Universal reference book for medicines
Product name: FARMORUBICIN ® FAST-SOLUBLE (FARMORUBICIN ®RAPID DISSOLUTION)

Active substance: epirubicin

Type: Antitumor antibiotic

Manufacturer: PFIZER ITALIA (Italy)
Composition, form of production and packaging
Lyophilizate for the preparation of a solution for intravascular and intravesical administration
in the form of a powder or a porous mass of red color;
The applied solvent is a clear, colorless liquid.
1 f.

epirubicin hydrochloride 10 mg,

which corresponds to the content of epirubicin 9.36 mg

Excipients: methylparahydroxybenzoate, anhydrous lactose.

Solvent: water d / u - 5 ml.

Vials of colorless glass (1) complete with a solvent (amp 1 pc.) - packs of cardboard.

Lyophilizate for the preparation of a solution for intravascular and intravesical administration in the form of a powder or a porous mass of red color.

1 f.

epirubicin hydrochloride 50 mg,

which corresponds to the content of epirubicin 46.8 mg

Excipients: methylparahydroxybenzoate, anhydrous lactose.

Vials of colorless glass (1) - packs cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2008.

PHARMACHOLOGIC EFFECT

Antitumor drug from the group of synthetic anthracycline antibiotics.
Rapidly penetrates into cells, localizes mainly in the nucleus. At the molecular level, epirubicin can form a complex with DNA by intercalation between the basic nucleotide pairs, which leads to a disruption in the synthesis of DNA, RNA, and proteins.Intercalation in DNA is the trigger mechanism of DNA cleavage under the action of topoisomerase II, leading to serious disturbances in the tertiary structure of DNA.Epirubicin (like doxorubicin) can be involved in oxidation / reduction reactions with the formation of highly active and highly toxic free radicals.
PHARMACOKINETICS

Distribution

After intravenous administration epirubicin is rapidly distributed in the tissues of the body;
does not penetrate the GEB in quantifiable amounts.
Metabolism

Epirubicin is intensely biotransformed, mainly in the liver.
The main established metabolites are epirubicinol, which has a certain degree of antitumor activity, as well as epirubicin and epirubicinol glucuronides. 4'-0-glucuronidation distinguishes epirubicin from doxorubicin and may cause its less toxicity.
Excretion

After intravenous administration (at a dose of 60-150 mg / m 2 ) in patients with normal liver and kidney function, epirubicin levels decrease in a three-exponential manner with a slow final phase lasting 30-40 hours. T 1/2 epirubicinol corresponds 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 (19%), epirubicinol and other metabolites. 9-12% of the dose is excreted in the urine (both in the form of metabolites, and in unchanged form). After 72 hours, approximately 43% of the administered dose is determined in bile and approximately 16% in the urine.
INDICATIONS

- transitional cell carcinoma of the bladder;

- mammary cancer;

- cancer of the stomach and esophagus;

- cancer of the head and neck;

- primary hepatocellular carcinoma;

acute leukemia;

- non-small cell and small cell lung cancer;

- non-Hodgkin's lymphoma;

- Hodgkin's disease;

- multiple myeloma;

ovarian cancer;

- pancreas cancer;

- prostate cancer;

- rectal cancer;

- soft tissue sarcoma;

osteosarcoma.

DOSING MODE

The drug is used as a monotherapy, and in combination with other cytostatics in different doses depending on the scheme of therapy.
For individual dose selection, reference should be made to the literature.
With IV introduction as a monotherapy, the recommended standard dose per cycle for adults is 60-90 mg / m 2 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.
If the drug is used in combination with other antitumor drugs, the recommended dose per cycle should be appropriately reduced.

In some cases, the drug can be used in higher doses of 90-120 mg / m 2 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 the hematologic and gastrointestinal tract).

Patients with impaired renal function and serum creatinine levels greater than 5 mg / dl should be given a drug in reduced doses.

In patients with impaired hepatic function, if the serum bilirubin concentration is 1.2-3 mg / dl or the AST value is 2-4 times higher than the upper limit of the norm, the administered dose should be reduced by 50% of the recommended dose.
If the serum bilirubin concentration is more than 3 mg / dl or the AST value exceeds the VGN by more than 4 times, the dose should be reduced by 75% of the recommended dose.
Patients who previously received massive antitumor therapy, as well as with bone marrow tumor infiltration, are recommended to prescribe the drug at lower doses or to increase the interval between cycles.

In elderly patients with initial therapy, the use of standard doses and regimens is possible.

