Active substanceDoxorubicinDoxorubicin
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  • Dosage form: & nbspLyophilizate for the preparation of solution for intravascular and intravesical administration.
    Composition:1 bottle contains:
    active substance:
    doxorubicin hydrochloride - 10 mg;
    auxiliary substance:
    Mannitol (mannitol) - 40 mg.
    Description:A porous mass of red color. It is hygroscopic.

    Pharmacotherapeutic group:Antitumor agent, antibiotic
    ATX: & nbsp

    L.01.D.B.01   Doxorubicin

    Pharmacodynamics:Antitumor antibiotic anthracycline, obtained by chemical synthesis from the substance daunorubicin hydrochloride. It has an anti-climatic and antiproliferative effect. The mechanism of action is the interaction with DNA, the formation of free radicals and direct action on the membrane of cells with the suppression of the synthesis of nucleic acids. The cells are sensitive to the drug in the S- and G2-phases.
    Pharmacokinetics:
    Absorption is high, distribution is relatively uniform. Through the blood-brain barrier 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. The half-life is from 20 to 48 hours for doxorubicin and doxorubicinol. Excretion: intestine - 40% unchanged for 7 days, kidneys - 5 to 12% doxorubicin and its metabolites for 5 days.
    Pharmacokinetics in special groups:
    Children. The clearance of doxorubicin in children older than 2 years exceeds that of adults. Clearance in children under 2 years of age is close to the values ​​of clearance in adults.
    Elderly. Dose adjustment with age is not required.
    Floor. The average clearance of doxorubicin in men is significantly higher than that of women. However, the terminal half-life of doxorubicin in men is longer than in women (54 and 35 hours, respectively).
    Race. The influence of the race on the pharmacokinetics of doxorubicin has not been studied.
    Impaired liver function. In patients with impaired hepatic function, the clearance of doxorubicin and doxorubicinol decreases.
    Impaired renal function. The effect of kidney function on the pharmacokinetics of doxorubicin has not been studied.
    Indications:Breast cancer, lung cancer (small cell), mesothelioma, esophagus cancer, stomach cancer, primary hepatocellular cancer, insulinoma, carcinoid, head and neck cancer, thyroid cancer, malignant thymoma, ovarian cancer, germiogenic testicular tumors, prostate cancer, cancer bladder cancer (treatment and prevention of relapses after surgery), endometrial cancer, cervical cancer, uterine sarcoma, Ewing's sarcoma, rhabdomyosarcoma, neuroblastoma, Wilms tumor, osteogenic sarcoma, soft tissue sarcoma, Kaposi's sarcoma, ostitis lymphoblastic leukemia, acute myeloblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease and non-Hodgkin's lymphomas, multiple myeloma.
    Contraindications:
    Hypersensitivity to doxorubicin or mannitol, as well as to other anthracyclines and anthracenedions. Pregnancy and lactation.
    Intravenous administration is contraindicated in: severe myelosuppression (the number of white blood cells is less than 2000 cells / mm3, the number of platelets less than 50,000 cells / mm3), hepatic insufficiency of severe severity, severe cardiovascular pathology (unstable angina, progressive heart failure, severe rhythm and conduction disorders, acute inflammatory heart diseases, myocardial infarction in the last 6 months, cardiomyopathy), previous therapy with other anthracyclines or anthracenedions in maximum total doses, acute viral infections (including chicken pox, herpes zoster).
    Introduction to the bladder is contraindicated in: invasive tumors with penetration into the wall of the bladder, infection of the urinary tract, inflammation of the bladder, hematuria.
    Carefully:
    Patients with risk factors for cardiotoxicity, with heart disease; patients who received previously intensive chemotherapy, children, elderly patients, obese patients, patients with tumoral bone marrow infiltration (a reduction in starting doses or an increase in the intervals between doses may be required); use in combination antitumor therapy, as well as in combination with radiation or other antitumor therapy; patients with impairedliver function of mild and moderate severity; patients with peptic ulcer of the stomach and duodenum (with intraarterial administration of doxorubicin), urate nephrolithiasis (including in the anamnesis), gout (including in the anamnesis), parasitic and infectious diseases of viral, fungal or bacterial nature.
    Pregnancy and lactation:The drug is contraindicated during pregnancy and breastfeeding.
