The mechanism of action buy andriol buy andriol is a recombinant humanized monoclonal antibody that selectively interact with the responsible for the dimerization of the extracellular subdomain II HER2 (receptor human epidermal growth factor type 2). Binding of buy andriol to the subdomain II process blocks ligand-dependent heterodimerization of HER2 with other HER family of proteins, including EGFR (receptor human epidermal growth factor), HER3 (receptor human epidermal growth factor type 3) and HER4 (receptor human epidermal growth factor 4- type). Thus, buy andriol inhibits ligand-initiated intracellular signaling transfer in two major signaling pathways: pathway-mitogen activated protein kinase (MAP) and the path of phosphoinositide 3-kinase (PI3K). Inhibition of the signaling data paths can lead to cell growth arrest and apoptosis, respectively. In addition, buy andriol promotes activation of antibody-dependent cellular cytotoxicity (ADCC). The molecular weight of buy andriol is about 148 kDa, and it is expected that, like other monoclonal antibody buy andriol practically it does not pass through the barrier gemagoentsefalichesky. buy andriol as monoagenta inhibits proliferation of human tumor cells. The enhancing antitumor activity of buy andriol at xenograft models with HER2 overexpressing when used in combination with trastuzumab. Trastuzumab Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively interact with the extracellular domain of the human epidermal growth factor type 2 (HER2) receptor. These antibodies are IgG 1consisting of human regions (constant regions of heavy chains) and complementarity determining murine portions antibody p185 HER2 by HER2. Proto-oncogene HER2, or c-erV2 encodes transmembrane retseptoropodobny protein with a molecular mass of 185 kDa, which is structurally similar to other members of the family of epidermal growth factor receptors. Overexpression of HER2 is found in breast cancer (BC) in 25-30% of patients with primary cancer tissue and tissue advanced gastric cancer in 6,8-42,6% of patients. Amplification of the HER2 gene results in HER2 protein overexpression on the membrane of tumor cells, which in turn causes a permanent activation of HER2 receptor. Studies have shown that breast cancer patients who have marked am amplification or overexpression of HER2 in tumor tissues, have lower survival without signs of disease as compared to patients without amplification or overexpression of HER2 in tumor tissue. trastuzumab blocks the proliferation of human tumor cells overexpressing HER2 in vivo and in vitro . in vitro antibody-dependent cellular cytotoxicity trastuzumab predominantly aimed at tumor cells overexpressing HER2. Immunogenicity buy andriol Approximately 6 2% of patients who received trastuzumab in combination therapy with docetaxel, and 2.8% of patients who received trastuzumab in combination with docetaxel and buy andriol were found antiterapevticheskie antibody (ATA). Communication antibody formation to buy andriol development of anaphylaxis / hypersensitivity reactions was not reliably installed in any of the patients. Trastuzumabantibodies trastuzumab were detected in one of 903 patients with breast cancer treated with drug alone or in combination with chemotherapy, and the phenomenon of allergy on trastuzumab her absent.Comparison frequency detection antibody buy andriol and trastuzumab, and the frequency of detection of antibodies to other biologicals may be uninformative because of the immunogenicity of analysis greatly depend on various factors such as the sensitivity and specificity of the assay, the methodology Ia analysis, manipulation pick up samples, sampling time, concomitant medications, and the nature of the underlying disease.
Pharmacokinetics buy andriol studied pharmacokinetics after intravenous administration of buy andriol (w / w) at various doses (from 2 to 25 mg / kg) in patients with different types of tumors. Clearance buy andriol did not depend on the dose and indication. The pharmacokinetic parameters are independent of age, gender and ethnicity (Japanese and other ethnic groups). The initial albumin concentration and the amount of “lean body mass” (a quantity that characterizes body weight minus fat mass) have little effect on the clearance of buy andriol, the need for dose adjustment of buy andriol, depending on the initial concentration of albumin or no weight. Suction buy andriol entered in / in. Other routes of administration have not been studied. Distribution After the on / in the volume of distribution in the central chamber (the V c ) was 3.07 l and is approximately equal to plasma volume. The values of V c , and the volume of distribution at equilibrium buy andriol (V ss ) indicate that the distribution takes place only in the plasma and extracellular fluid. Metabolism Metabolism buy andriol was not studied. Like other antibody buy andriol advantageously subjected catabolism. Withdrawal clearance of buy andriol is approximately 0.239 l / day half-life (T ½ ) is approximately 17.2 days. Trastuzumab When administered drug in the form of short intravenous infusion at a dose of 10, 50, 100, 250 and 500 mg once a week wore pharmacokinetics nonlinear. With increasing doses of the drug decreased clearance. The half-life The half-life of 28-38 days, therefore, the period of removal after the drug -. To 27 weeks (190 days or 5 half-lives) pharmacokinetics of trastuzumab on the background of the equilibrium state of equilibrium state should be achieved after approximately 25 weeks. if you are using a population pharmacokinetic method (two-chamber model, model-dependent