Composition, form of production and packaging
Concentrate for the preparation of solution for intravascular and intravesical administration of red color, transparent, free from foreign particles.
doxorubicin hydrochloride 2 mg
Excipients: sodium chloride - 9 mg, hydrochloric acid (10% solution) - 0.26 mg, water d / and - 993.74 mg.
5 ml - bottles of dark glass (1) - packs of cardboard.
10 ml - bottles of dark glass (1) - packs of cardboard.
25 ml - bottles of dark glass (1) - packs of cardboard.
50 ml - bottles of dark glass (1) - packs of cardboard.
100 ml - bottles of dark glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
Antitumor antibiotic anthracycline, isolated from the culture of Streptomyces peucetius var. caesius.
Has antimitotic and antiproliferative effect. Three main mechanisms of the action of doxorubicin are described: interaction with DNA, inhibition of topoisomerase I, DNA and RNA polymerases, formation of free radicals and direct action on cell membranes, which leads to suppression of DNA replication and nucleic acid synthesis, and direct cytotoxic action. Cells are sensitive to the drug in the S and G2 phases of mitosis.
Absorption is high, distribution is relatively uniform. Through the BBB does not penetrate. The connection with plasma proteins is about 75%.
Metabolised in the liver with the formation of an active metabolite of doxorubicinol. Enzymatic reduction of doxorubicin under the influence of oxidases, reductases and dehydrogenases leads to the formation of free radicals, which can contribute to the manifestation of cardiotoxic action. After iv introduction quickly disappears from the blood, concentrating in the liver, kidneys, myocardium, spleen, lungs.
T 1/2 - 20-48 h for doxorubicin and doxorubicinol.
Excretion: with bile 40% unchanged for 7 days, with urine 5-12% doxorubicin and its metabolites for 5 days.
- mammary cancer;
- Lung cancer (small cell);
- esophageal carcinoma;
- stomach cancer;
- primary hepatocellular carcinoma;
- pancreas cancer;
- malignant tumors of the head and neck;
- Thyroid cancer;
- malignant thymoma;
germ cell tumors of the testis;
- trophoblastic tumors;
- prostate cancer;
- Bladder cancer (treatment and prevention of relapse after surgery);
- endometrial cancer;
- cervical cancer;
- sarcoma of the uterus;
- soft tissue sarcoma;
- a neuroblastoma;
- Wilms tumor;
- Kaposi's sarcoma;
acute lymphoblastic leukemia;
acute myeloblastic leukemia;
- chronic lymphocytic leukemia;
- disease Hodgkin's and non-Hodgkin's lymphomas;
- multiple myeloma.
Doxorubicin can be used as a monotherapy or in combination with other cytostatics in different doses depending on the therapy scheme. When individual dose selection should be guided data of the specialized literature.
- as monotherapy the recommended dose per cycle is 60-75 mg / m 2 every 3 weeks. Usually the drug is administered once during the cycle; however, the cyclic dose can be divided into several administrations (eg, administered for the first 3 consecutive days, or on the first and the eighth day of the cycle). The cycles are repeated every 3-4 weeks;
- To reduce the toxic effect of doxorubicin, especially cardiotoxicity, a weekly regimen of 10-20 mg / m 2 is administered;
- in combination with other antitumor drugs, doxorubicin is prescribed in a cyclic dose of 30-60 mg / m 2 every 3-4 weeks.
Violation of the function of the liver. In patients with hyperbilirubinemia The dose of doxorubicin should be reduced in accordance with the concentration of total bilirubin:
- by 50% at a concentration of bilirubin in blood serum 1.2-3.0 mg / dl;
- by 75% with serum bilirubin concentration above 3.0 mg / dl.
The total dose of doxorubicin should not exceed 550 mg / m 2. In patients who received previous radiation therapy in the lung and mediastinal region or treated with other cardiotoxic drugs, the total dose of doxorubicin should not be more than 400 mg / m 2 .
Intravenous administration of doxorubicin should be conducted with caution. To reduce the risk of thrombosis and extravasation, it is recommended that doxorubicin is administered through the tube of the system for intravenous administration, during the infusion of 0.9% sodium chloride solution or 5% dextrose solution, for 3-5 minutes.
Introduction to the bladder
Introduction to the bladder is used to treat superficial bladder tumors, as well as prevent relapse after transurethral resection . Introduction to the bladder is not used to treat invasive tumors with germination into the muscular wall of the bladder.