    Dosing and Administration:
    Intravenous, intravesical or intra-arterial. Doxorubicin can be used both as a monotherapy, and in combination with other antitumor drugs in different doses depending on the scheme of therapy. Correction of the dose when suppressing the function of the bone marrow, depending on the blood values, namely:
    Leucocytes, in 1 μl more than 5000 - the doxorubicin dose is 100%;
    Leucocytes, in 1 μl 4000 - 5000 - doxorubicin dose 75%;
    Leucocytes, in 1 μl 3000 - 4000 - doxorubicin dose 50%;
    Leucocytes, in 1 μl 2000 - 3000 - the dose of doxorubicin is 25%;
    Leukocytes, in 1 μl less than 2000 - doxorubicin dose 0%;
    Platelets, in 1 μl more than 150,000 - dose of doxorubicin 100%;
    Platelets, in 1 μl 100,000 - 150,000 - dose of doxorubicin 75%;
    Platelets, in 1 μl 75,000 - 100,000 - dose of doxorubicin 50%;
    Platelets, in 1 μl 50000 - 75000 - doxorubicin dose 25%;
    Platelets, in 1 μl less than 50,000 - doxorubicin dose 0%;
    For individual dose selection, reference should be made to the literature.
    Dosing regimen:
    - as a monotherapy, the recommended dose per cycle is 60-75 mg /m2 every three weeks. Typically, the drug is administered once during the cycle, but the cyclic dose can be divided into several administrations (for example: administered for the first 3 consecutive days, or on the first and the eighth day of the cycle), with cycles repeated every 3-4 weeks;
    - To reduce the toxic effect of doxorubicin, especially cardiotoxicity, a weekly regimen of 10-20 mg /m2;
    - in combination with other antineoplastic agents doxorubicin is administered at a cyclic dose of 30-60 mg / m2 every 3-4 weeks.
    Violation of the function of the liver. In patients with hyperbilirubinemia, the doxorubicin dose should be reduced in accordance with the concentration of total bilirubin: by 50% at a serum bilirubin concentration of 12-30 mg / l; on 75% at a concentration of bilirubin in blood serum above 30 mg / l.
    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 children, elderly patients, obese patients (if body weight is more than 130% of "ideal", there is a decrease in systemic clearance of doxorubicin ), as well as patients with tumor infiltration of the bone marrow.
    Preparation of the solution: doxorubicin lyophilizate is dissolved in 5 ml of water for injection. The resulting solution with the required amount of doxorubicin is further diluted with 0.9% sodium chloride solution or water for injection to a concentration of not more than 1 mg / ml. The reconstituted solution of the preparation is recommended to be used immediately after preparation.
    Intravenous administration
    The drug is injected intravenously slowly (within 3-5 minutes) into the injection port of the intravenous infusion system, during a rapid infusion of 5% dextrose solution or 0.9% sodium chloride solution. Before injection, make sure that the needle or catheter is positioned exactly in the vein. Avoid the introduction of small veins and veins over the joints,care should be taken not to perform venipuncture and subsequent administration of doxorubicin on the limbs, where there are violations of venous and lymphatic outflow. The total dose of doxorubicin should not exceed 550 mg /m2. Patients who received previous radiotherapy for the mediastinal / pericardial region or who took other cardiotoxic drugs, if necessary, increase the total dose of doxorubicin more than 450 mg / m2 The drug should be administered under strict monitoring of heart function. Re-introduction of the drug is possible only if all signs of toxicity (especially gastrointestinal and hematological) disappear.
    Introduction to the bladder
    The recommended dose for intravesical administration is 30-50 mg per installation, with intervals between administrations from 1 week to 1 month, depending on the purpose of therapy-treatment or prevention. The recommended concentration of the solution is 1 mg / 1 ml of water for injection or 0.9% solution of sodium chloride. After completion of the installation, to ensure a uniform effect of the drug on the mucosa of the bladder, patients should flip from side to side every fifteen minutes. As a rule, the drug should be in the bladder for 1-2 hours.At the end of the installation, the patient should empty the bladder. To prevent excessive dilution of the drug with urine, patients should be warned that they should refrain from taking liquid for 12 hours before the installation. Systemic absorption of doxorubicin during installation in the bladder is very low. In cases of local toxic effects (chemical cystitis, which may be manifested by dysuria, polyuria, nicturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall), the dose to be reinstalled should be dissolved in water for injection, and then up to 50-100 ml with 0.9% sodium chloride solution. Particular attention should be paid to problems associated with catheterization (for example, with obstruction of the urethra caused by massive intravesical tumors). Intraarterial administration:
    Patients with hepatocellular carcinoma to provide intensive local effects while reducing the overall toxic effect, doxorubicin can be injected intraarterially into the main hepatic artery at a dose of 30-150 mg / m2 with an interval of 3 weeks to 3 months. Higher doses should be used only in those cases when the extracorporeal elimination of the drug is simultaneously carried out. Since this method is potentially dangerous, and when it is used, widespread necrosis of the tissue can occur, intraarterial administration can only be performed by physicians who are proficient in this technique.
