Доксорубицин-Ферейн®

General characteristics. Structure:

Active ingredient: 10 mg of doxorubicine of a hydrochloride in 1 bottle.

Excipients: mannitol.

Pharmacological properties:

Pharmacodynamics. The antineoplastic antibiotic of an anthracycline row allocated from culture of Streptomyces peucetius var. caesius.

Has antimitotic and anti-proliferative effect. The mechanism of action consists in interaction with DNA, education of free radicals and direct impact on membranes of cells with suppression of synthesis of nucleic acids. Cells are sensitive to drug in S-and G2 phases.

Pharmacokinetics. Absorption - high, distribution - rather uniform. Through a blood-brain barrier does not get. Communication with proteins of plasma makes about 75%. It is metabolized in a liver with formation of an active metabolite of a doksorubitsinol. Enzymatic recovery of doxorubicine under the influence of oxidases, reductases and dehydrogenases leads to education of free radicals that can promote manifestation of cardiotoxic action.

Later in/in introductions quickly disappears from blood, concentrating in a liver, kidneys, a myocardium, a spleen, lungs. An elimination half-life - 20-48 h for doxorubicine and a doksorubitsinol. Removal: with bile - 40% in not changed look within 7 days, with urine - 5-12% of doxorubicine and its metabolites within 5 days.

Indications to use:

Breast cancer, lung cancer (small-celled), mesothelioma, gullet cancer, a carcinoma of the stomach, primary hepatocellular cancer, a pancreatic cancer, an insulinoma, carcinoid, cancer of the head and neck, cancer of a thyroid gland, a malignant thymoma, ovarian cancer, germinogenny tumors of a small egg, trophoblastic tumors, a prostate cancer, bladder cancer (treatment and prevention of a recurrence after an operative measure), endometrial cancer, cancer of a neck of uterus, uterus sarcoma, Ewing's sarcoma, a rhabdomyosarcoma, a neuroblastoma, Vilms's tumor, an osteosarcoma, sarcoma of soft tissues, Kaposha's sarcoma, an acute lymphoblastoid leukosis, an acute miyeloblastny leukosis, a chronic lymphoid leukosis, Hodzhkin's disease and nekhodzhkinsky lymphoma, a multiple myeloma.

Route of administration and doses:

Doxorubicine can be applied both as monotherapy, and in a combination with other cytostatics in various doses depending on the scheme of therapy. At individual selection of a dose it is necessary to be guided by data of special literature.

Intravenous administration:

• as monotherapy the recommended dose on a cycle makes 60-75 mg/sq.m each three weeks. Usually the drug is administered once during a cycle; however, the cyclic dose can be divided into several introductions (for example, to enter during the first three days in a row, or into the first and in the eighth day of a cycle). The cycles are repeated each 3-4 weeks.

• for reduction of toxic effect of Doxorubicine, especially cardiotoxicities the weekly mode of administration of drug on 10-20 mg/sq.m is applied;

• in a combination with other antineoplastic drugs Doxorubicine it is appointed in a cyclic dose of 30-60 mg/sq.m each 3-4 weeks.

Abnormal liver function. At patients with a hyperbilirubinemia the dose of doxorubicine has to be reduced according to concentration of the general bilirubin:

- for 50% at concentration of bilirubin in blood serum of 1,2-3,0 mg/dl;

- for 75% at concentration of bilirubin in blood serum it is higher than 3,0 mg/dl.

Other special groups of patients. Purpose of lower doses or increase in intervals between cycles at patients who received massive antineoplastic therapy earlier, at children, at patients of advanced age is recommended, at patients with obesity (if body weight makes more than 130% of ideal, decrease in system clearance of doxorubicine), and also at patients with tumoral infiltration of marrow is noted. Intravenous administration of doxorubicine should be carried out with care. For reduction of risk of development of thromboses and an ekstravazation it is recommended to enter Doxorubicine through a system tube for intravenous administration, during infusion of 0,9% of solution of sodium chloride or 5% of solution of a dextrose, within 3-5 minutes.

The total dose of doxorubicine should not exceed 550 mg/sq.m. The patients receiving earlier radiation therapy on area of lungs and a mediastinum or treated by other cardiotoxic drugs, a total dose of doxorubicine should have no more than 400 mg/sq.m.

