Composition, form of production and packaging
Lyophilizate for the preparation of a solution for intravascular and intravesical administration 1 fl.
doxorubicin hydrochloride 10 mg
Solvent: water d / u - 5 ml.
Vials (1) complete with a solvent - packs cardboard.
Lyophilizate for the preparation of a solution for intravascular and intravesical administration 1 fl.
doxorubicin hydrochloride 50 mg
Vials (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from a culture of Streptomyces peucetius var. caesius.
The cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs is probably due to the intercalation of nucleotide bases and the ability of doxorubicin to bind to the lipids of the cell membrane. Intercalation inhibits the replication of nucleotides and the activity of DNA and RNA polymerases. The interaction of doxorubicin with topoisomerase II with the formation of DNA-cleavable complexes is considered to be an important mechanism for the cytotoxic effect of doxorubicin.
The initial T 1/2 is about 5 minutes and indicates a rapid distribution of doxorubicin in tissues; Terminal T 1/2 - 20 - 48 hours. The relationship between doxorubicin and its main metabolite, doxorubicinol, with plasma proteins is 74-76% and does not depend on the concentration of doxorubicin in plasma (up to 1.1 Ојg / ml). Doxorubicin does not penetrate the blood-brain barrier.
Enzymatic reduction in position 7 and splitting of daunosamine sugar leads to the formation of aglycons, which is also accompanied by the formation of free radicals. The latter can cause cardiotoxic effects of doxorubicin. T 1/2 of doxorubicinol is similar to doxorubicin. The ratio between doxorubicinol AUC and doxorubicin AUC in comparison with doxorubicin is 0.4-0.6.
The clearance of doxorubicin is carried out, mainly, by metabolism and excretion with bile. Approximately 40% of the dose is excreted with bile within 5 days. Only 5-12% of doxorubicin and its metabolites are found in the urine over the same period of time. Within 7 days in the form of doxorubicinol, less than 3% of the dose is excreted in the urine.
Systemic clearance of doxorubicin is significantly reduced in obese women whose body weight is more than 130% of the optimal.
Pharmacokinetics in special groups
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 вЂ‹вЂ‹of clearance in adults.
Dose adjustment with age is not required.
The average clearance of doxorubicin in men is significantly higher than that of women. However, terminal T 1/2 doxorubicin in men is longer than in women (54 and 35 hours, respectively).
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.
acute lymphoblastic leukemia;
acute myeloblastic leukemia;
- chronic leukemia;
Hodgkin's disease and non-Hodgkin's lymphoma;
- multiple myeloma;
- Ewing Hodge's sarcoma;
- soft tissue sarcoma;
- a neuroblastoma;
- Wilms tumor;
- mammary cancer;
- endometrial cancer;
- germinogenic tumors;
- prostate cancer;
- transitional cell carcinoma of the bladder;
- lung cancer;
- stomach cancer;
- primary hepatocellular carcinoma;
- cancer of the head and neck;
- Thyroid cancer.
Intravenous, intravesical or intra-arterial.
Adriablastin В®, which is instantly soluble, can be used both in monotherapy and in combination with other antitumor drugs, therefore, when choosing the doses and the mode of administration of the drug, reference should be made to the literature. The reconstituted solution of the preparation is recommended to be used immediately after preparation.
As a monotherapy, the recommended standard dose per cycle for adults is 60-90 mg / m 2 . The total dose of the drug per cycle (every 3-4 weeks) can be administered either simultaneously or divided into several administrations, for 3 consecutive days or on the first and eighth days of the cycle. A weekly regimen of 10-20 mg / m 2 is also administered. When doxorubicin is used in combination with other antitumor drugs with similar toxicity, the recommended dose per cycle is 30-60 mg / m 2
Repeated administration of the drug is possible only with the disappearance of all signs of toxicity (especially gastrointestinal and hematological).
To reduce the risk of thrombosis and extravasation, it is recommended to administer adrenoblastinВ® instantaneously through the tube of the intravenous infusion system, during the infusion of 0.9% sodium chloride solution or 5% dextrose solution. The duration of the infusion should be between 3 and 10 minutes.