    Side effects:
    Allergic reactions: skin rash, dermatitis, urticaria, flushing of the skin of the palms and soles, bronchospasm, anaphylaxis (rarely).
    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 doxorubicin 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.
    From the skin and skin appendages: in most cases, reversible alopecia develops.The resumption of hair growth usually begins 2-3 months after the drug is discontinued. Hyperpigmentation of the skin and nails, photosensitivity, urticaria, rash, itching may also occur. In some patients who had previously received radiation therapy, after the administration of doxorubicin (usually after 4-7 days), hypersensitivity of the irritated skin, the appearance of erythema with the formation of vesicles, erythema acroma, edema, severe pain, wet epidermitis in places corresponding to irradiation fields, palmar - Sodium erythrodysesthesia.
    From the urinary system: staining the urine in red for 1-2 days after the administration of doxorubicin.
    From the digestive system: anorexia, nausea, vomiting, mucositis, stomatitis, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, erosion of the stomach, bleeding from the gastrointestinal tract, diarrhea, necrotic colitis, dehydration, increased activity of "liver" transaminases, hyperbilirubinemia.
    From the hematopoiesis: dose-dependent, reversible leukopenia and neutropenia.Thrombocytopenia and anemia are also possible. Leukopenia 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. Bleeding.
    From the side of the organ of vision: conjunctivitis, keratitis, lachrymation.
    From the side of the cardiovascular system: with anthracycline therapy, there is a risk of developing cardiotoxicity - early (ie acute) or late (delayed). Cardiotoxic effects usually occur within 1 to 6 months after initiation of treatment. The manifestation of early (acute) cardiotoxicity of doxorubicin is primarily sinus tachycardia and / or pathological changes on the ECG (nonspecific changes in ST-T waves). There may also be tachyarrhythmias (including ventricular tachycardia), ventricular extrasystole, as well as bradycardia, atrioventricular blockade, and blockade of the legs of the bundle. The appearance of these phenomena is not always a prognostic factor in the development of subsequently delayed cardiotoxicity, they are rarely clinically significant and do not require the abolition of doxorubicin therapy.Later (delayed) myocardial damage is manifested by a decrease in the left ventricular ejection fraction without clinical symptoms and / or symptoms of chronic heart failure (CHF) (shortness of breath, pulmonary edema, peripheral edema, cardiomegaly and hepatomegaly, oliguria ascites, exudative pleurisy, gallop rhythm). Also may be celebrated subacute phenomenon (pericarditis / myocarditis). The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is life-threatening CHF. Phlebitis, thrombophlebitis, thromboembolic complications, including pulmonary embolism (in some cases, with a fatal outcome).
    On the part of the reproductive 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).
    With intra-arterial administration: In addition to systemic toxicity, gastric and duodenal ulcers can occur (probably due to refluxpreparations in the gastric artery); narrowing of the bile ducts due to drug-induced sclerosing cholangitis, widespread necrosis of perfused tissue.
    With intravesical injection: chemical cystitis (dysuria, polyuria, nocturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall), constriction of the bladder.
    Other: malaise, asthenia, fever, chills, "tide" of blood to the skin of the face (with rapid intravenous administration), acute renal failure, weight gain, radiation pneumonia, Quincke's edema, in children development of late neoplastic diseases, hyperuricemia or nephropathy associated with increased uric acid formation, lymphoblastic or myeloblastic leukemia, secondary infections, sepsis / septicemia, bleeding, septic shock.
    Overdose:
    Acute overdose of doxorubicin can lead to severe myelosuppression (mainly to leukopenia and thrombocytopenia), to toxic effects from the gastrointestinal tract, to cause acute cardiotoxicity.
    Antidote to doxorubicin is unknown.In case of overdose, symptomatic therapy is recommended.
