Treatment of many cancerous conditions, including breast cancer and stomach cancer. A beneficial effect of intravesical epirubicin in the treatment of papillary bladder carcinoma from transient epithelial cells, pre-invasional carcinoma (in situ) of the bladder, in the prophylaxis of recurrences of superficial bladder cancer after transurethral resection.
Composition:
1 ml contains 2 mg epirubicin hydrochloride. The drug contains sodium (3.54 mg / ml).
Action:
A cytostatic agent from the group of anthracycline antibiotics. The mechanism of action of epirubicin is related to its ability to bind to DNA. Studies on cell cultures have shown rapid cell penetration, localization in the cell nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has been shown to be effective in a broad spectrum of experimental cancers, such as L1210 and P388 leukemia, SA180 sarcomas (solid and ascites), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colorectal cancer 38. Epirubicin has also been shown to be effective against human cancers (melanoma, cancer of the mammary gland, lungs, prostate and ovarian) transplanted so-called naked mice with a lack of thymus. In patients with normal liver and kidney function, after an intravenous injection of 60-150 mg / m2 drug, its plasma concentration changes in accordance with the decreasing three-exponential function with a very fast first phase and a slow final phase, with a medium T0,5 approximately 40 h. These doses are within the pharmacokinetic linearity in both the plasma clearance value and the metabolic pathway. At doses between 60 and 120 mg / m2 pharmacokinetics have a linear characteristic, whereas a dose of 150 mg / m2 is on the edge of the dose linearity. The main metabolites identified so far are: epirubicinol and epirubicin and epirubicinol glucuronides. In pharmacokinetic studies in patients with cancerin situ urinary bladder was found to have low serum concentrations of epirubicin (<10 ng / ml) after bladder administration. Therefore, no significant absorption of the drug and its systemic effect can be assumed. However, greater absorption of the drug may be expected in patients with damaged bladder mucosa (eg due to cancer, cystitis or surgery). Epirubicin is eliminated mainly by the liver; high plasma clearance values (0.9 l / min) indicate that slow elimination is caused by wide drug distribution in tissues. Approx. 9-10% of the administered dose is excreted in the urine within 48 hours. Approx. 40% of the administered dose is recovered from the bile within 72 h. Epirubicin does not cross the blood-brain barrier.
Contraindications:
Hypersensitivity to the active substance or to any of the excipients, and other anthracyclines or anthracenediones. Breast-feeding. Intravenous use: permanent bone marrow suppression; significant bone marrow depression as a result of previous treatment with other anticancer medicines or radiotherapy of the pericardial part of the mediastinum and / or in patients undergoing treatment with potential cardiotoxic agents; treatment with maximum cumulative doses of epirubicin and / or other anthracyclines (e.g., doxorubicin or daunorubicin) or anthracenediones; heart failure and current or history of myocardial infarction; acute systemic infection; severe liver problems; severe arrhythmia; unstable angina; cardiomyopathy. Intravesical administration: urinary tract infection; invasive tumors penetrating the walls of the bladder; problems with catheterization; cystitis; hematuria.
Precautions:
Treatment with epirubicin can only be initiated after acute toxicity symptoms resulting from previous cytotoxic treatments (such as stomatitis, mucous membranes, neutropenia, thrombocytopenia and generalized infections). Although treatment with high doses of epirubicin (eg ≥90 mg / m2 every 3 or 4 weeks) causes side effects generally similar to those seen after the standard doses (<90 mg / m2 every 3 or 4 weeks), however, the severity of neutropenia and oral mucositis may be higher. Treatment with high doses of epirubicin requires special attention due to the possibility of clinical complications due to severe bone marrow suppression. Cardiotoxicity is a risk associated with anthracycline treatment, the symptoms of which may appear as early (ie acute) or late (ie delayed) side effects. Early cardiotoxicity of epirubicin mainly includes sinus tachycardia and / or electrocardiogram (ECG) abnormalities such as non-specific ST-T changes, but tachyarrhythmia, including premature ventricular contraction, ventricular tachycardia, as well as bradycardia, atrioventricular block, and bundle branch block - these symptoms do not always indicate the occurrence of delayed cardiotoxicity, are rarely of clinical significance and are usually transient, reversible and do not prompt treatment discontinuation of epirubicin. Time-delayed cardiotoxicity usually appears in the later phase of treatment with epirubicin or within 2-3 months after discontinuation of treatment, but later symptoms have also been observed (from several months to several years after discontinuation of treatment). The symptom of delayed cardiomyopathy is a reduction in left ventricular ejection fraction (LVEF) and / or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary edema, orthostatic edema, enlargement of the heart and liver, oliguria, ascites, pleural effusion and gallium rhythm. Life-threatening congestive heart failure