The total dose of doxorubicin should not exceed 550 mg / m 2 .
Patients who received previous radiotherapy for mediastinal / pericardial area or who took other cardiotoxic drugs, if necessary to increase the total doxorubicin dose of more than 450 mg / m 2 , should be administered under strict monitoring of heart function.
Violation of liver function:
- if the serum bilirubin level is 1.2-3 mg / dL, the administered dose should be reduced by 50% of the recommended dose;
- if the serum bilirubin level exceeds 3 mg / dl, the administered dose should be reduced by 75% of the recommended dose.
Other special patient groups: lower doses are recommended, or intervals between cycles are increased for patients who previously received intensive chemotherapy, children, elderly patients, obese patients (if the body weight is more than 130% of the optimal, there is a decrease in the systemic clearance of the drug); and also to patients with tumor infiltration of the bone marrow.
Introduction to the bladder
Introduction to the bladder is used to treat superficial bladder tumors, and also as a prophylaxis to reduce the likelihood of recurrence after transurethral resection. Introduction to the bladder is not suitable for the treatment of invasive tumors with penetration into the muscular wall of the bladder.
The recommended dose for the installation is 30-50 mg in 25-50 ml of 0.9% sodium chloride solution. If the local toxicity (chemical cystitis) develops, the dose should be dissolved in 50-100 ml of 0.9% sodium chloride solution. Instillations can be carried out at intervals of 1 week to 1 month.
Instillation should be performed with a catheter, and the drug should remain in the bladder for 1-2 hours. To ensure a uniform effect of the drug on the bladder mucosa during the instillation, you should turn from side to side. 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.
Patients with hepatocellular carcinoma to ensure intensive local effects while reducing the overall toxic effect of the drug can be administered intraarterially to the main hepatic artery at a dose of 30-150 mg / m 2 at intervals of 3 weeks to 3 months. Higher doses should be used only in cases of simultaneous extracorporeal withdrawal of the drug. Lower doses are suitable for administration of doxorubicin in combination with iodinated oil. Since this method is potentially dangerous and can lead to widespread necrosis of tissue, intraarterial administration should be performed only by physicians who are proficient in this technique.
On the part of the hematopoiesis system: leukopenia, neutropenia, anemia, thrombocytopenia.
From the cardiovascular system: sinus tachycardia, tachyarrhythmias, atrio-ventricular blockade, bundle branch blockade, congestive heart failure, hemorrhage, hot flashes, phlebitis, thrombophlebitis, thromboembolism, shock, ECG changes, asymptomatic reduction of the left ventricular ejection fraction.
With anthracycline therapy, there is a risk of developing cardiotoxicity - early (ie acute) or late (delayed).
The early cardiotoxicity of doxorubicin is manifested mainly by sinus tachycardia and / or anomalies on the ECG (nonspecific changes in ST-T waves). 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 subsequently delayed cardiotoxicity, are rarely clinically significant and usually do not require withdrawal of drug therapy.
Late cardiotoxicity usually develops in the late stages of the course of therapy or within 2-3 months after its termination, however, more delayed side effects may develop (several months or even years after the end of therapy). Late cardiotoxicity is manifested by a decrease in the left ventricular ejection fraction and / or symptoms of congestive heart failure, such as dyspnea, pulmonary edema, edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy and gallop rhythm. Also subacute phenomena such as pericarditis and myocarditis can be noted. The most severe form of anthracycline-induced cardiomyopathy, which limits the cumulative dose of the drug, is life-threatening congestive heart failure. With the use of doxorubicin, 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, hyperpigmentation of the oral mucosa, esophagitis, abdominal pain, erosion of the stomach, bleeding from the gastrointestinal tract, diarrhea, colitis, dehydration, change in the level of transaminases.
On the part of the urinary system: staining the urine in red for 1-2 days after drug administration, hyperuricemia.