The recommended dose for intravesical administration is 30-50 mg per instillation, with intervals between administrations from 1 week to 1 month, in depending on the purpose of therapy - treatment or prevention. The recommended concentration of the solution is 1 mg / 1 ml water for injection or 0.9% solution of sodium chloride. After the instillation is completed, to ensure a uniform effect of the drug on the mucosa of the bladder, patients should flip from side to side every 15 minutes.As a rule, the drug should be in the bladder for 1-2 hours. At the end of instillation the patient should empty the bladder.
To avoid excessive dilution of the drug with urine, patients should be warned about that they should refrain from the reception of liquid for 12 hours before instillation. The systemic absorption of doxorubicin during instillation into the bladder is very low.
When the manifestations of local toxic effects (chemical cystitis, which can manifest dysuria, polyuria, nicture, painful urination, hematuria, discomfort in the area bladder, and necrosis of the bladder wall), the dose intended for instillation should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Particular attention should be given to problems associated with catheterization (for example, with urethra obstruction due to massive intravesical tumors).
Patients with hepatocellular carcinoma to provide intensive local effects while reducing the overall toxic effect of doxorubicin can be entered intraarterially into the main hepatic artery in dose of 30-150 mg / m 2 with an interval of 3 weeks to 3 months. Higher doses should be used only when the extracorporeal excretion of the drug.
Because this method is potentially dangerous, and when it is used, air embolism and / or arterial thrombosis can result, leading to widespread necrosis of the tissue, intraarterial administration can only be performed by physicians who are proficient in this technique.
On the part of the hematopoiesis system: very often - dose-dependent reversible myelosuppression (leukopenia and neutropenia, thrombocytopenia, anemia).Leukopenia usually reaches a minimum value 10-14 days after the drug administration, the restoration of the blood picture is usually observed on day 21.
From the cardiovascular system: often - early (acute) cardiotoxicity, manifestations of which are sinus tachycardia, tachyarrhythmias (including ventricular tachycardia), supraventricular or ventricular extrasystole, as well as bradycardia, AV blockade and bundle branch blockade and / or abnormal ECG changes (nonspecific changes in ST-T waves), decreased blood pressure, palpitations, late ( delayed) cardiotoxicity, which is manifested by a decrease in the left ventricular ejection fraction of the heart without clinical symptoms and / or with symptoms of congestive heart failure - dyspnea, pulmonary edema, peripheral edema, cardiomegaly and hepatomegal lya, oliguria, ascites, exudative pleurisy, gallop rhythm, pericarditis, myocarditis; very rarely - phlebitis, thrombophlebitis, thromboembolic complications, including pulmonary embolism (in some cases, with a fatal outcome.
From the digestive system: very often - nausea, vomiting, ulcerative lesions of the mucous membranes of the gastrointestinal tract (stomatitis, esophagitis, ulcerative colitis, usually 5-10 days after the start of treatment and can progress with repeated therapeutic cycles), hyperpigmentation of the oral mucosa, abdominal pain , bleeding from the digestive tract, diarrhea, colitis. Increase in the concentration of total bilirubin and activity of hepatic transaminases in blood serum.
From the side of the urinary system: often - staining the urine in red for 1-2 days after the administration of doxorubicin, hematuria, polyuria, stranguria, painful urination, hemorrhagic cystitis, amenorrhea (after 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 levels, this can happen several years after the end of therapy); rarely - nephropathy associated with increased formation of uric acid.
On the part of the reproductive system: often amenorrhea (after the end of the therapy, ovulation recovers, but premature menopause may occur), oligospermia, 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 sense organs: conjunctivitis, keratitis, lacrimation.
From the skin and skin appendages: very often - reversible complete alopecia (the resumption of hair growth usually begins 2-3 months after stopping the administration of the drug), hyperpigmentation of the skin and nails, photosensitivity, urticaria, rash, itching. Some patients who received radiation therapy after doxorubicin administration (usually after 4-7 days) showed hypersensitivity of the irritated skin, erythema with the formation of vesicles, edema, severe pain, wet epidermitis in places corresponding to irradiation fields.
From the respiratory system: very rare - tachypnoe, dyspnea, exudative pleurisy, bronchospasm, interstitial pneumonia.
Local reactions: infrequently - erythematous striation along the vein into which the infusion was made, then local phlebitis or thrombophlebitis may occur. Also, phlebosclerosis may develop, especially if doxorubicin is re-injected 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 tissues.
With intra-arterial administration in addition to systemic toxicity, gastric and duodenal ulcers can be observed (probably due to reflux of drugs in the gastric artery);narrowing of the bile duct due to drug-induced sclerosing cholangitis.
With intravesical injection: cystitis.
Other: malaise, drowsiness, asthenia, fever, chills, flushing to the face, development of acute lymphocytic or myelocytic leukemia, in children - development of late neoplastic diseases, in particular - myeloid leukemia.
