Beyodeime® (Beyodym®)

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  • Beyodeime®
    concentrate d / infusion 
    R-PHARM, CJSC     Russia
  • Perieta®
    concentrate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbsp

    set: Perieta® (pertuzumab) concentrate for solution for infusion; Terrentine (trastuzumab) lyophilizate for the preparation of a concentrate for the preparation of a solution for infusions, complete with a solvent - bacteriostatic water for injections

    Composition:

    1 bottle with Perieta® contains: active substance: pertuzumab 420 mg;

    Excipients: L-histidine 43.5 mg, glacial acetic acid 9.2 mg, sucrose 575.1 mg, polysorbate 20 2.8 mg, water for injection up to 14 ml.

    The concentration of pertuzumab is 30 mg / ml.

    1 bottle with Herceptin preparation® contains:

    active substance: trastuzumab - 440 mg;

    Excipients: L-histidine hydrochloride - 9.9 mg L-histidine - 6.4 mg, a, a-trehalose dihydrate - 400.0 mg Polysorbate 20 - 1.8 mg benzyl alcohol - 229.9 mg Water for injection - 20.9 ml.

    Bacteriostatic water for injection (20 ml) contains 1.1% benzyl alcohol as an antimicrobial preservative.

    Description:

    Perieta® (pertuzumab)

    Transparent or opalescent colorless or slightly brownish liquid.

    Herceptin® (trastuzumab)

    Lyophilizate from white to light yellow color.

    The reconstituted solution is a clear or slightly opalescent liquid from colorless to light yellow in color.

    Bacteriostatic water for injections (solvent for Herceptin)

    Transparent colorless or with a weak yellowish tinge liquid.

    Pharmacotherapeutic group:Antineoplastic agent, monoclonal antibodies
    ATX: & nbsp

    L.01.X.C.13   Pertuzumab

    Pharmacodynamics:

    Mechanism of action

    Pertuzumab

    Pertuzumab is a recombinant humanized monoclonal antibody that selectively interacts with the extracellular subdomain II responsible for dimerization HER2 (human epidermal growth factor receptor of type 2). Binding of pertuzumab to subdomain II blocks the process of ligand-dependent heterodimerization HER2 with other proteins of the family HER, including EGFR (epidermal growth factor receptor), HER3 (human epidermal growth factor receptor of type 3) and HER4 (the receptor of epidermal growth factor of human type 4). In this way, pertuzumab inhibits ligand-initiated transfer of intracellular signals along two main signaling pathways: the pathway of mitogen-activated protein kinase (MAP) and the pathway of phosphoinositide-3-kinase (PI3K). The inhibition of these signaling pathways can lead to the arrest of cell growth and apoptosis, respectively. Besides, pertuzumab promotes activation of antibody-dependent cellular cytotoxicity (AZKTS).

    The molecular weight of pertuzumab is about 148 kDa, and it is expected that, like other monoclonal antibodies, pertuzumab practically does not pass through the blood-brain barrier.

    Pertuzumab in the form of a monoagent inhibits the proliferation of human tumor cells. An increase in the antitumor activity of pertuzumab on xenograft models with overexpression HER2 when used in combination with trastuzumab.

    Trastuzumab

    Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively interacts with the extracellular domain of the human type 2 epidermal growth factor receptor (HER2). These antibodies are IgGi, consisting of human regions (constant sections of heavy chains) and determining the complementarity of mouse regions of the p185 antibody HER2 to HER2.

    Proto-oncogene HER2 or c-erB2 encodes a transmembrane receptor-like protein with a molecular weight of 185 kDa,which is structurally similar to other members of the epidermal growth factor receptor family. Hyperexpression HER2 is found in the tissue of primary breast cancer (breast cancer) in 25-30% of patients and in the tissues of advanced stomach cancer in 6.8-42.6% of patients. Amplification of the gene HER2 leads to overexpression of the protein HER2 on the membrane of tumor cells, which in turn causes a constant activation of the receptor HER2.