    Interaction:
    Doxorubicin may enhance the cardiotoxicity of other antitumor agents (daunorubicin, dactinomycin, mitomycin), myelotoxicity and toxic effects on the gastrointestinal tract. With simultaneous use of doxorubicin with other cytotoxic drugs that have potential cardiotoxicity (for example, fluorouracil and / or cyclophosphamide), as well as with blockers of "slow" calcium channels (for example: verapamil), requires more careful monitoring of heart function throughout the course of therapy. Inhibitor of enzymes of cytochrome P450 system (cimetidine) can slow the metabolism of doxorubicin, which leads to increased toxic effects.
    Inductors of cytochrome P450 enzymes (phenytoin, rifampicin, barbiturates, carbamazepine) can accelerate the metabolism of doxorubicin, reducing the effectiveness of therapy.
    Doxorubicin may reduce the bioavailability of digoxin when administered orally. Therefore, during treatment with doxorubicin, the concentration of digoxin in the blood plasma must be checked regularly.Combinations of doxorubicin with amphotericin B should be avoided because it can lead to severe nephrotoxicity. With the simultaneous use of doxorubicin and ritonavir, an increase in the level of doxorubicin in serum was reported. The use of trastuzumab in combination with doxorubicin (and other anthracyclines) is associated with high cardiotoxic risk, so to date trastuzumab should not be used in combination with anthracyclines. The use of anthracyclines after the end of trastuzumab therapy may have an increased risk of cardiac toxicity. If possible, between the end of therapy with trastuzumab and the initiation of treatment with anthracyclines, a sufficient time interval (up to 24 weeks) should be maintained. In any case, it is necessary to carefully monitor the state of cardiac activity. Against the background of doxorubicin, it is possible to enhance the phenomena of hemorrhagic cystitis caused by cyclophosphamide and increase the hepatotoxicity of 6-mercaptopurine. With the use of doxorubicin (IV for 3 days) in combination with cytarabine (in the form of infusion for 7 days), cases of development of necrotic colitis and severe infectious complications are described.With simultaneous use of doxorubicin with cyclosporine, cases of coma and / or seizures are described. Streptozotocin increases the half-life of doxorubicin. Progesterone enhances doxorubicin-induced neutrophobic and thrombocytopenia, dexrazoxane - enhances myelosunpressive effect of doxorubicin, phenobarbital - accelerates elimination.
    The administration of paclitaxel to doxorubicin may lead to an increase in plasma concentrations of doxorubicin and / or its metabolites in plasma. This effect is minimal when doxorubicin is administered before paclitaxel. Doxorubicin increases the radiation-induced toxic effect on the myocardium, mucous membranes, skin and liver. Urikozuric antidotal drugs increase the risk of developing nephropathy. Hepatotoxic drugs, worsening the function of the liver, can lead to an increase in the toxicity of doxorubicin. Doxorubicin can not be mixed with other drugs. Do not allow contact with alkaline solutions, as the ego can lead to hydrolysis of doxorubicin. Pharmaceutically incompatible with heparin, dexamethasone, hydrocortisone, sodium succinate, aminophylline, cephalothin, fluorouracil and other antitumor drugs.With simultaneous administration with live viral vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side / adverse effects and / or reduce the production of antibodies in the patient's body in response to the introduction of the vaccine.
    Special instructions:
    Treatment with doxorubicin should be performed under the supervision of physicians with experience in the use of antitumor drugs.
    To reduce the risk of severe toxic cardiac damage, it is recommended that cardiac functions be regularly monitored before and during doxorubicin therapy, including assessment of the left ventricular ejection fraction by echocardiography or multichannel radioisotope angiography, and ECG monitoring. An early clinical diagnosis of heart failure due to the use of the drug is very important for its successful treatment. If the amplitude of the QRS complex decreases by 30% of the initial value, the QRS complex is extended to the ECG, or the fraction of the left ventricle shortening is reduced by 5% according to the echocardiogram, it is recommended to stop doxorubicin treatment.
    Acute cardiotoxicity in most cases is transient (reversible), and usually it is not considered as an indication for the abolition of doxorubicin therapy.