analysis) assessment of these studies phase I, II of phase and phase III trial in metastatic breast cancer, the median expected area under “concentration-time” curve (AUC) at steady state after 3 weeks was 1677 day * mg / l after 3 doses (2 mg / kg) weekly and 1,793 mg per day * / l when administered 3 weeks in a dose of 6 mg / kg. The calculated median maximum concentration (C max ) reached 104 mg / l and 189 mg / l, and the minimum concentration (C min ) – 64.9 mg / l 47.3 mg / l, respectively. When using model-independent or “nekamernogo” analysis method (pop-compartmental analysis, NCA) average the C min at steady state to 13 cycle (37 weeks) was 63 mg / L in patients with early-stage breast cancer treated with trastuzumab at a loading dose of 8 mg / kg, followed by a maintenance of 6 mg / kg, after 3 weeks, and was comparable to that of patients with MBC who received trastuzumab weekly. clearance typical clearance trastuzumab (for a patient of 68 kg body weight) was 0.241 l / day. volume distribution in all clinical studies, volume of distribution in the central chamber (the V c ) was 3.02 l in the peripheral (the V p ) – 2.68 liters for a typical patient.The circulating extracellular domain of the receptor HER2- ( “exfoliated” cells with antigen) in the serum of some patients breast cancer and HER2 overexpression is found circulating extracellular domain of the receptor HER2- ( “exfoliated” cells with antigen). In 64% of patients studied in baseline serum samples detected “exfoliated” cells with antigen at a concentration that reached 1880 ng / mL (median 11 ng / ml). Patients who had a high level of “exfoliated” cell antigen concentration, could probably have lower Cm; n. However, most patients with elevated levels of “exfoliated” antigen cells upon administration of the drug weekly target concentration of trastuzumab in the serum reaches to 6 weeks. No significant relationship between the original “exfoliated” level of antigen cells and clinical response was observed.Pharmacokinetics in special patient groups buy andriol patients elderly Advanced studies pharmacokinetics of buy andriol in elderly patients ( > 65 years) and elderly ( > 75 years) of age was conducted.As a result of the analysis of the age of the population has no impact on the pharmacokinetic parameters of buy andriol. Patients with renal impairment Specific studies of pharmacokinetics of buy andriol in patients with renal impairment have been conducted. According to the results of population analysis mild renal insufficiency (creatinine clearance (CC) of 60-90 mL / min), moderate (creatinine clearance 30-60 ml / min) and severe (creatinine clearance <30 mL / min) no effect on the exposure of buy andriol. Data for patients with moderate to severe renal insufficiency is limited. Patients with impaired liver functionstudy of the pharmacokinetics of buy andriol in patients with impaired liver function nonconductive. Trastuzumab Advanced Studies pharmacokinetics of trastuzumab in patients elderly and patients with renal or hepatic impairment have not been carried out. Elderly patients and old age has no effect on the distribution of trastuzumab.
Metastatic or locally recurrent, unresectable breast cancer with HER2-positive tumor in combination with docetaxel in the absence of prior therapy or disease progression after adjuvant therapy.
Hypersensitivity to buy andriol, trastuzumab, benzyl alcohol, or any auxiliary substance, a part of Beyodaym set of components ® .
Pregnancy and lactation.
Children under 18 years of age (efficacy and safety have not been established).
Ejection fraction of the left ventricle of the heart ( LVEF) before treatment < 50%.
Congestive heart failure in history. Uncontrolled hypertension.
Recently, myocardial infarction.
Severe cardiac arrhythmia requiring medication at the time of appointment set Beyodaym ® , with the exception of atrial fibrillation and paroxysmal supraventricular tachycardia.
Previous treatment with anthracyclines with a cumulative dose of doxorubicin or equivalent preparation> 360 mg / m 2 .
abnormal liver function (efficacy and safety have not been studied).
Severe shortness of breath at rest, caused by metastases to the lungs or requiring maintenance therapy with oxygen.
Reduced LVEF to <50% on the prior adjuvant therapy with Herceptin ® values of LVEF <55%; previous treatment with cardiotoxic medicaments including anthracycline / cyclophosphamide or prior radiation therapy to the chest area; coronary heart disease, hypertension, heart failure, lung disease or concomitant metastases to the lungs; conditions that can disrupt the function of the left ventricle; renal dysfunction.
Use during pregnancy and during breastfeeding
Women have reproductive potential, and women of childbearing age who are sexual partners of patients treated with kit components Beyodaym ® , during treatment and for at least 6 months after the end of treatment must use reliable methods of contraception.
Must notify women about in the case of pregnancy possible adverse effects on the fetus. If a pregnant woman continue to receive treatment, first it has to be under the close supervision of doctors of different specialties.
Breastfeeding is not recommended during treatment and for at least 6 months after completion of therapy.
The effect of the drug Pereta on fertility has not been studied. The results of experiments in animals showed no evidence of impaired fertility.
It is not known whether Herceptin affects ® on the reproductive ability of women. The results of experiments in animals showed no evidence of impaired fertility or the adverse effects on the fetus.