To reduce the risk of thrombosis and extravasation, Pharmorubicin is rapidly soluble, it is recommended to inject a 0.9% solution of sodium chloride or a 5% solution of glucose through the tube of the IV infusion system.
The duration of the infusion should be from 3 to 20 minutes, depending on the dose of the drug and the volume of the infusion solution.
For the treatment of superficial bladder tumors , 8 weekly instillations of the drug in the bladder at a dose of 50 mg (dissolved in 25-50 ml of physiological saline) are recommended.
When symptoms of local toxic effects appear (chemical cystitis, manifested by dysuria, polyuria, nicturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall), the dose should be reduced to 30 mg.
In the treatment of bladder cancer in situ , depending on the individual tolerability, the dose of the drug can be increased to 80 mg.

To prevent relapse after transurethral resection of superficial tumors, it is recommended to perform 4 weekly instillations of 50 mg, followed by 11 monthly instillations at the same dose.

Farmorubicin instantly should be instillated through a catheter and left inside the bladder for 1 hour. During instillation, the patient must turn over to ensure a uniform effect of the solution on the mucosa of the bladder.
To avoid excessive dilution of the drug with urine, the patient should be warned about the need to refrain from drinking for 12 hours before instillation. At the end of the instillation procedure, the patient should empty the bladder.
Particular attention should be paid to problems associated with catheterization (including with obstruction of the urethra caused by massive intravesical tumors).

In hepatocellular carcinoma, in order to provide intensive local action and simultaneous reduction of the overall toxic effect, the rapidly dissolving pharmacorubicin can be injected intraarterially into the main hepatic artery at a dose of 60-90 mg / m 2 at intervals of 3 weeks to 3 months or at doses of 40-60 mg / m 2 with an interval of 4 weeks.

SIDE EFFECT

On the part of the hematopoiesis system: leukopenia, neutropenia (usually transient, reaching the lowest level 10-14 days after drug administration, restoration of the blood picture is usually observed by day 21), thrombocytopenia, anemia.

From the cardiovascular system: manifestations of early (acute) cardiotoxicity - sinus tachycardia and / or anomalies on the ECG (nonspecific changes in the ST segment and T wave), possibly - tachyarrhythmias, including ventricular extrasystole and ventricular tachycardia, as well as bradycardia, AV blockade , blockade of the bundle legs (these phenomena are not always a predictor of the subsequent development of delayed cardiotoxicity, are rarely clinically significant and usually do not require withdrawal of drug therapy).
Late (delayed) cardiotoxicity manifestations include a decrease in the left ventricular ejection fraction and / or development of symptoms of congestive heart failure such as dyspnea, pulmonary edema, orthostatic edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm. Possible pericarditis, myocarditis. The most severe form of anthracycline-induced cardiomyopathy is life-threatening congestive heart failure, which limits the cumulative dose of the drug. Possible thromboembolic complications, including pulmonary embolism (in some cases, with a fatal outcome).
On the part of the digestive system: anorexia, stomatitis, nausea, vomiting, hyperpigmentation of the oral mucosa, esophagitis, pain or burning sensation in the abdomen, erosion of the stomach, bleeding from the gastrointestinal tract, colitis, diarrhea;
increased activity of hepatic transaminases and serum levels of bilirubin.
From the urinary system: staining the urine in red for 1-2 days after drug administration;
possibly the appearance of hyperuricemia.
From the side of the organ of vision: conjunctivitis, keratitis.

On the part of the endocrine system: amenorrhea (usually after the treatment ovulation is restored, but the development of premature menopause);
oligospermia, azoospermia (in a number of cases the number of spermatozoa is restored to the normal level, this can happen several years after the end of treatment); hot flushes to the face.
Dermatological reactions: alopecia, rash, pruritus, sudden reddening of the skin, hyperpigmentation of the skin and nails, photosensitivity, hypersensitivity to previously irradiated skin.

Other: malaise, asthenia, fever, chills, anaphylactic reactions, acute lymphocytic leukemia, myeloid leukemia.

Local reactions: erythematous striation along the vein into which the infusion was performed;
then there may be local phlebitis or thrombophlebitis; phlebosclerosis, especially with repeated insertion into a small vein. In case of getting a drug in the surrounding tissue, local soreness, severe cellulite, tissue necrosis may occur.
Adverse events possible with intra-arterial administration: in addition to systemic toxicity, gastric and duodenal ulcer (probably due to reflux into the gastric artery);narrowing of the bile duct due to drug-induced sclerosing cholangitis.

CONTRAINDICATIONS

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

- Pregnancy;

- lactation (breastfeeding).