Introduction to a bladder. The recommended dose for intravesical introduction - 30-50 mg on installation, bucketed between introductions from 1 week to 1 month, depending on the therapy purposes - treatment or prevention. The recommended concentration of solution - 1 mg / 1 water ml for injections or 0,9% of solution of sodium of chloride. After completion of instillation, for ensuring uniform influence of drug on mucous a bladder, patients have to turn over with a side sideways each fifteen minutes. As a rule, drug has to be in a bladder within 1-2 hours. At the end of instillation the patient has to empty a bladder.

Not to allow excessive dilution of drug urine, patients have to be warned that they should abstain from reception of liquid within 12 hours before instillation. System absorption of doxorubicine at instillation in a bladder is very low.

At manifestations of local toxic action (chemical cystitis which can be shown by a dysuria a polyuria, a nocturia, an urodynia, a hamaturia, discomfort in a bladder, a bladder wall necrosis) the dose intended for instillation it is necessary to dissolve 0,9% of solution of sodium of chloride in 50-100 ml. Special attention should be paid to the problems connected with catheterization (for example, at the obstruction of an urethra caused by massive intravesical tumors).

Intra arterial introduction. Doxorubicine can be vnutriarterialno entered by the patient with hepatocellular cancer for ensuring intensive local influence at simultaneous reduction of the systemic toxic effect into the main hepatic artery in a dose of 30-150 mg/sq.m with an interval from 3 weeks to 3 months. Higher doses should be applied only when extracorporal removal of drug is at the same time carried out.

As this method is potentially dangerous, and at its use there can be a widespread necrosis of fabric, only the doctors who are perfectly knowing this technique can carry out intra arterial introduction.

Features of use:

Treatment by doxorubicine has to be carried out under observation of the doctors having experience of use of antineoplastic drugs.

For decrease in risk of toxic damage of heart it is recommended before during therapy by doxorubicine to carry out regular control of its function, including assessment of fraction of emission of a left ventricle according to an echocardiography or a multichannel scintiangiography, and also ECG control. The early clinical diagnosis of the heart failure caused by drug use is very important for its successful treatment. At detection of signs of chronic cardiotoxicity treatment by doxorubicine is immediately stopped.

• Acute cardiotoxicity in most cases has tranzitorny (reversible) character, and usually it is not considered as the indication to therapy cancellation by doxorubicine. The late (delayed) cardiotoxicity (cardiomyopathy) depends on a total dose. The probability of development of dysfunction of a myocardium makes about 1-2% at the total dose equal of 300 mg/sq.m; the probability of it slowly increases at the general total dose in 450-550 mg/sq.m. At exceeding of this dose the risk of development of congestive heart failure sharply increases in this connection treatment by doxorubicine is recommended to be stopped on reaching the general total dose in 550 mg/sq.m. If the patient has any additional risk of emergence of cardiotoxicity (for example, instructions in the anamnesis on a heart disease, the previous therapy by anthracyclines or antratsenediona, the previous radiation therapy of area of a mediastinum, simultaneous use of other potentially cardiotoxic drugs, such as cyclophosphamide and 5-ftoruratsit), then toxic action can be shown also at lower cumulative doses, and control of function of heart has to be especially careful. The cardiotoxicity caused by doxorubicine develops preferential during a course of therapy or within two months after its termination, however, there can be delayed side effects (in several months or even years after the end of therapy).

• In the course of treatment by doxorubicine it is necessary to carry out assessment of hematologic indicators to and during each cycle of therapy, including determination of quantity of leukocytes, thrombocytes, hemoglobin, uniform elements of blood and hepatic functional tests.

• At emergence of the first signs of an ekstravazation of doxorubicine (burning or morbidity in the place of an injection) infusion should be stopped immediately, and then to resume infusion in other vein before introduction of a full dose. To locally hold events for elimination of effects of an ekstravazation. It is reasonable to use packages of ice.

• Whenever possible it is necessary to avoid introduction to veins over joints or in veins of extremities with the broken venous or lymphatic drainage.