From the side of the organ of vision: conjunctivitis / keratitis, lacrimation.
From the skin and skin appendages: alopecia, rash / itching, skin changes, hyperpigmentation of skin and nails, photosensitivity, irritated skin hypersensitivity (acumestic reaction to irradiation), urticaria, erythema of the extremities, palmar-plantar erythrodysesthesia.
From the side of the reproductive system: amenorrhea, oligospermia, azoospermia.
Local reactions: extravasation during intravenous infusion of doxorubicin can lead to pain, 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, anaphylaxis, development of acute lymphocytic leukemia or acute myelogenous leukemia, secondary infections, sepsis / septicemia, weight gain.
Introduction to the bladder 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.
The intra-arterial administration of doxorubicin can cause ulceration of the stomach and duodenum (possibly due to reflux of the drug in the gastric artery) in addition to systemic toxicity, and narrowing of the bile ducts (drug sclerosing cholangitis), as well as widespread necrosis of perfused tissue.
- pregnancy and the period of breastfeeding;
- hypersensitivity to doxorubicin or other components of the drug, as well as to other anthracyclines and anthracenedions.
Intravenous administration is contraindicated in persistent myelosuppression, severe liver function abnormalities, severe heart failure and severe arrhythmias, recent myocardial infarction, prior therapy with doxorubicin, daunorubicin, epirubicin, idarubicin, and / or other anthracyclines and anthracenedones at the maximum total doses.
Introduction to the bladder is contraindicated in infections of the urinary tract, inflammation of the bladder, hematuria.
With caution: patients with risk factors for cardiotoxicity; 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 impaired liver function.
PREGNANCY AND LACTATION
Contraindicated during pregnancy and lactation.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Use with caution in liver function disorders
APPLICATION FOR CHILDREN
Children are encouraged to prescribe lower doses or increase the intervals between cycles.
APPLICATION IN ELDERLY PATIENTS
Older patients are encouraged to prescribe lower doses or increase the intervals between cycles.
Adriablastin В®, which is instantly soluble, should be used only under the supervision of physicians experienced in the use of cytotoxic drugs.
Before starting treatment, the patient should recover from the acute toxic effects of previous cytotoxic therapy (such as stomatitis, neutropenia, thrombocytopenia, and systemic infections).
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 left ventricular ejection fraction should be regularly determined and immediately discontinued if the first signs of worsening heart function appear. Appropriate methods of quantitative analysis of heart function (measurement of left ventricular ejection fractions) include radioisotope angiography (MUGA) and echocardiography. Before the start of treatment, it is recommended to evaluate cardiac function with ECG and one of the following methods - radioisotope scanning or echocardiography, especially in patients with risk factors for increased cardiotoxicity (for example, obvious or latent cardiovascular disease, previous or concomitant radiotherapy in the mediastinum / pericardial, prior therapy with other anthracyclines or anthracendones and concomitant therapy with drugs that reduce the contractility of the heart). The left ventricular ejection fraction should be measured in dynamics, especially with an increase in cumulative doses of anthracycline. It is advisable to constantly use the same method.
The risk of developing congestive heart failure, which is about 1-2% when using a cumulative dose of 300 mg / m 2 , increases slowly until a cumulative dose of 450-550 mg / m 2 is reached, after which a sharp increase in risk is noted. In this regard, the maximum cumulative dose should not exceed 550 mg / m 2 .
Heart function monitoring should be particularly severe in patients receiving high cumulative doses of the drug and in patients with risk factors for increased cardiotoxicity. However, cardiotoxicity may also develop with lower cumulative doses of doxorubicin, regardless of the presence of risk factors.
Children and adolescents are at increased risk of developing late cardiotoxicity of doxorubicin. In women, this risk may be higher than that of men.
The toxicity of doxorubicin and other anthracyclines or anthracendones is probably additive.