Dosing and Administration
Before beginning treatment components set Beyodaym ® is necessary to conduct tests on the tumor expression of HER2. Essential criteria a score of 3+ on the results of immunohistochemistry (IHC) and / or the degree of amplification of > 2.0 as a result of hybridization in situ conservation (the ISH). You must use accurate and validated test methods. Detailed instructions for the HER2-testing and interpretation of the results are given in the instructions for use of validated test systems for determining HER2 status. The kit components Beyodaym ® (PeretaPereta ® and Herceptin ® ) is administered only intravenously! Introducing a set of components Beyodaym ® intravenous bolus or bolus can not be! Components in this kit Beyodaym ® (Pereta ® and Herceptin ® ) can be administered in any order. After each infusion Pereta ® and before the introduction of the drug Herceptin 5 or docetaxel observation of the patient is recommended for 30-60 minutes. Docetaxel should enter after the introduction of a set of components Beyodaym ® . Dosage Peretad ® (buy andriol) – component №1 duration of infusion when administered the first dose should be 60 minutes. If the first infusion is well tolerated, subsequent may be carried over 30-60 minutes. Loading dose of the drug Pereta ® – 840 mg in a 60-minute intravenous drip infusion. Maintenance dose preparation Pereta ®– 420 mg every 3 weeks as an intravenous drip infusion for 30-60 minutes. Maintenance dose is administered 3 weeks after the loading. Gertseptyn ® (trastuzumab) – №2 component loading dose of the drug Herceptin – 8 mg / kg of body weight in a 90-minute intravenous drip infusion. The maintenance dose of the drug Herceptin ® – 6 mg / kg body weight every 3 weeks as an intravenous drip infusion over 30-90 minutes. The maintenance dose is administered 3 weeks after the loading. If prior loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion. Dopetaksel When used in combination with a set Beyodaym ® recommended initial dose of docetaxel is 75 mg / m 2 as an intravenous infusion, then the drug should be administered in the same dose every 3 weeks. With good endurance in the first cycle of docetaxel dose can be increased to 100 mg / m 2 in subsequent cycles. Duration of treatment Treatment should be continued until evidence of disease progression or unacceptable toxicity. Skip to the planned introduction of Pereta ® (buy andriol) – component №1 If a break routinely administered drug Pereta ® was less than 6 weeks, it can be used to introduce a drug at a dose of 420 mg as a 30-60-minute intravenous drip infusion, without waiting for the next scheduled administration. If the break in the introduction Pereta preparation ® was 6 weeks or more, it is necessary to introduce the drug in an initial dose of 840 mg as a 60 minute intravenous drip infusion. Then, after 3 weeks, continued administration of the drug at a maintenance dose of 420 mg every 3 weeks as a 30 -60-minute intravenous infusion. Herceptin ® (trastuzumab) – №2 component If a break in the planned introduction of the drug Herceptin ® was less than 6 weeks, should the drug can be used to introduce a dose of 6 mg / kg, without waiting for the next scheduled injection. If a break administering the drug Herceptin ® was 6 weeks or more, the drug should enter a loading dose of 8 mg / kg by intravenous drip infusion lasting about 90 minutes. Then, after 3 weeks, continued administration of the drug at a maintenance dose of 6 mg / kg every 3 weeks. Correction dose Reduced dose of each component is not recommended. In the case of treatment with one of Beyodaym kit components ® revoked, the application of another Beyodaym kit component ® should also cancel. In the period of occurrence of reversible myelosuppression caused by chemotherapy, therapy kit components Beyodaym ® may be continued, subject to careful monitoring of complications arising from neutropenia. Notes on the docetaxel dose modifications are provided in the medical application of docetaxel instructions. In case of cancellation of docetaxel treatment kit components Beyodaym ® can continue until disease progression or unacceptable toxicity. Left ventricular dysfunction therapy kit components Beyodaym ® should be suspended for at least 3 weeks in the following cases:
- decrease in LVEF to below 40%;
- LVEF values of 40-45% with a decrease in LVEF to > 10% in relation to the values observed before treatment.
Possible to resume treatment if the LVEF was restored to a level of> 45% or 40-45% with a decrease of <10% relative to the values observed before treatment. If according to the re-evaluation after 3 weeks LVEF does not increase or will it further reduction, treatment should be discontinued, unless the benefits for the individual patient is not greater than the risk. Infusion reactions Infusion should conduct a medical specialist with experience in the treatment of anaphylaxis, as well as access to the means to emergency relief. With the development of infusion reactions should be reduced infusion rate or time to stop the introduction. With the development of severe hypersensitivity reactions should immediately stop the infusion and the complete cessation of therapy. Specific guidance on dosing patients elderlydose adjustment kit components Beyodaym ® in elderly patients and in elderly patients is not required. patients with impaired renal function The efficacy and safety components Beyodaym dial ® in patients with impaired renal function have not been studied. patients with impaired hepatic function The efficacy and safety components set Beyodaym ® in patients with hepatic impairment have not been studied.child patients Efficacy and safety components set Beyodaym ® in children and adolescents under the age of 18 years have not been studied. Preparation of the solution for infusion kit components Beyodaym ® (Pereta ® and Herceptin ® ) should only be used in series. P azvedenie components necessarily be carried out in separate infusion bags! Pereta ® (buy andriol) – component №1 ! Attention drug Pereta ® is not compatible with 5% dextrose. Dilution in such a solution leads to chemical and physical instability buy andriol. The drug should be diluted only in 0.9% sodium chloride solution.The drug Pereta ® should not be mixed or diluted with other medicinal products. The solution of the drug Pereta ® is compatible with infusion bags made from polyvinylchloride (PVC), polyethylene, PVC and free of the polyolefin. Preparations for the introduction of the drug must be carried out under aseptic conditions. Pereta ® (buy andriol) contains antimicrobial preservatives. Therefore precautions should be taken to maintain sterility of the prepared solution for infusions. From bottle (bottles) should be selected, and the entire liquid concentrate enter it in the infusion bag with 250 ml of 0.9% sodium chloride solution. Final solution concentration is approximately 3.36 mg / ml (840 mg / 250 ml) for loading and 1.68 mg / ml (420 mg / 250 ml) to a maintenance dose. Then the infusion package Carefully invert the stirring solution while avoiding foaming . Before the introduction of the drug should