• At use of doxorubicine owing to a bystry lysis of tumor cells the hyperuricemia in this connection, patients during therapy are recommended to define concentration of uric acid, potassium, calcium and creatinine can be observed. Such actions as the increased hydration, alkalization of urine and preventive purpose of Allopyrinolum for prevention of a hyperuricemia allow to minimize risk of the complications connected with a syndrome of a lysis of a tumor. At treatment of a hyperuricemia and gout correction of doses of antigouty means as a result of increase in concentration of uric acid against the background of treatment by drug can be required.

• Patients with the developed neutropenia/leukopenia should be observed carefully for identification of signs of developing of an infection.

• Refusal of immunization if it is not approved by the doctor in the range from 3 months till 1 year after administration of drug; other members of the family of the patient living with him should refuse immunization by a peroral vaccine against poliomyelitis; to avoid contacts with the people receiving a vaccine against poliomyelitis or to wear the protective mask closing a nose and a mouth.

• Men and women of childbearing age during treatment by doxorubicine and at least within 3 months later should apply reliable methods of contraception.

• During the work with doxorubicine it is necessary to follow rules of the treatment of cytotoxic substances. The surface contaminated by drug is recommended to be processed the weak solution of sodium hypochlorite (containing 1% of chlorine). At hit of drug on skin - immediately to make plentiful washing of skin water with soap or solution of Natrii hydrocarbonas; at hit in eyes - to delay eyelids and to make washing of an eye (eyes) a large amount of water within not less than 15 minutes.

Side effects:

From bodies of a hemopoiesis: dozozavisimy, reversible leukopenia and neutropenia. Perhaps also development of thrombocytopenia and anemia. The leukopenia usually reaches the lowest value in 10-14 days after administration of drug, recovery of a picture of blood is usually observed for 21 days.

From cardiovascular a sistemy:proyavleniye of early (acute) cardiotoxicity of doxorubicine is first of all sinus tachycardia and/or anomalies on an ECG (nonspecific changes of waves of ST-T). Also tachyarrhythmias (including and ventricular tachycardia), ventricular premature ventricular contraction, and also bradycardia, an atrioventricular block and blockade of legs of a ventriculonector can be noted. Emergence of these phenomena not always is a predictive factor of development afterwards of the delayed cardiotoxicity, they seldom happen clinically significant, and do not demand therapy cancellation by doxorubicine. The late (delayed) damage of a myocardium is shown by decrease in fraction of emission of a left ventricle without clinical symptoms and/or symptoms of the congestive heart failure (CHF) (an asthma, a fluid lungs, peripheral hypostases, a cardiomegaly and a hepatomegalia, an oliguria, ascites, exudative pleurisy, a cantering rhythm). Also the phenomena of a pericardis and myocarditis can be noted. The most severe form caused by cardiomyopathy anthracyclines is the life-threatening ZSN limiting a cumulative dose of drug. Phlebitis, thrombophlebitis, tromboembolic episodes, including an embolism of a pulmonary artery (in some cases with a lethal outcome).

From digestive a sistemy:anoreksiya, nausea, vomiting, stomatitis or an esophagitis (in hard cases the ulceration of mucous membranes of digestive tract can develop), a hyperpegmentation of a mucous membrane of an oral cavity, pain in a stomach, bleedings from digestive tract, diarrhea, colitis. Increase in concentration of the general bilirubin and activity of "hepatic" transaminases in blood serum.

From an urinary system. Coloring of urine in red color within 1-2 days after administration of doxorubicine.

From bodies chuvstv:konjyunktivit, a keratitis, dacryagogue.

From a reproductive sistemy:amenoreya (upon termination of therapy there is a recovery of an ovulation, however there can come the premature menopause); an oligospermatism, an azoospermism (in some cases the quantity of spermatozoa is recovered to normal level; it can occur in several years after the end of therapy).

From skin and skin придатков:в the majority of cases the reversible full alopecia develops. The regrowth of hair usually begins in 2-3 months after the termination of administration of drug. Also there can be a hyperpegmentation of skin and nails, photosensitivity, urticaria, rash, an itch. At some patients to whom radiation therapy after administration of doxorubicine was carried out earlier (usually in 4-7 days) hypersensitivity of the angry skin, emergence of an erythema with vesiculation were noted, hypostasis, severe pain, wet epidermit in the places corresponding to fields of radiation.