is the most severe form of anthracycline-induced cardiomyopathy and is a toxic effect of the drug that limits the maximum cumulative dose. The risk of developing CHF increases rapidly with an increase in the total cumulative dose of epirubicin exceeding 900 mg / m2; if cumulative dose is exceeded, special care should be taken. To reduce the risk of severe heart failure, assess its effects before starting treatment with epirubicin and monitor throughout treatment. After first symptoms of cardiac dysfunction, treatment should be stopped immediately. Adequate quantitative repetitive heart rate assessment (LVEF assessment) includes multidrug angiography using a radionuclide (MUGA) and echocardiography (ECHO). Initial evaluation of cardiac function with ECG examination and MUGA or ECHO examination is recommended, especially for patients with agents that increase the risk of cardiotoxicity. The LVEF assessment should be repeated in MUGA or ECHO studies, especially when the cumulative anthracycline dose increases. Evaluation of cardiac function should be carried out with the same method of examination throughout the observation period. Anthracycline-induced cardiomyopathy is associated with a permanent reduction in the amplitude of the QRS complex, with the extension beyond the normal intervals of contraction intervals (PEP) and the reduction of the ejection fraction (LVET). Although ECG changes may be an indicator of cardiomyopathy caused by anthracyclines, ECG is not a sensitive or specific method to determine cardiac toxicity associated with anthracyclines. The factors that increase the risk of cardiotoxicity are: active or asymptomatic heart disease, previous or simultaneous radiotherapy of the mediastinal area, previous treatment with other anthracyclines or anthracenediones and the concurrent use of other drugs that impair cardiac function or cardiotoxic drugs (eg trastuzumab). However, cardiotoxicity following the use of epirubicin may occur at lower cumulative doses, regardless of the presence of risk factors. Probably the toxicity of epirubicin and other anthracyclines or anthracenediones is added together. Epirubicin may cause bone marrow suppression - haematological tests should be performed before each treatment cycle with epirubicin, including the white blood cell count (WBC) with an interest formula. Dose-dependent, reversible leukopenia and / or granulocytopenia (neutropenia) are the most common dose-limiting acute haematological toxicities of epirubicin. Leukopenia and neutropenia are generally more pronounced after using regimens with high doses of epirubicin. Nadir leucopenia and neutropenia usually occur between 10 and 14.one day after administration of epirubicin, this effect is usually transient, and the number of leukocytes / neutrophils returns in most cases to normal values around the 21st day. The clinical consequences of severe bone marrow suppression may be fever, infection, sepsis / sepsis, septic shock, bleeding, tissue hypoxia or death. The total serum bilirubin and ASAT serum concentrations should be evaluated before initiation of treatment with epirubicin and during treatment. In patients with elevated bilirubin or AST, the clearance of the drug may be lowered and its overall toxic effect more pronounced; a dose reduction is recommended in such patients. The serum creatinine should be determined before and during treatment. In patients with a creatinine concentration> 5 mg / dl, a dose adjustment is necessary. If signs or symptoms of extravasation occur during intravenous administration of epirubicin, treatment should be discontinued immediately. Epirubicin may cause hyperuricaemia as a result of the severity of purine catabolism accompanying the rapid breakdown of tumor cells following the action of the drug (tumor lysis syndrome). After the initial treatment, the concentration of uric acid, potassium, Calcium phosphate and creatinine in the blood should be assessed. In order to limit the potential complications of the tumor lysis syndrome, the patient should be irrigated, the urine should be alkalinized and hyperuricemia should be prevented by administering allopurinol. There are no data on the safety and efficacy of epirubicin in children.
Pregnancy and lactation:
As part of tumor chemotherapy, epirubicin in pregnant women and in women of childbearing age can only be used if the benefits of treatment outweigh the potential risk to the fetus. Studies have not been conducted in pregnant women. Experimental data from animal studies indicate that epirubicin given to a pregnant woman can cause fetal damage. Genetic consultation should be considered if the patient became pregnant during treatment with epirubicin. However, it is not known whether epirubicin is excreted in breast milk. Because many medicines, including other anthracyclines, are excreted in breast milk and because of the potential for epirubicin to cause serious adverse reactions in a child, the mother should discontinue breast-feeding before using this medicine. Epirubicin may cause genotoxicity. Men and women being treated with epirubicin should use appropriate contraceptive measures. Epirubicin may cause chromosomal damage in human sperm. Men should seek advice on the possibility of storing sperm due to possible infertility caused by the treatment. Epirubicin may cause a lack of menstruation or premature menopause in women before menopause.