    Studies show that patients with breast cancer who are noted for amplification or overexpression HER2 in tumor tissue, have a less survival without symptoms of disease compared to patients without amplification or overexpression HER2 in the tumor tissue.

    Trastuzumab blocks proliferation of human tumor cells with overexpression HER2 in vivo and in vitro. In vitro the antibody-dependent cellular cytotoxicity of trastuzumab is predominantly directed to tumor cells with overexpression HER2.

    Immunogenicity

    Pertuzumab

    Approximately 6.2% of patients treated with trastuzumab in combination with docetaxel and 2.8% of patients who received trastuzumab in combination with docetaxel and pertuzumab, anti-therapeutic antibodies (ATA) have been found. The association of the formation of antibodies to pertuzumab with the development of anaphylactic reaction / hypersensitivity reaction has not been reliably established in any of the patients.

    Trastuzumab

    Antibodies to trastuzumab were found in one of the 903 women with breast cancer who received the drug in monotherapy or in combination with chemotherapy, with allergic reactions to trastuzumab she was absent.

    Comparing the frequency of detection of antibodies to pertuzumab and trastuzumab and the frequency of detection of antibodies to other biological preparations may not be informative, since the results of the immunogenicity assay are highly dependent on various factors, such as the sensitivity and specificity of the assay, the assay methodology, the manipulation of the collected samples, the time of sampling samples, concomitant medications and the nature of the underlying disease.

    Pharmacokinetics:

    Pertuzumab

    The pharmacokinetics of pertuzumab following intravenous administration (iv) in various doses (from 2 to 25 mg / kg) in patients with different types of tumor was studied.

    The clearance of pertuzumab was independent of the dose and indications.

    Pharmacokinetic parameters do not depend on age, gender and ethnicity (Japanese and other ethnic groups).

    The initial concentration of albumin and the "lean body weight" (a value that characterizes the body weight minus the fat mass of the fat) have a negligible effect on the clearance of pertuzumab, and there is no need to adjust the dose of pertuzumab depending on the initial concentration of albumin or body weight.

    Suction

    Pertuzumab is administered iv. Other ways of drug administration have not been studied.

    Distribution

    After IV introduction, the volume of distribution in the central chamber (Vc) is 3.07 liters and is approximately equal to the volume of the plasma. Values Vc and volume of distribution of pertuzumab at an equilibrium state (Vss) suggest that the distribution occurs only in plasma and extracellular fluid.

    Metabolism

    Metabolism of pertuzumab has not been studied. Like other antibodies, pertuzumab predominantly subjected to catabolism.

    Excretion

    The clearance of pertuzumab is approximately 0.239 l / day, the elimination half-life (Tg) is approximately equal to 17.2 days.

    Trastuzumab

    When the drug was administered in the form of short intravenous infusions at a dose of 10, 50, 100, 250 and 500 mg once a week, the pharmacokinetics was nonlinear. With increasing dose, the clearance of the drug decreased.

    Half-life

    The half-life is 28-38 days, therefore, the withdrawal period after discontinuation of the drug is up to 27 weeks (190 days or 5 half-lives). Pharmacokinetics of trastuzumab against the background of the equilibrium state The equilibrium state should be reached in about 25 weeks.

    Using the population pharmacokinetic method (two-chamber model, model-dependent analysis) of the data of Phase I, Phase II and Phase III studies for metastatic breast cancer, the median of the expected area under the concentration-time curve (AUC) in the equilibrium state after 3 weeks was 1677 mg * day / l after the administration of 3 doses (2 mg / kg) weekly and 1793 mg * day / l after 3 weeks at a dose of 6 mg / kg. Calculated medians of maximum concentration (Cmax) were 104 mg / l and 189 mg / l, and the minimum concentration (Cmin) - 64.9 mg / l and 47.3 mg / l, respectively. When using a model-independent or "non-chamber" method of analysis (pop- compartmental analysis, NCA) mean Cmin in the equilibrium state to the 13th cycle (37 weeks) was 63 mg / l in patients with early stages of breast cancer who received trastuzumab in a loading dose of 8 mg / kg, then in a maintenance dose of 6 mg / kg, after 3 weeks, and was comparable to that in patients with MMR who received trastuzumab weekly.