    Late (delayed) cardiotoxicity (cardiomyopathy) depends on the total dose. The probability of myocardial dysfunction is approximately 1-2% at a total dose of 300 mg /m2; the probability of this slowly increases at a total cumulative dose of 450-550 mg /m2. Then the risk of developing congestive heart failure increases dramatically, so it is recommended not to exceed the total total dose of 550 mg /m2. If the patient has any additional risk of cardiotoxicity (eg, history of heart disease, previous therapy with anthracyclines or anthracenedion, previous radiotherapy of the mediastinum, simultaneous use of other potentially cardiotoxic drugs such as cyclophosphamide and fluorouracil), toxic effects may also occur at lower cumulative doses. In these cases, monitoring the function of the heart should be particularly strict. 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). The cumulative dose should not exceed 400 mg / m2. In children and adolescents, the risk of late cardiotoxicity of doxorubicin is increased. In women, this risk may be higher than that of men. In patients with excess body weight (more than 130% of ideal weight), systemic clearance of doxorubicin decreases.
    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 function tests.
    If possible, the introduction of veins into the veins over the joints, small veins or veins of the extremities with impaired venous or lymphatic drainage. Due to injection into the small vein or due to the repeated administration of the drug in the same vein, phlebosclerosis may form.
    When the first signs of doxorubicin extravasation appear (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 administered. Local measures to eliminate the consequences of extravasation: immediately remove the injection needle, chop the hydrocortisone solution at a dose of 100 mg, sprinkle with chloroethyl or put ice, then apply an alcohol bandage.It is advisable to use ice packs.
    Nausea and vomiting that occur within the first few hours after taking the drug can be alleviated with antiemetic drugs.
    The toxicity of doxorubicin and other anthracyclines or anthracendones is probably additive. In patients receiving anthracyclines, including doxorubicin, 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.
    Mucositis / stomatitis usually develops shortly after the administration of the drug and in severe cases for several days can lead to the expression of the mucous membrane. In most cases, these undesirable phenomena are resolved by the third week of therapy.
    When doxorubicin is used due to the rapid lysis of tumor cells, hyperuricemia can occur,Therefore, patients during therapy are recommended to determine the concentration of uric acid, potassium, calcium and creatinine. Such measures as increased hydration, alkalinization of urine and preventive prescription of allopurinol to prevent hyperuricemia, allow to minimize the risk of complications associated with tumor lysis syndrome. In the treatment of hyperuricemia and gout, it may be necessary to adjust the doses of antidotal drugs as a result of an increase in the concentration of uric acid against the background of drug treatment.
    Patients with advanced neutropenia / leukopenia should be carefully monitored to identify signs of infection.
    Immunization is not recommended, if it is not approved by the doctor, in the interval from 3 months to 1 year after taking the drug; other family members of the patient living with it should opt out of immunization with oral polio vaccine; should avoid contact with people who received a polio vaccine, or wear a face mask covering the nose and mouth.
    In women, doxorubicin can cause infertility and amenorrhea.Ovulation and menstruation usually recover after cessation of treatment, although early menopause may occur. In men, doxorubicin has a mutagenic effect and can cause damage to the chromosomes of spermatozoa. Oligospermia or azoospermia can be irreversible, although in some cases there has been a recovery in the number of spermatozoa, sometimes several years after cessation of treatment. Men and women of childbearing age during treatment with doxorubicin and, at least, within 3 months after, should use reliable methods of contraception. Doxorubic excretion, mainly with bile. Before and during treatment, the total bilirubin in the serum should be monitored. Patients with elevated bilirubin values ​​tend to have slower clearance and a higher percentage of toxic effects. In such cases, a dose reduction is recommended. Patients with severe impairment of hepatic doxorubic function can not be used.
    When working with doxorubicin, the rules for handling cytotoxic substances must be observed.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; In case of contact with eyes, pull eyelids and rinse eyes (eyes) with plenty of water for at least 15 minutes.
    Effect on the ability to drive transp. cf. and fur:The drug can cause nausea, vomiting and other side effects, so you should be careful when driving vehicles or other mechanisms. When these undesirable phenomena appear, one should refrain from performing these activities.
    Form release / dosage:
    Lyophilizate for the preparation of solution for intravascular and intravesical administration.
    Packaging:
    For 10 mg of active substance in bottles with a capacity of 10 ml.
    1 bottle with instructions for use in a pack of cardboard.

    Storage conditions:
    In the dark place at a temperature of no higher than 5 ° C.
    Keep out of the reach of children.

    Shelf life:
    2 years.
    Do not use after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-003280
    Date of registration:30.10.2015
    Expiration Date:30.10.2020
    The owner of the registration certificate:OMUTNINSK SCIENTIFIC EXPERIMENTAL-INDUSTRIAL BASE, OJSC OMUTNINSK SCIENTIFIC EXPERIMENTAL-INDUSTRIAL BASE, OJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp07.01.2016
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