Side effects:
Very common: bone marrow suppression (leukopenia, granulocytopenia and neutropenia, anemia and febrile neutropenia); baldness (usually reversible); red urine for 1-2 days after drug administration. Common: infection; mucositis, which may appear 5-10 days after the start of treatment and is usually associated with the occurrence of stomatitis, painful erosions, ulceration and bleeding, mainly on the tongue and sublingual mucous membrane of the esophagus, oesophagitis, vomiting, diarrhea, nausea ; redness along the vein to which the drug is administered, induration of veins, local pain and tissue necrosis (after accidental administration of the drug outside the vein); bladder inflammation, in some cases haemorrhagic, was observed after intravesical administration. Uncommon: thrombocytopenia; thrombophlebitis. Rare: acute lymphocytic leukemia, secondary myeloid leukemia with or without pre-leukemic phase in patients who have been treated with epirubicin in combination with DNA-damaging antineoplastic agents (these leukemias have a latent period of 1-3 years); anaphylaxis; hyperuricemia; dizziness; cardiotoxicity (ECG changes, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure - shortness of breath, enlargement of the liver, ascites, pulmonary edema, fluid in the pleura, galloping heart rhythm); ventricular tachycardia, bradycardia, atrioventricular block, branch bundle branches); hives; lack of menstruation, azoospermia; bad mood, weakness, fever (including very high), chills, dizziness; increase in aminotransferases.Not known: septic shock, sepsis, pneumonia; bleeding and tissue hypoxia resulting from myelosuppression; conjunctivitis, keratitis; shock, thromboembolism, including pulmonary embolism; local toxic effects, rash, pruritus, skin changes, erythema, redness, discoloration of the skin and nails, hypersensitivity to light, hypersensitivity to irradiated skin; asymptomatic reduction of the left ventricle ejection fraction.
Dosage:
Intravenously. Adults. Do not exceed the total cumulative dose of epirubicin of 900-1000 mg / m2 pc. Monotherapy: usually 60-90 mg / m2 pc. by injection for 3-5 min every 21 days depending on the haematological parameters and bone marrow function in the patient. If signs of toxicity appear, such as neutropenia / febrile neutropenia and thrombocytopenia (which may also be present at day 21), a dose adjustment or delay in the Next dose may be required. High doses: small cell lung cancer (previously untreated) - 120 mg / m2 pc. on day 1, every 3 weeks; breast cancer as part of adjuvant treatment of patients with early breast cancer and lymph node involvement - 100 mg / m2 (as a single dose of the first day of therapy) up to 120 mg / m2 (divided into 2 doses on day 1 and day 8) every 3-4 weeks in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen. In patients with bone marrow disorders due to prior chemotherapy or radiotherapy, older age or cancer of the bone marrow, smaller doses (60-75 mg / m2 in conventional dosage and 105-120 mg / m2 in high dosage). You can divide the total dose of one treatment cycle by giving partial doses for 2-3 consecutive days. In high-dose treatment, epirubicin may be administered as an intravenous injection over 3-5 minutes or as an infusion lasting up to 30 minutes. Combination treatment: the dose of epirubicin should be reduced accordingly when used with other cytotoxic agents - advanced ovarian cancer: 50-100 mg / m2; stomach cancer: 50 mg / m2. In the treatment of small cell lung cancer, the dose should be as in monotherapy (120 mg / m2). Patients with impaired liver function: the dose should be reduced depending on the concentration of bilirubin - bilirubin 1.4-3.0 mg / 100 ml: 50% of the normal dose; > 3.0 mg / 100 ml: 25% of the normal dose. It should be given by injection into a vein lasting not less than 3-5 minutes or by intravenous infusion with 0.9% sodium chloride, 5% glucose. intravesically. Surface cancer of the bladder: 8 infusions of 50 mg / 50 ml (physiological saline or water for injections) at weekly intervals; in the event of local toxicity, a dose reduction of 30 mg / 50 ml is recommended. Cancerin situ: increase the dose to 80 mg / 50 ml (depending on individual patient tolerance). Preventive recurrence of bladder surface cancer after transurethral excision: 4 infusions of 50 mg / 50 ml at weekly intervals, followed by 11 infusions at monthly intervals at the same dose. The solution should be kept in the bladder for 1-2 h. To prevent unwanted dilution by urine, patients should not be allowed to drink fluids for 12 h before the solution is introduced. The patient with bladder should be rotated from time to time and he should urinate at the end of the procedure.
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