    Clearance

    The typical clearance of trastuzumab (for a patient with a body weight of 68 kg) was 0.241 l / day.

    Volume of distribution

    In all clinical studies, the volume of distribution in the central chamber (Vc) was 3.02 liters, in the peripheral (Vp) - 2.68 l for a typical patient.

    Circulating extracellular domain HER2- receptor ("sluschivayuschiesya" with the cell antigen)

    In the serum of some patients with breast cancer and HER2 Overexpression revealed circulating extracellular domain HER2- receptor ("sluschivayuschiesya" with the cell antigen). In 64% of patients studied in baseline serum samples detected "exfoliated" cells with antigen at a concentration reaches 1880 ng / ml (median 11 ng / ml). Patients who had a high concentration of "slipping" from the cell antigen, probably could have a lower Cmin. However, in most patients with an elevated "sluschivayuschegosya" with the cell antigen when the drug was administered weekly, the target concentration of trastuzumab in the serum was reached by week 6.There was no significant relationship between the baseline level of the antigen "slipping" from the cell and the clinical response.

    Pharmacokinetics in specific patient groups Peutuzumab

    Patients of elderly and senile age

    Special studies of the pharmacokinetics of pertuzumab in elderly patients (> 65 years) and senile (> 75 years) were not conducted. According to the results of the population analysis, age does not affect the pharmacokinetic parameters of pertuzumab. Patients with impaired renal function

    Special studies of the pharmacokinetics of pertuzumab in patients with renal insufficiency have not been carried out. According to the results of the population analysis, renal failure is mild (creatinine clearance 60-90 ml / min), medium (Q30-60 ml / min) and severe (QC <30 ml / min) does not affect the exposure of pertuzumab. Data for patients with moderate to severe renal failure are limited.

    Patients with impaired hepatic function

    The study of the pharmacokinetics of pertuzumab in patients with impaired liver function was not conducted.

    Tuastuzumab

    Special studies of the pharmacokinetics of trastuzumab in elderly and senile patients and patients with renal or hepatic insufficiency have not been carried out.

    Patients of elderly and senile age Age does not affect the distribution of trastuzumab.

    Indications:Metastatic or locally recurrent, inoperable breast cancer with tumor overexpression HER2 in combination with docetaxel in the absence of previous treatment or in the progression of the disease after adjuvant therapy.
    Contraindications:

    Hypersensitivity to pertuzumab, trastuzumab, benzyl alcohol or to any auxiliary substance that is part of the components of the Beyondime® kit.

    Pregnancy and the period of breastfeeding.

    Children under 18 years of age (efficacy and safety of use not established). Values ​​of left ventricular ejection fraction (LVEF) before treatment <50%.

    Congestive heart failure in history.

    Uncontrolled hypertension.

    Recently suffered myocardial infarction.
    Serious heart rhythm disorders requiring drug therapy at the time of the appointment of the Beyodime® kit, with the exception of atrial fibrillation and paroxysmal supraventricular tachycardia.

    Prior treatment with anthracyclines with a cumulative dose of doxorubicin or equivalent preparation> 360 mg / m2.

    Dysfunction of the liver (efficacy and safety of use have not been studied). Severe shortness of breath at rest, caused by metastases to the lungs or requiring maintenance therapy with oxygen.

    Carefully:

    Reduction of LVEF to <50% against previous adjuvant therapy with Herceptin; LVEF values ​​<55%; previous treatment with cardiotoxic drugs, incl. anthracycline / cyclophosphamide or previous radiation therapy to the thoracic region; coronary heart disease, arterial hypertension, heart failure, concomitant lung disease, or lung metastases; conditions that can disrupt the function of the left ventricle; impaired renal function.
    Pregnancy and lactation:

    Women with reproductive potential and women of childbearing age who are the sexual partners of patients receiving treatment with the components of the Beyondime® set should use reliable contraceptive methods during treatment and at least 6 months after the end of treatment.