be checked (visually) for mechanical impurities and discoloration. The solution for infusion is administered immediately after preparation. In exceptional cases, the solution of the drug prepared Pereta ® can be stored for no longer than 24 hours at 2-8 ° C, if the solution for infusion occurred in controlled and validated aseptic conditions. At the same time due to storage conditions (the rules of storage and duration) responsible professionals ready solution. Herceptin ® (trastuzumab) – component №2 ! Attention Herceptin ® is not compatible with 5% dextrose solution because of the possibility of protein aggregation. Herceptin ® should not be mixed or diluted together with other drugs. a solution of the drug Herceptin ® compatible with infusion bags made of polyvinyl chloride, polyethylene and polypropylene. Preparation of the drug to the introduction should be conducted under aseptic conditions. Instructions for preparing the concentratecontents of the vial with the drug Herceptin ® dissolved in 20 ml supplied in the kit bacteriostatic water for injection containing 1.1% benzyl alcohol as an antimicrobial preservative. The result is a solution concentrate, suitable for multiple use, containing 21 mg of the drug Herceptin ® in 1 ml and having a pH of 6.0. At the time of dissolution should be handled carefully and with the drug. When dissolved to avoid excessive foaming, the latter may make it difficult to set the right dose of medication from the vial. 1. Sterile syringes slowly introduce 20 ml of bacteriostatic water for injection into the vial with 440 mg of the drug Herceptin ® , directing a jet of fluid directly to the lyophilisate. 2. To dissolve gently shake the bottle rotary motion. Do not shake! The dissolution of the drug is often a small amount of foam. To avoid this, you must give the solution stand for about 5 minutes. The prepared concentrate must be clear and colorless or have a light yellow color. The concentrate solution of the drug Herceptin ® , cooked in bacteriostatic water for injection, is stable for 28 days at 2-8 ° C. The prepared concentrate contains a preservative and therefore, can be used repeatedly. After 28 days, the unused balance of the concentrate should be destroyed. Do not freeze! As the solvent, the drug Herceptin ® allowed to use sterile water for injection (preservative-free). The use of other solvents is not rekomenduetsya.V case of using water as a solvent sterile injectable concentrate physically and chemically stable for only 24 hours at 2-8 ° C and should be discarded after this time. Do not freeze the Guide for the preparation of the solution infusion Determine concentrate volume: volume required for loading dose of the drug Herceptin ® , 8 mg / kg body weight, or maintenance doses of 6 mg / kg every three weeks is determined by the following formula:
|Volume (ml) =||body weight (kg) x dose ( 8 mg / kg loading or 6 mg / kg maintenance)|
|21 (mg / ml concentration of the prepared solution)|
From the concentrate vial should dial the appropriate volume and enter it into the infusion bag with 250 ml of 0.9% sodium chloride solution. Then the infusion bag should be gently invert to mix the solution and avoid foaming. Before the introduction of the solution should be checked (visually) for mechanical impurities and discoloration. The solution for infusion is administered immediately after preparation.
In exceptional cases, the solution for infusion may be stored for no more than 24 hours at 2-8 ° C unless dilution of concentrate and solution for infusion occurred in controlled and validated aseptic conditions.At the same time due to storage conditions (the rules of storage and duration) responsible professionals ready solution. The instructions for the destruction of unused drugs or medications that have expired Contact medicines into the environment should be minimized. Do not dispose of medicines via wastewater or with household waste. Destruction of unused medicines or drugs that have expired should be in accordance with the requirements of the facility. If possible, a special system for the disposal of drugs should be used.
The most common adverse reactions (observed in more than 50% of patients) associated with use of the drug Pereta ® in combination with the drug Herceptin ® and docetaxel were diarrhea, alopecia, and neutropenia.
The most frequently observed (> 10%) adverse reactions 3 4th degree tyazhe STI on the classification of the National cancer Institute National cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE), version 3, were neutropenia, febrile neutropenia and leukopenia.
The most severe and clinically relevant adverse reactions observed at a frequency of less than 10 % had left ventricular dysfunction, including symptomatic left ventricular systolic dysfunction (congestive heart failure).
As used combination of drugs is problematic precisely to establish a causal relationship between an adverse event and a particular drug. To describe the frequency of adverse reactions following classification is used: very common ( > 1/10), common ( > 1/100 and <1/10), uncommon ( > 1/1000 and <1/100), rare ( > 1/10000 and <1/1000) and very rare (<1/10000), including isolated cases. Violations of the blood and lymphatic system: very often – neutropenia, anemia, leukopenia, febrile neutropenia (including fatal). Violations immune system : very often – hypersensitivity / anaphylactic reactions, infusion reactions / syndrome, cytokine release. Violations of the metabolism and nutrition : very often – loss of appetite. mental Disorders : very often – insomnia. Disorders of the nervous system : very often – peripheral neuropathy, headache, dysgeusia (distortion of taste sensations), dizziness. Violations of the organ of vision : very often – increased tearing. Violations of the heart : often – left ventricular dysfunction, including congestive heart failure. Disorders of the respiratory system of the chest and mediastinal disorders : often – shortness of breath, cough; often – pleural effusion; rarely – interstitial lung disease.Violations of the gastrointestinal tract : often – diarrhea, nausea, vomiting, constipation, stomatitis, dyspepsia. Violations of the skin and subcutaneous tissue disorders : very often – alopecia, rash, pathology nails, itching, dryness leather; often – paronychia. Violations of the musculoskeletal and connective tissue disorders : very often – myalgia, arthralgia. General disorders and at the injection site: very often – fatigue, asthenia, peripheral edema, inflammation of the mucous membranes of various localization, pain, fever body connection of secondary infections (upper respiratory tract infection, nasopharyngitis);often -. chills After the cancellation of docetaxel all adverse reactions were observed less frequently (<10%, with the exception of diarrhea, upper respiratory tract infections, rash, headache and fatigue (> 10%)). Infusion reactions, hypersensitivity / anaphylaxis reactions Any adverse reaction, the development of which occurred during the infusion or IV infusion day, were assigned to infusion reactions. After administration of the drug only Pereta ® majority of