- hypersensitivity to doxorubicin or other components of the drug, as well as to other anthracyclines and anthracenedions;
lactation period (breastfeeding).
IV introduction is contraindicated when:
- pronounced myelosuppression (neutrophil count less than 1500 cells / Ојl);
- severe hepatic impairment;
- severe heart failure and arrhythmias;
- recently transferred myocardial infarction;
- previous therapy with other anthracyclines or anthracenedions in the maximum total doses;
- Acute viral infections (including with chickenpox, shingles herpes).
Introduction and the bladder is contraindicated when:
- invasive tumors with penetration into the wall of the bladder;
- urinary tract infections;
- inflammatory diseases of the bladder.
With caution should be used in patients who received previous intensive chemotherapy; with heart diseases; with risk factors for cardiotoxicity; with obesity, with tumor infiltration of the bone marrow, with pronounced impairment of liver function (may need to reduce starting doses or increase intervals between doses); urate nephrolithiasis (including in the anamnesis); as part of combined antitumor therapy, as well as in combination with radiation or other antitumor therapy; in children; in elderly patients.
PREGNANCY AND LACTATION
Controlled studies of doxorubicin in pregnant women have not been conducted. Studies in animals have shown embryotoxic, teratogenic and mutagenic effects of doxorubicin. Therefore, doxorubicin should not be used during pregnancy.
Since doxorubicin is excreted in breast milk, in order to avoid the toxic effect of the drug on the baby, during the treatment period, breastfeeding should be stopped
Men and women of childbearing age, during treatment with doxorubicin and at least 3 months afterwards, should use reliable contraceptive methods.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with hyperbilirubinemia, doxorubicin dose should be reduced in accordance with the concentration of total bilirubin:
- by 50% with serum bilirubin concentration of 1.2-3.0 mg / dL;
- by 75% with serum bilirubin concentration above 3.0 mg / dl.
Intravenous administration is contraindicated in severe hepatic insufficiency.
APPLICATION FOR CHILDREN
It is recommended that lower doses are administered or that the intervals between cycles in children are increased.
APPLICATION IN ELDERLY PATIENTS
It is recommended that lower doses are administered or that the intervals between cycles are increased in elderly patients.
Treatment of Doxorubicin-Ebove should be performed under the supervision of physicians with experience in the use of antitumor drugs.
To reduce the risk of toxic cardiac damage, it is recommended to perform regular monitoring of its function by various diagnostic methods (echocardiography, scintigraphy, ECG) before and during therapy with doxorubicin. An early clinical diagnosis of heart failure due to the use of the drug is very important for successful treatment. If there are signs of cardiotoxicity (clinical signs - blood pressure lowering, cardiac arrhythmias, pain in the heart area, instrumental signs - lowering the left ventricular ejection fraction by more than 10% or less than 50% in patients with initially normal contractile function of the heart, increasing heart size) treatment with doxorubicin is immediately stopped.
Acute cardiotoxicity is reversible in most cases (ST-segment depression or rhythm abnormalities are recorded on the ECG) and it is not usually considered as an indication for the abolition of doxorubicin therapy. However, if the amplitude of the QRS complex decreases by 30% of the initial value, the QRS complex is extended to the ECG, or the reduction of the left ventricular contraction fraction is reduced by 5% according to the echocardiogram, it is recommended to stop doxorubicin treatment. Late (delayed) cardiotoxicity (cardiomyopathy) depends on the total dose. The probability of developing myocardial dysfunction is approximately 1-2% with a total dose of 300 mg / m 2 ; The probability of this increases slowly at a total cumulative dose of 450-550 mg / m 2 . If this dose is exceeded, the risk of developing congestive heart failure increases dramatically, and therefore treatment with doxorubicin is recommended to stop when the total dose of 550 mg / m 2 isreached. If the patient has any additional risk of cardiotoxicity (eg, a history of heart disease, previous therapy with anthracyclines or anthracene dione, previous radiation therapy in the mediastinum region, simultaneous use of other potentially cardiotoxic drugs such as cyclophosphamide and 5-fluorouracil, age is less 15 years old and over 70 years of age), then toxic effects can occur at lower cumulative doses, and monitoring of heart function should be particularly careful nym.Doxorubicin-induced cardiotoxicity develops primarily during the course of therapy or within two months after its termination, however, delayed side effects may occur (several months or even years after the end of therapy).
During the treatment with doxorubicin, it is necessary to evaluate hematological parameters before and during each cycle of therapy, including determination of the number of leukocytes, platelets, hemoglobin, blood elements and liver functional tests.
Patients with advanced neutropenia / leukopenia should be carefully monitored to identify signs of superinfection.