Like other cytotoxic agents, doxorubicin can cause myelosuppression. A general blood test, including the leukocyte formula, should be performed before and during each treatment cycle with doxorubicin. Dose-dependent reversible leukopenia and / or granulocytopenia (neutropenia) are the main manifestation of hematological toxicity of doxorubicin and the most frequent sign of acute toxicity, which limits the dose of the drug. Leukopenia and neutropenia in most cases reach a maximum severity 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, sepsis / septicemia, septic shock, bleeding, tissue hypoxia, or death.
Patients who received anthracyclines, including doxorubicin, described cases of secondary leukemia with or without the preleukemic phase. Secondary leukemia is more common in the use of these drugs in combination with other anticancer agents that cause DNA damage, radiation therapy and in patients receiving intensive previously cytotoxic anthracycline therapy or at high doses. Secondary leukemias can have a latency period lasting 1-3 years.
Mucositis / stomatitis usually develops shortly after drug administration, and in severe cases for several days can lead to ulceration of the mucosa. Most patients recovered from these adverse events to the third week of therapy.
Prior to and during therapy with patients need to monitor liver function tests (total bilirubin level in blood serum). Patients with elevated bilirubin may slow drug clearance and increased systemic toxicity. At the first signs of doxorubicin extravasation (burning or pain at the injection site) infusion should be stopped immediately, and then resume the infusion to another vein until a full dose; locally to carry out activities to address the consequences of extravasation. It is advisable to use ice packs.
Strict adherence to the instructions for use of the drug makes it possible to minimize the risk of phlebitis / thrombophlebitis at the injection site.
The intravesical drug application, special attention should be given to the states, which create obstacles to the catheterization (eg, urethral obstruction due to massive bladder tumors).
In applying doxorubicin due to rapid lysis of tumor cells can be observed hyperuricemia, and therefore the patients during therapy to determine the level of uric acid, potassium, calcium and creatinine in the blood. Events such as hydration, alkalinisation and prophylaxis with allopurinol to prevent hyperuricemia minimize the risk of complications associated with tumor lysis syndrome.
In women, doxorubicin may cause infertility and amenorrhea. Ovulation and menstruation usually recover after cessation of treatment, although it is possible onset of early menopause.
In men, doxorubicin is mutagenic effects and may cause damage to sperm chromosomes. Oligospermia or azoospermia may be irreversible, although in some cases there is recovery of sperm, sometimes several years after the cessation of treatment.
Men and women receiving therapy with adriblastin В® instant, should use reliable methods of contraception.
When working with the preparation 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 and water or sodium bicarbonate; if it hits the eye - to pull eyelids and producing lavage eye (s) with water for at least 15 minutes.
Acute overdosage of doxorubicin may lead to the development of severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects on the gastrointestinal tract (mainly mucositis) and cause acute heart disease.
The antidote for doxorubicin is not known. In case of overdose, symptomatic treatment is recommended.
In the application of doxorubicin in combination with other cytotoxic agents may be a manifestation of toxicity of the additive, especially a bone marrow / blood system and gastrointestinal tract. In the application of doxorubicin in combination with other potentially cardiotoxic chemotherapeutic agents, and cardiovascular drugs (e.g., calcium channel blockers) necessary to control the function of the heart. acute hemorrhagic cystitis cases have been described caused by cyclophosphamide, and increased hepatotoxicity 6-mercaptopurine. Doxorubicin may potentiate radiation-induced toxic effects on the myocardium, mucous membranes, skin, and liver. Changes in the liver caused by concomitant therapy may affect the metabolism, pharmacokinetics, therapeutic efficacy and / or toxicity of doxorubicin.
Administration of paclitaxel to doxorubicin may lead to increased plasma concentrations of doxorubicin and / or its metabolites in plasma. This effect is minimal when doxorubicin is used to paclitaxel.
Doxorubicin should not be mixed with other drugs. Do not allow contact with alkaline solutions because this can lead to hydrolysis of doxorubicin. Because of chemical incompatibility doxorubicin can not be mixed with heparin (by mixing a precipitate formed).
TERMS OF RELEASE FROM PHARMACY