infusion reactions were mild or moderate and occurred in approximately 20% of patients. The most common infusion reactions (> 1.5%) were nausea, fever, diarrhea, chills, fatigue and headache. After a time (one day) administration Pereta ® , the drug Herceptin ® and docetaxel starting from the second cycle of therapy most frequent (> 1.5%), infusion reactions were alopecia, nausea, decreased appetite, fatigue, constipation, diarrhea, stomatitis, and drug hypersensitivity. The overall incidence of the phenomena of hypersensitivity / anaphylaxis was 9.1% on the same time (in one day) administration of the drug Herceptin and docetaxel and 10.8% after simultaneous administration Pereta ® , the drug Herceptin ® and docetaxel; of these phenomena 2.5% and 2% were characterized by the 3rd and 4th degrees of severity classification NCI-CTCAE, version 3, respectively. A total of 2 patients after co-administration of the drug Herceptin ® and docetaxel, and in 4 patients after simultaneous administration Pereta ® , the drug Herceptin ® and docetaxel developed anaphylaxis. Most hypersensitivity reactions were mild or moderate and resolved after appropriate treatment.According to the analysis of hypersensitivity reactions when changing the dosing regimens of drugs, found that the effects have been associated with hypersensitivity infusion of docetaxel. Abnormal laboratory values incidence reduction in the number of neutrophils 3-4th severity classification NCI-CTCAE, version 3, was about same with the combination of the drug Herceptin ® and docetaxel simultaneously with the preparation Pereta ® without it. The following are adverse reactions reported with the use of the drug Herceptin ® for all approved indications in the modes other than the mode of application set Beyodaym ® in combination with docetaxel . The drug Herceptin ® is often used in combination with chemotherapeutic agents, as well as after the completion of radiation therapy, so the definition of causation of adverse reactions to one of the drugs / radiation therapy difficult. currently, the most serious and / or common adverse reactions of reported using the drug Herceptin ® , are cardiotoxicity, infusion reactions hematotoxicity (in particular neutropenia) and disorders of the lung. the following classification is used to describe the rate of adverse reactions in this section: very often ( >10.1), often ( > 1/100, but <1/10), uncommon ( > 1/1000, but <1/100), rare ( > 1/10000, but <1/1000), very rare (<1/10000) not known (can not be calculated on the basis of available data). Within each group, adverse reactions are presented in accordance with a decrease in severity. The frequency is specified in accordance with the maximum met in basic clinical research. Infectious and parasitic diseases : often – pneumonia † (<1%), neutropenic sepsis, cystitis, Herpes zoster, infection, influenza, nasopharyngitis, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection, erysipelas, cellulitis; infrequently – sepsis. A obrokachestvennye, malignant neoplasms, and unspecified (including cysts and polyps): unknown – the progression of cancer, neoplasm progression. Violations of the blood and lymphatic system : very often – febrile neutropenia; often – anemia, neutropenia, thrombocytopenia, leukopenia; unknown -gipoprotrombinemiya. Violations of the immune system : often – a hypersensitivity reaction; unknown – anaphylactic reactions † , anaphylactic shock † . Violations of the metabolism : often – weight loss, anorexia; unknown – hyperkalemia. mental disorders : often – anxiety, depression, insomnia, abnormal thinking. Disorders of the nervous system : very often – tremor 1 , dizziness, headaches; often – peripheral neuropathy, paresthesia, muscle hypertonicity, somnolence, dysgeusia (distortion of taste perception), ataxia; rare – paresis; unknown -otek brain. Violations of the organ of vision : very often – conjunctivitis, increased tearing; often – dry eyes; unknown – swelling of the optic nerve, bleeding in the retina. Violations of the organ of hearing and labyrinth disorders :. infrequently – deafness Disorders of the cardiovascular system : very often – a decrease and increase in blood pressure (BP) 1 , irregular heartbeat 1 , serdtsebienie1, fibrillation (atrial or ventricular) 1 , reduction in left ventricular ejection fraction *, “tides”; often – heart failure (congestive) † (2%), supraventricular tachyarrhythmia † 1 cardiomyopathy, hypotension † 1 vasodilation; infrequently – pericardial effusion; unknown – cardiogenic shock, pericarditis, bradycardia, rhythm “gallop.” Disorders of the respiratory system, organs, thoracic and mediastinal disorders : very common – wheezing † 1 , dyspnoea † (14%), cough, epistaxis, rhinorrhea; often -bronhialnaya asthma, lung function, pharyngitis; infrequently – pleural effusion † ; rarely – pneumonitis; unknown – pulmonary fibrosis † , respiratory failure † , infiltration of the lungs † , acute pulmonary edema † , acute respiratory distress syndrome † , bronchospasm † , hypoxia †, hemoglobin desaturation oxygen † , laryngeal edema, orthopnea, pulmonary edema. Violations of the gastrointestinal -kishechnogo tract : often – diarrhea, vomiting, nausea, swelling of the lips 1 , abdominal pain; often – pancreatitis, indigestion, hemorrhoids, constipation, dry mouth Violations of the liver and biliary tract : often – hepatitis, pain in the liver, hepatocellular damage; rarely – jaundice; . unknown – liver failure Disorders of the skin and subcutaneous tissue disorders : very often – erythema, rash, swelling of the face 1 ; often – Acne, alopecia, dry skin, ecchymosis, rash, maculopapular rash, nail structure violation, itching; unknown – angioneurotic edema, dermatitis, urticaria. Violations of the musculoskeletal and connective tissue disorders : very often – arthralgia, muscle stiffness 1 , myalgia; often – arthritis, back pain, ossalgia, muscle spasms, pain in the neck. Violations of the kidney and urinary tract: often – kidney disease; unknown – membranous glomerulonephritis, glomerulonefropatiya, kidney failure. The effect on the course of pregnancy, postpartum and perinatal conditions : unknown – oligohydramnios, fatal pulmonary hypoplasia and hypoplasia of the kidneys in the fetus. Violations of the genital organs and the breast : often – an inflammation of the breast / mastitis. General disorders and injection site : very often – asthenia, chest pain, chills, fatigue, flu-like syndrome, infusion reactions, pain, fever; often – peripheral edema, malaise, mucositis, edema. Injury, poisoning and complications of manipulation : often – a bruise. † – adverse reactions, which in the messages associated with a fatal outcome. 