    In case of pregnancy it is necessary to warn a woman about the possibility of harmful effects on the fetus.If the pregnant woman continues to receive therapy, then she should be under the careful supervision of doctors of different specialties. Breastfeeding is not recommended during treatment and at least 6 months after the end of therapy.

    The effect of Peret's preparation on fertility has not been studied. The results of experiments on animals showed no signs of impaired fertility.

    • It is not known whether Herceptin® affects reproductive capacity in women. The results of experiments on animals showed no signs of impaired fertility or a negative effect on the fetus.
    Dosing and Administration:

    Before the start of treatment, the components of the Beyondime® kit should be tested for tumor expression HER2. An obligatory criterion is 3+ points according to the results of immunohistochemical analysis (IHC) and / or degree of amplification> 2.0 based on hybridization results in situ (ISH). It is necessary to use accurate and validated testing methods. Detailed instructions for conducting HER2- testing and interpretation of its results are given in the instructions for the use of validated test systems designed to determine HER2 status. Components of the Beyodeim set® (Perieta8 and Herceptin®) are administered only by intravenous drip! Enter the components of the Beyodeim set® intravenously struino or bolusno it is impossible!

    Components of the Beyodeim set® (Perieta® and Herceptin8) can be entered in any sequence. After each infusion of the drug Perieta ~ and until the introduction of the drug Herceptin 5 or docetaxel, patient monitoring is recommended for 30-60 minutes. Docetaxel It is recommended to enter after the introduction of all components of the Beyondime® kit.

    Dosing regimen

    Perieta® (pertuzumab) - component number 1

    The duration of infusion with the administration of the first dose should be 60 minutes. If the first infusion is well tolerated, subsequent ones can be carried out for 30-60 minutes.

    The loading dose of Perieta® - 840 mg in the form of a 60-minute intravenous drip infusion.

    Supportive dose of Perieta® - 420 mg every 3 weeks as an intravenous drip infusion for 30-60 minutes. The maintenance dose is given 3 weeks after loading.

    Herceptin® (trastuzumab) - component number 2

    The loading dose of Herceptin - 8 mg / kg of body weight as a 90-minute intravenous drip infusion.

    Supportive dose of Herceptin - 6 mg / kg body weight every 3 weeks as an intravenous drip infusion for 30-90 minutes. The maintenance dose is given 3 weeks after loading. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drop infusion. Finished

    When used in combination with the Beyondime® kit, the recommended initial dose of doxetaxel is 75 mg / m as an intravenous infusion, after which the drug should be given at the same dose every 3 weeks. With good tolerability in the first cycle, the dose of docetaxel can be increased to 100 mg / m in subsequent cycles.

    Duration of treatment

    Treatment should continue until signs of disease progression or unacceptable toxicity.

    Skipping in the planned introduction

    Perieta®(pertuzumab) - component number 1

    If a break in the planned introduction of the drug Perieta® was less than 6 weeks, should be administered as soon as possible drug at a dose of 420 mg as a 30-60-minute intravenous drip infusion, without waiting for the next scheduled introduction.

    If a break in the introduction of Perieta® was 6 weeks or more, the drug should be administered at an initial dose of 840 mg in the form of a 60-minute intravenous drip infusion.Then, after 3 weeks, continue the administration of the drug in a maintenance dose of 420 mg every 3 weeks as a 30-60-minute intravenous infusion.

    Herceptin® (trastuzumab) - component number 2

    If the break in the planned introduction of the drug Herceptin was less than 6 weeks, should be administered as soon as possible drug at a dose of 6 mg / kg, without waiting for the next scheduled introduction.

