubicin® rapid dissolution)