1 – adverse reactions, which are mainly reported in association with infusion reactions ( the exact percentage of not installed). * – adverse reactions observed with combination therapy following anthracyclines and combined with taxanes. in parentheses is represented by the exact percentage rate for those terms, which were reported with fatal outcome with the frequency of “often” or “very often” . Percentage refers to the total number of these phenomena fatal without it. The following adverse reactions were reported in clinical studies with base frequency of > 10.1 therapy in any of the groups without significant difference between the treatment group containing trastuzumab and treatment group comparisons: lethargy, hypoesthesia, pain in the limbs, pain in the mouth and throat, conjunctivitis, lymphoedema, weight increase of Gela, onihoklaziya, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, epigastric pain, gastritis, stomatitis, vertigo, hypertension, hiccups, hand-foot syndrome, pain in the breast, onihoreksis, exertional dyspnea, and dysuria. The following provides information on selected adverse reactions. infusion reactions and hypersensitivity it is estimated that about 40% of patients treated with the drug Herceptin ® , experiencing infusion reaction in one form or another. However, the majority of infusion reactions were mild to moderate in severity (according to NCI-CTC) and tend to occur at the beginning of treatment, ie during the 1st, 2nd and 3rd infusions, occur less frequently in subsequent administrations. Reactions include (but are not limited to) the following symptoms: chills, fever, rash, nausea and vomiting, shortness of breath and headache. Severe anaphylactic reactions requiring immediate additional medical interventions are most likely to occur during the first or second infusion of Herceptin ® , such reactions have been associated with a fatal outcome. Kardiotoksichnost Cardiotoxicity (heart failure) II-IV functional class NYHA (classification of the New York Association Cardiology) is a common adverse reaction when using the drug Herceptin ® and associated with a fatal outcome. The 3 basic clinical studies of the drug Herceptin in combination with adjuvant chemotherapy, the frequency of cardiac dysfunction 3/4 degree (symptomatic congestive heart failure) was similar to that in patients receiving chemotherapy alone (i.e., without the drug Herceptin ® ), and in patients receiving taxane and drug Herceptin ® series (0.3-0.4%). Rates were highest in patients receiving Herceptin ~ together with the taxane (2.0%). Secure the continuation or resumption of therapy with Herceptin ® in patients experiencing cardiac events, has not been studied prospectively. However, the condition of most patients experiencing heart failure in basic research, improved in the appointment of standard therapy, which included beta-blockers and angiotensin converting enzyme inhibitors or angiotensin receptor blockers. The majority of patients with cardiac symptoms and evidence of a clinical benefit from trastuzumab continued therapy without incurring additional clinically significant cardiac events. Experience Gertseptin’8 use of the drug in combination with low-dose anthracycline regimes in the neoadjuvant therapy is limited. Hematological toxicity often occurs febrile neutropenia. Adverse reactions commonly encountered include anemia, leukopenia, neutropenia and thrombocytopenia. The frequency of occurrence of hypoprothrombinemia is not known. The risk of neutropenia may be slightly higher when using the drug Herceptin ® in combination with docetaxel after treatment with anthracyclines. Violations by the light With the application of the drug Herceptin ® associated severe adverse events in the lungs (including fatal). These reactions turn! in (but not limited to): pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory distress.
The maximum tolerated dose of the drug Pereta ® (buy andriol) is not installed. Single doses greater than 25 mg / kg (1727 mg) has not been studied.
In case of overdose should carefully monitor patients for signs or symptoms of adverse reactions and assigning an appropriate symptomatic treatment.
In clinical trials, cases of drug overdose Herceptin ® (trastuzumab) is not observed. The introduction of the drug Herceptin ® in single doses greater than 10 mg / kg have not been studied. Herceptin ® in doses of < 10 mg / kg was well tolerated.
Interaction with other drugs Pereta ® (buy andriol) No evidence of pharmacokinetic interaction between buy andriol with trastuzumab, docetaxel, gemcitabine, erlotinib, capecitabine has been detected.Herceptin ® (trastuzumab) Special studies of drug interactions drug Herceptin ® have not been conducted in humans. In clinical studies no clinically significant interactions with the same time use the drug (including doksorbitsin, paclitaxel, docetaxel, capecitabine, or cisplatin) were observed. The effect of trastuzumab on the pharmacokinetics of other antineoplastic drugs pharmacokinetic data obtained in women with HER2- positive metastatic breast cancer suggest that exposure paclitaxel and doxorubicin and their main metabolites (6-alpha gidroksipaklitaksel and doxorubicinol) does not change in the presence of trastuzumab when administered in a loading dose (8 mg / kg or 4 mg / kg / h), and then the maintenance dose (6 mg / kg every 3 weeks, or 2 mg / kg every week on / in). However, trastuzumab can increase the overall exposure of one of the metabolites of doxorubicin (7-deoxy-13-digidrodoksorubitsinon), the biological activity of the metabolite, and the clinical significance of increasing its exposure unknown . The data obtained in the study of the use of trastuzumab (4 mg / kg loading dose and 2 mg / kg once a week, I / O, in support) and docetaxel (60 mg / m 2 ) in Japanese patients with HER2- positive metastatic breast cancer, suggest that the simultaneous administration of trastuzumab did not affect the pharmacokinetics of a single administration of docetaxel. The results of the study of the pharmacokinetics of capecitabine and cisplatin when used in combination with trastuzumab or no in Japanese patients of both sexes with advanced gastric cancer suggest that exposure of biologically active metabolites of capecitabine (such as fluorouracil) did not change, while the use of cisplatin or cisplatin and trastuzumab. However shregistrirovany were higher concentrations of capecitabine and its longer half-life period in combination with trastuzumab. The data also indicate that the pharmacokinetics of cisplatin remained unchanged while capecitabine or capecitabine in combination with trastuzumab. The effect of anticancer drugs on the pharmacokinetics of trastuzumab When comparing simulated serum trastuzumab concentrations when monotherapy (loading dose 4 mg / kg and maintenance of 2 mg / kg every week / in) and trastuzumab concentrations when used in combination with docetaxel in Japanese patients with HER2- positive metastatic breast cancer no indication that the effect of docetaxel on the pharmacokinetics of trastuzumab is not found. a comparison of pharmacokinetic parameters in patients with HER2- positive patients metastatic breast cancer when used trastuzumab simultaneously with paclitaxel and trastuzumab monotherapy showed that individual and average minimum serum concentration of trastuzumab varied both within the same group, and between groups, but no obvious effect of simultaneous administration of paclitaxel pharmacokinetics trastuzumab was not observed. The combined use of anastrozole did not affect the pharmacokinetics of trastuzumab.