When there are first signs of extravasation of doxorubicin (burning or soreness at the injection site), the infusion should be stopped immediately, and then resumed infusion into another vein before the full dose is given. Local activities to eliminate the consequences of extravasation. It is advisable to use ice packs.
If possible, the introduction of veins into the veins over the joints or into the veins of the extremities with impaired venous or lymphatic drainage should be avoided.
In applying doxorubicin due to rapid lysis of tumor cells can be observed hyperuricemia, in this connection, the patients during therapy to determine the concentration of uric acid, potassium, calcium and creatinine. Such measures as increased hydration, urine alkalinisation and prophylactic allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome. In the treatment of hyperuricemia and gout may require correction doses protivopodagricakih means by increasing the concentration of uric acid pas background drug treatment.
Immunization is not recommended unless it is approved by a physician in the range of 3 months to 1 year after taking the drug; other members of the patient's family, residing with him, should abandon immunization oral polio vaccine; avoid contact with people who received the polio vaccine or wearing a protective mask that covers the nose and mouth.
Doxorubicin can cause staining of urine red.
When working with doxorubicin is necessary to observe the rules of treatment with cytotoxic agents. The contaminated preparation is recommended to treat the surface with a dilute sodium hypochlorite solution (containing 1% available chlorine). If the product enters the skin - immediately produce copious water washing the skin with soap or sodium hydrogen carbonate; After eye - to pull eyelids and producing lavage eye (s) with water for at least 15 min.
Remains of the drug and all the tools and materials used for the preparation of solutions for intravascular and intravesical drug Doxorubicin-Ebewe, must be disposed of in accordance with standard hospital waste disposal procedure cytotoxic substances with regard to the existing regulations destruction of hazardous waste.
Impact on the ability to drive vehicles and manage mechanisms
Because of the likelihood of side effects such as nausea, vomiting, drowsiness, use caution when engaging in potentially hazardous activities that require high concentration and psychomotor speed reactions.
Symptoms: severe myelosuppression (mainly leukopenia, thrombocytopenia), toxic shock syndrome (nausea, vomiting, stomatitis, enteritis and diarrhea), acute heart disease (reduced blood pressure, tachycardia, dysrhythmia, heart pain, acute heart failure).
Treatment: an antidote for doxorubicin is not known. In case of overdose, symptomatic treatment is recommended. Hemodialysis is not effective.
Doxorubicin may potentiate the toxicity of other anticancer agents, especially myelotoxicity and toxic effects on the gastrointestinal tract.
With simultaneous use of doxorubicin and other cytotoxic agents that have a potential cardiotoxicity (e.g., daunorubicin, dactinomycin, 5-fluorouracil, mitomycin, cyclophosphamide) requires a thorough monitoring of cardiac function during the entire course of therapy. The recommended dose of doxorubicin - no more than 400 mg / m 2 . The use of doxorubicin in patients receiving total cumulative doses of daunorubicin or doxorubicin (in history), is not recommended.
Against the background of doxorubicin may increase effects of hemorrhagic cystitis caused by cyclophosphamide and increased hepatotoxicity of 6-mercaptopurine.
Streptozotocin increases T 1/2 doxorubicin.
Doxorubicin enhances radiation-induced toxic effects on the myocardium, mucous membranes, skin, and liver.
Urikozuricheskih arthrifuge drugs increase the risk of developing nephropathy.
When the joint application of cyclosporin and doxorubicin increasing concentrations of both drugs in plasma. This can lead to increased risk of myelotoxicity and immunosuppression.
Hepatotoxic drugs, deteriorating liver function may increase the toxicity of doxorubicin.
Inhibitors of cytochrome P450 enzyme system (e.g. cimetidine, ranitidine) may decrease the metabolism of doxorubicin, resulting in increasing the risk of its toxic effects.
Inducers of cytochrome P450 enzyme systems (e.g., rifampicin, barbiturates) can increase the rate of metabolism of doxorubicin, thus reducing its effectiveness.
When combined with calcium channel blockers slow (e.g., verapamil) increases the cytotoxicity of doxorubicin.
Due to the fact that the treatment of doxorubicin may suppress the natural defense mechanisms, vaccination is recommended after a certain time (from 3 months to 1 year) after the end of treatment
Doxorubicin should not be mixed with other drugs. Do not allow contact with alkaline solutions because this can lead to hydrolysis of doxorubicin.
Pharmaceutically compatible with heparin, dexamethasone, fluorouracil, hydrocortisone sodium succinate, aminophylline, cephalothin, other anticancer drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, protected from light at a temperature of 2 В° to 8 В° C. Shelf life - 2 years.