For intravenous administration

- expressed myelosuppression;

- pronounced violations of the liver function;

- severe heart failure;

- arrhythmia;

- recently transferred myocardial infarction;

- previous therapy with cumulative doses of anthracyclines or anthracendones.

For administration to the bladder

- Invasive tumors with penetration into the wall of the bladder;

- urinary tract infections;

- cystitis.

PREGNANCY AND LACTATION

The drug is contraindicated for use in pregnancy and lactation.

APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with impaired renal function and serum creatinine levels greater than 5 mg / dl should be given a drug in reduced doses.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Patients with violations of the function of the liver dose of the drug set individually.
If the serum bilirubin concentration is 1.2-3 mg / dl or the AST value is 2-4 times higher than the IGN, the administered dose should be reduced by 50%. If the serum bilirubin concentration is more than 3 mg / dl or the AST value exceeds the VGN by more than 4 times, the dose is reduced by 75% of the recommended dose.
Contraindication: severe liver dysfunction



APPLICATION IN ELDERLY PATIENTS

In elderly patients with initial therapy, the use of standard doses and regimens is possible.

SPECIAL INSTRUCTIONS

Pharmorubicin instantly should be administered only under the supervision of qualified physicians with experience in antitumor therapy.

To reduce the risk of toxic cardiac damage, it is recommended to monitor its function regularly, including the assessment of the left ventricular ejection fraction from EchoCG or multichannel radioisotope angiography (ICPA), and ECG monitoring before and during the treatment with Farmorubicin.
If there are signs of chronic cardiotoxicity, the drug is immediately stopped.
Acute cardiotoxicity in most cases is reversible and usually is not an indication for the withdrawal of the drug.
The late (delayed) toxicity (cardiomyopathy) depends on the total dose, and therefore the cumulative dose of the rapidly dissolving (900-1000 mg / m 2 ) of Pharmorubicin can be exceeded only in exceptional cases.Cardiovascular risk factors include cardiovascular diseases (including latent forms), a course of radiotherapy in the mediastinum region (ongoing or previous), anthracycline or anthracenedione therapy in an anamnesis, simultaneous administration of other drugs with negative inotropic action. Cardiotoxic manifestations usually develop on the background of therapy or within 2 months after its termination, however, in some cases, delayed side effects may occur (several months or even years after the end of therapy).
Before and during each cycle of therapy (especially when using the drug in high doses) it is necessary to evaluate hematological parameters (number of leukocytes, platelets and other blood elements, hemoglobin content) and liver functional tests.

When the first signs of extravasation appear (burning or pain at the injection site), the infusion should be stopped immediately, and then resumed the injection of the drug into another vein.
If necessary, perform local symptomatic therapy (including ice packs).
Farmorubicin instantly can cause hyperuricemia as a result of rapid lysis of tumor cells, and therefore patients need to determine the level of uric acid, potassium, calcium and creatinine during therapy.
To reduce the risk of complications associated with tumor lysis syndrome and to prevent hyperuricemia, adequate hydration of the patient, correction of acid-base balance (alkalinization) and prophylactic allopurinol should be ensured.
Men and women who receive Farmorubicin instantly must use reliable contraceptive methods.

When working with the drug must comply with the rules for handling cytotoxic substances.
The surface contaminated with the drug is recommended to be treated with a dilute solution of sodium hypochlorite (with a chlorine content of 1%). In case of accidental ingestion of a powder or solution onto the skin, immediate washing with soap or sodium bicarbonate water is required, in case of contact with the eyes, rinse the eyes with plenty of water for 15 minutes.
OVERDOSE

Symptoms: severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic manifestations of the gastrointestinal tract (mucositis), acute complications from the heart.

Treatment: conduct symptomatic therapy.
Antidote to epirubicin is unknown.
DRUG INTERACTION

With a joint application of Farmorubicin instantly can enhance the toxic effect of other antitumor drugs, especially myelotoxic effect and action on the gastrointestinal tract.

With simultaneous application of Pharmorubicin, which is rapidly dissolving with other potentially cardiotoxic or cardioactive drugs (calcium channel blockers), it is necessary to monitor the state of cardiac activity during the entire treatment period.

When combined, cimetidine increases the half-life of epirubicin (this combination is not recommended).

Pharmaceutical interaction

Pharmorubicin should not be mixed with other drugs.

Do not contact Pharmorubicin with solutions that have an alkaline reaction.
this can lead to the hydrolysis of epirubicin.
Pharmorubicin instantly should not be mixed with heparin because of their chemical incompatibility, resulting in a precipitate.

TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of the reach of children at room temperature (15 ° to 25 ° C).
Shelf life - 4 years.
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