The patient’s medical records should indicate the trade name set Beyodaym ® . Replacing components of the kit (Pereta ® (buy andriol) or Herceptin ® (trastuzumab)) to any other similar biological medicinal products requires approval of the treating physician. The information provided in this manual applies only to the components of Pereta ® (buy andriol) and Herceptin ® (trastuzumab).
Treatment kit components Beyodaym ® should only be undertaken under the supervision of an oncologist.
Set Beyodaym8 should be applied only if there is a tumor overexpression of HER2, a specific immunological method histochemical reaction (IHC), or HER2 gene amplification as determined by hybridizationin situ conservation (of FISH or CISH). HER2 testing must be performed in a specialized laboratory, which can ensure quality control procedures treatment with drugs that block the activity of HER2, including drug Pereta ® , there was a decrease in LVEF. Use of the drug Pereta ® and the drug Herceptin ® in combination with docetaxel was not associated with an increased incidence of symptomatic left ventricular systolic dysfunction or reduced LVEF compared with only 8 drug Herceptin and docetaxel. However, in patients previously treated with anthracyclines or radiation therapy to the chest area, reducing the risk of left ventricular ejection fraction may be higher. The efficacy and safety of the drug Pereta ® have not been studied in patients with LVEF <5 0%; chronic heart failure history; when previously there was a decline in LVEF to a value < 50% in the adjuvant treatment of drug Herceptin ® ; in states that are able to break the left ventricular function, such as uncontrolled hypertension, recent myocardial infarction, severe cardiac arrhythmia requiring drug therapy or previous treatment with anthracyclines with a cumulative dose of doxorubicin or equivalent preparation> 360 mg / m 2 . LVEF should be evaluated before use of the drug Pereta ® and regularly (eg every 3 months) to determine during the treatment in order to ensure that LVEF is within the normal values established in the facility. If LVEF less than 40% or 40-45% with a decrease of> 10% from baseline to treatment, use of the drug Pereta ® and the drug Herceptin ® should be suspended. If the re-evaluation carried out in a period of approximately 3 weeks, no LVEF improve or will reduce it further, should consider the abolition of therapy with Pereta ® and drug Herceptin ® , unless it is decided that the benefits of applying for a particular patient the drug outweigh the risk. infusion reactions and hypersensitivity reactions When using Pereta drug ® may develop infusion reactions and hypersensitivity reactions. When administered Pereta preparation ® should carefully watch the patient during the first infusion and for 60 minutes after its completion, but also for subsequent infusion and 30 minutes after. With the development of clinically relevant reactions to infusion should slow infusion rate or interrupt it and undertake appropriate remedial measures. Careful observation of the patient and an assessment of its condition are recommended until complete resolution of symptoms.In patients with severe infusion reactions should assess the need for the full withdrawal of the drug Pereta ® based on the severity of observed responses, and the nature of the response to treatment, designated in connection with the unwanted reaction. Febrile neutropenia in patients receiving therapy with Pereta ® , the drug Herceptin ® and docetaxel, an increased risk of febrile neutropenia compared with patients receiving only drug Herceptin ® and docetaxel, particularly during the first 3 cycles of therapy. The minimum number of neutrophils are similar in patients receiving the drug Pereta ® , the drug Herceptin ® and docetaxel, and in patients who received only a drug Herceptin ® and docetaxel. Thus, a higher incidence of febrile neutropenia in patients treated with the drug Pereta ® , may be associated with a higher incidence of mucositis and diarrhea in these patients, and therefore should be considered symptomatic the treatment of mucositis and diarrhea. During the reference clinical studies have not reported cases of febrile neutropenia after the exclusion of the treatment regimen receiving Herceptin ® as a single agent or in combination with paclitaxel or docetaxel, particularly after chemotherapy including anthracyclines (doxorubicin or epirubicin) have an increased risk of congestive heart failure (CHF) (II-IV functional class NYHA) or asymptomatic cardiac function . The severity of these effects may vary from mild to severe. These events can be fatal. In addition, caution should be exercised when treating patients with high cardiovascular risk, such as elderly patients with hypertension, documented coronary artery disease, congestive heart failure, left ventricular ejection fraction (LVEF) <55%. Patients who are scheduled appointment drug Herceptin ® , especially those who have previously received preparations of anthracyclines and cyclophosphamide, must first undergo a thorough cardiac evaluation, including history taking, physical examination, electrocardiography, echocardiography (ECG) and / or radionuclide ventriculography or magnetic resonance imaging (MRI ). Conducted before treatment cardiological examination must be repeated every 3 months during treatment and every 6 months after its completion within 24 months after the last dose of the drug. Before starting treatment with Herceptin ® is necessary to carefully compare the possible benefits and risks of its use. As half-life of the drug Herceptin ® is about 28-38 days, the preparation may be in the blood up to 27 weeks after completion of therapy. Patients who receive anthracyclines after completion of treatment with Herceptin ® , may increase the risk of cardiotoxicity. If possible, physicians should avoid the use of anthracycline-based chemotherapy for 27 weeks after completion of therapy with Herceptin ® . When using drugs anthracyclines should be careful monitoring of cardiac function. It is necessary to assess the need for a standard cardiac examination in patients with suspected cardiovascular disease. All patients should be monitored cardiac function during treatment (with the recommended frequency of once every 3 months). The monitoring can identify patients who develop cardiac dysfunction. Patients with asymptomatic cardiac dysfunction more frequent monitoring may be useful (eg, every 6-8 weeks). In long-term deterioration of left ventricular function, not detected symptomatically, it is advisable