    If a break in the administration of Gercerptin® was 6 weeks or more, the drug should be given at a loading dose of 8 mg / kg in the form of an intravenous drip infusion lasting approximately 90 minutes. Then, after 3 weeks, continue the administration of the drug in a maintenance dose of 6 mg / kg every 3 weeks.

    Correction of dose

    Dose reduction of each of the components is not recommended.

    If treatment with one of the components of the Beyondime® set is canceled, the use of another component of the Beyondime® kit should also be discarded.

    During the onset of reversible myelosuppression caused by chemotherapy, therapy with the components of the Beyondime® set can be continued, provided that the complications caused by neutropenia are closely monitored. Instructions for modifying the dose of docetaxel are given in the instructions for the medical use of docetaxel.In the event of docetaxel withdrawal, treatment with the components of the Beyondime® kit can be continued until the disease progresses or the development of unacceptable toxicity.

    Violation of the function of the left ventricle

    Therapy with Beyondime® components should be suspended for at least 3 weeks in the following cases:

    - decreased LVEF to below 40%;

    - Values ​​of LVEF 40-45% with a decrease in LVEF by> 10% relative to the values ​​observed before treatment.

    The treatment can be resumed if LVEF is restored to> 45% or 40-45% with a decrease of <10% relative to the values ​​observed before treatment. If, according to the reevaluation data, after 3 weeks, LVEF does not increase or further decline occurs, treatment should be canceled, unless the benefit for a particular patient exceeds the risk.

    Infusion reactions

    Infusion should be carried out by a medical specialist who has experience in the treatment of anaphylaxis, as well as access to funds for emergency care.

    With the development of an infusion reaction, the rate of infusion should be reduced or discontinued for a while.

    When developing a serious hypersensitivity reaction, you should immediately stop the infusion and stop the therapy completely.

    Special instructions for dosing

    Patients of elderly and senile age

    Correction of the dose of components of the Beyondime® kit in elderly patients and in senile patients is not required.

    Patients with impaired renal function

    The efficacy and safety of the components of the Beyodeim set in patients with impaired renal function have not been studied.

    Patients with impaired hepatic function

    The effectiveness and safety of the components of the Beyodeim set® in patients with impaired liver function were not studied.

    Patients of childhood

    The effectiveness and safety of the components of the Beyodeim set® in children and adolescents under the age of 18 years have not been studied.

    Preparation of a solution for infusions

    Components of the Beyondime® kit (Perieta® and Herceptin® ) should only be applied sequentially. Dilution of components must be carried out in separate infusion packs!

    Perieta® (pertuzumab) - component number 1

    Attention! Preparation of Perieta® not compatible with 5% dextrose solution. Dilution in such a solution leads to chemical and physical instability of pertuzumab. The drug should be diluted only in 0.9% sodium chloride solution.

    Preparation of Perieta® Do not mix or dilute with other medicines.

    The Perieta solution is compatible with infusion bags made of polyvinyl chloride (PVC), polyethylene and PVC-free polyolefin.

    Preparation of the drug for administration should be carried out under aseptic conditions.

    Perieta (pertuzumab) does not contain antimicrobial preservatives. In this regard, it is necessary to take precautions to maintain the sterility of the prepared solution for infusion.

    From the vial (flasks), you should take all the liquid concentrate and enter it into the infusion bag with 250 ml of 0.9% sodium chloride solution. The concentration of the final solution is approximately 3.36 mg / ml (840 mg / 250 ml) for loading and 1.68 mg / ml (420 mg / 250 ml) for the maintenance dose.

    Then the infusion bag must be turned gently to mix the solution, avoiding foaming. Before administration, the drug should be checked (visually) for lack of mechanical impurities and discoloration. Solution for infusion is administered immediately after its preparation.

    In exceptional cases, the prepared solution of the Perieta preparation can be stored for no more than 24 hours at a temperature of 2-8 ° C if the preparation of the infusion solution occurred in controlled and validated aseptic conditions.At the same time for the storage conditions (storage rules and duration) is the specialist who prepared the solution.