Allergic reaktsii:kozhny rash, dermatitis, small tortoiseshell, dermahemia of palms and soles, bronchospasm, anaphylaxis (seldom).

Local reactions. Quite often erythematic striation on the course of a vein in which infusion was made comes to light, then there can be local phlebitis or thrombophlebitis. Also the phlebosclerosis, especially, can develop if doxorubicine is entered repeatedly into a small vein. In case of hit of drug in surrounding fabrics there can be a local morbidity, a heavy inflammation of hypodermic cellulose and a necrosis of fabrics.

At an intra arterial vvedeniiv addition to system toxicity can be observed stomach ulcer and a duodenum (possibly, at the expense of a reflux of drugs in a gastric artery); narrowing of bilious channels owing to the sclerosing cholangitis caused by drug.

At intravesical introduction: cystitis, coloring of urine in red color.

Others: an indisposition, an adynamy, fever, a fever, inflows of heat to the person, the hyperuricemia or a nephropathy connected with the increased formation of uric acid, development of an acute lymphocytic or miyelotsitarny leukosis.

Interaction with other medicines:

Doxorubicine can increase toxicity of other antineoplastic means, especially a miyelotoksichnost and toxic impact on digestive tract.

At simultaneous use of doxorubicine and other cytotoxic drugs which have potential cardiotoxicity (for example, 5-ftoruratsit and/or cyclophosphamide) carrying out careful control of function of heart during all course of therapy is required.

Against the background of doxorubicine strengthening of the phenomena of the hemorrhagic cystitis caused by cyclophosphamide and strengthening of a hepatotoxic 6 Mercaptopurinums is possible.

Streptozototsin increases a doxorubicine elimination half-life.

Doxorubicine strengthens the toxic action caused by radiation on a myocardium, mucous membranes, skin and a liver.

Uricosuric antigouty drugs increase risk of development of a nephropathy.

Gepatotoksichny drugs, worsening function of a liver, can increase toxicity of doxorubicine.

Doxorubicine cannot be mixed with other drugs. It is not necessary to allow contact with alkaline solutions as it can lead to doxorubicine hydrolysis.

Pharmaceutical it is incompatible with heparin, dexamethasone, flyuorouratsily, a hydrocortisone, sodium succinate, Aminophyllinum, cefalotin, other antineoplastic drugs.

Because at treatment by doxorubicine suppression of natural protective mechanisms is possible, vaccination is recommended to be carried out after the end of treatment after a while: the interval varies from 3 months to 1 year.

Contraindications:

Hypersensitivity to doxorubicine or other components of drug, and also to other anthracyclines and antratsendiona. Pregnancy and period of feeding by a breast

Intravenous administration is contraindicated at: the expressed miyelosupressiya expressed to a liver failure, heavy heart failure and arrhythmias, recently postponed myocardial infarction, the previous therapy by other anthracyclines or antratsendiona in limit total doses, chicken pox, the surrounding herpes. Introduction to a bladder is contraindicated at: invasive tumors with a penetration in a wall of a bladder, an infection of uric ways, a bladder inflammation.

With care: a peptic ulcer of a stomach and duodenum, a hyperbilirubinemia, earlier carried out radiation therapy or chemotherapy, an uratny nephrolithiasis (including in the anamnesis), a liver failure, infiltration of marrow tumor cells.

Overdose:

The acute overdose of doxorubicine can lead to a heavy miyelosupressiya (preferential to a leukopenia and thrombocytopenia), to toxic effects from digestive tract, to cause acute damages of heart.

The antidote to doxorubicine is not known. In case of overdose symptomatic therapy is recommended.

Storage conditions:

List A. In the dry, protected from light place unavailable to children, at a temperature not above + 5 °C. A period of validity - 2 years. Not to apply after the period of validity specified on packaging. Issue conditions from drugstores. According to the recipe.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate in bottles on 10 mg. On 1 bottle in a cardboard pack with the enclosed application instruction. On 5 bottles in a blister strip packaging, on 1 or 2 blister strip packagings together with the application instruction in a cardboard pack. On 10 blister strip packagings together with 5 application instructions in a cardboard box (for hospitals).