to consider the abolition of therapy if the clinical benefit of its use is missing. Safety continuation or resumption of therapy with Herceptin in patients who developed cardiac dysfunction, has not been studied. If in the course of therapy with Herceptin ® in the various modes of therapy (except for the combination with a drug Pereta ® and docetaxel) decreased left ventricular ejection fraction (LVEF)> 10 units of the original value andbelow 50%, treatment should be suspended. Re-evaluation of LVEF should be performed about 3 weeks. In the absence of the improvement in LVEF or a further reduction, or when symptoms of chronic heart failure (CHF) is necessary to consider discontinuing treatment with Herceptin if the only use for a particular patient is not greater than the risks. These patients should be referred to a cardiologist for examination and be supervised. If the background of therapy with Herceptin ® developing symptomatic heart failure, it is necessary to hold the appropriate standard pharmacological treatment of CHF. The majority of patients with heart failure or asymptomatic cardiac dysfunction in basic studies observed improvement on the background of the standard drug therapy CHF (angiotensin converting enzyme inhibitors or angiotensin blockers and beta-blockers receptors). In the presence of clinical benefit from the drug Herceptin, “the majority of patients with adverse reactions on the part of the heart continued therapy without causing additional clinically significant reactions. Features of the application in metastatic breast cancer is not recommended to use the drug Herceptin ® together in combination with anthracyclines in the treatment of metastatic breast cancer . The risk of cardiotoxicity in patients with metastatic cancer patients breast higher with prior therapy with anthracyclines, however, it is lower compared to that, while the use of anthracyclines and Herceptin drug ® . infusion reactions and hypersensitivity reactions Infrequently, the introduction of Herceptin drug ® had serious infusion adverse reactions : dyspnea, hypotension, wheezing in the lungs, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduction in hemoglobin saturation with oxygen, anaphylaxis, respiratory distress, urticaria and angioedema. Most of them occurred during infusion, or within 2.5 h from the start of the first injection. In the event of an infusion reaction, the introduction should be stopped. It is necessary to carefully monitor the patient until the elimination of all symptoms. Effective therapy of serious reactions is the use of beta-agonists, corticosteroids and oxygen inhalation. In the case of severe and life-threatening infusion reactions should consider discontinuing further treatment. In rare cases, these reactions have been associated with a fatal outcome. The risk of fatal infusion reactions is higher in patients with shortness of breath at rest, caused by metastases to the lungs or concomitant diseases, so there should be no treatment for such patients. Reported cases in which after the initial improvement was observed deterioration, as well as cases of delayed rapid deterioration. Lethal outcome occurs within hours, or one week after infusion. In very rare cases, patients develop symptoms of infusion reactions and pulmonary symptoms (6 hours or more after the start of administration of the drug Herceptin ® ). It should warn patients of a possible delayed the development of these symptoms and the need for immediate contact with their physician if they occur. Violations of the lung In applying the drug Herceptin ® in the post-registration period recorded severe effects in the lungs, which are sometimes accompanied by death. In addition, cases of interstitial lung disease (ILD) observed, including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory distress. Risk factors associated with ILD include: previous or concomitant therapy undertaken other anti-neoplastic agents, which are known to be associated with ILD (taxanes, gemcitabine, vinorelbine and radiotherapy). These phenomena may occur both during the infusion (infusion reactions as displays) and delayed. The risk of severe reactions in the lungs is higher in patients with metastatic lung, comorbidities, accompanied by shortness of breath at rest. Therefore, such patients should not receive the drug Herceptin ® . Care should be taken, particularly in patients receiving concomitant therapy with taxanes, due pneumonitis. In applying the drug Herceptin ® in patients with giperchuvstvitelnostyu to benzyl alcohol drug must dissolve the water for injection, while of each multi-dose vial can select only one dose. The remaining drug should be destroyed (when recycling, please. Above). Benzyl alcohol is contained as a preservative in bacteriostatic water for injection, is attached to each multi-dose vials of the drug Herceptin ® , has a toxic effect in infants and children up to 3 years.
Effects on ability to drive vehicles and mechanisms
Influence of therapy kit components Beyodaym ® on ability to drive and operate machinery has not been studied. With the development of some adverse reactions, such as dizziness, should refrain from driving vehicles and mechanisms. In case of symptoms of infusion reactions patients should not drive a car or operate machinery until complete resolution of symptoms.
Pereta ® (buy andriol) – №1 ingredient : 420 mg / 14 ml of buy andriol in a vial of colorless glass (hydrolytic class 1 EP) rubber stoppers of butyl rubber, laminated fluoropolymer, crimped aluminum caps and plastic lid closed brown. Herceptin ® (trastuzumab ) – №2 ingredient : 440 mg of trastuzumab into the vial of colorless glass (hydrolytic class 1 EP) rubber stoppers of butyl rubber, crimped aluminum caps and plastic cover indoor light green color. B akteriostaticheskaya water for injection (solvent for the drug Herceptin ® ) – component №3 : 20 ml of bacteriostatic water for injection into the vial of colorless glass (hydrolytic class 1 EP) rubber stoppers of butyl rubber, crimped aluminum caps and plastic lid closed white. 1 vial Pereta ® (component №1) 1 vial of Herceptin ® (component №2) and 1 bottle with bacteriostatic water for injection – is placed in a cardboard tray, which, together with instructions for use Beyodaym set solvent for the drug Herceptin “(component №3) ® placed in a pile of cardboard consumer packaging sub-chromium-ersatz in accordance with GOST 7933-89 or imported with partitions inside. in order to control the first opening of a pack of self-adhesive paste stackers with the logo JSC “ORTAT”.