    Herceptin® (trastuzumab) - component number 2

    Attention! Herceptin® is not compatible with a 5% dextrose solution because of the possibility of protein aggregation.

    Herceptin® Do not mix or dilute with other medicines.

    Solution Herceptin ® is compatible with infusion bags made of polyvinyl chloride, polyethylene and polypropylene.

    Preparation of the drug for administration should be carried out under aseptic conditions. Instructions for preparing the concentrate

    Contents of the bottle with the drug Herceptin® is dissolved in 20 ml of supplied bacteriostatic water for injection containing 1.1% benzyl alcohol as antimicrobial preservative. As a result, a solution concentrate is prepared, suitable for repeated use, containing 21 mg of Herceptin® in 1 ml and having a pH of 6.0.

    During the dissolution should be carefully treated with the drug. When dissolving, excessive pricing should be avoided, the latter may make it difficult to obtain the desired dose of the drug from the vial.

    1. Sterile syringe slowly enter 20 ml of bacteriostatic water for injection (TO) in a vial of 440 mg of Herceptin, directing the liquid stream directly to the lyophilizate.

    2. For dissolution, gently shake the bottle with rotational movements. Do not shake!

    When the preparation is dissolved, a small amount of foam is often formed. To avoid this, allow the solution to stand for about 5 minutes. The prepared concentrate should be clear and colorless or have a light yellow color.

    Herceptin solution concentrate formulation prepared in the bacteriostatic water for injection, is stable for 28 days at 2-8 ° C. The prepared concentrate contains a preservative and can therefore be used repeatedly. After 28 days, the unused concentrate residue should be disposed of. Do not freeze!

    As a solvent for Herceptin® the use of sterile water for injection (without preservative). The use of other solvents is not recommended. In the case of using sterile water for injection as a solvent, the concentrate is physically and chemically stable only for 24 hours at a temperature of 2- 8 ° C and must be destroyed after this time. Do not freeze! Instructions for preparing a solution for infusion

    Determine the amount of concentrate:

    the volume required to introduce a loading dose of Herceptin® , equal to 8 mg / kg body weight, or maintenance dose equal to 6 mg / kg every 3 weeks, is determined by the following formula:

    Scope (ml) = [body mass (kg) x dose (8 mg / kg loading or 6 mg / kg maintenance)] / [21 (mg / ml, concentration of the prepared solution)]

    From the vial with the prepared concentrate, you should dial the appropriate volume and enter it into the infusion bag with 250 ml of 0.9% sodium chloride solution. Then the infusion pack should be carefully turned over to mix the solution, avoiding foaming. Before administration, the solution should be checked (visually) for the absence of mechanical impurities and discoloration. Solution for infusion is administered immediately after its preparation.

    In exceptional cases, the prepared infusion solution can be stored for no more than 24 hours at a temperature of 2-8 ° C if dissolution of the concentrate and preparation of the solution for infusions occur in controlled and validated aseptic conditions.At the same time for the storage conditions (storage rules and duration) is the specialist who prepared the solution.

    Instructions for the destruction of unused preparations or preparations with expired shelf life

    The presence of drugs in the environment should be minimized. Do not dispose of drugs with sewage or with household waste. Destruction of unused drugs or drugs with expired shelf life should be carried out in accordance with the requirements of the medical institution. If possible, it is necessary to use special systems for the disposal of medicinal products.

    Side effects:

    The most frequent adverse reactions (observed in more than 50% of patients) associated with the use of preparation Perieta ® in combination with the drug Herceptin ® and docetaxel, there was diarrhea, alopecia and neutropenia.

    The most frequently observed (> 10%) undesired reactions of the 3rd-4th degree of severity according to the classification of the National Cancer Institute National Cancer Institute Common

    Terminology Criteria of Adverse Events (NCI-CTCAE), version 3, there were neutropenia, febrile neutropenia, and leukopenia.

    The most severe and clinically significant adverse reaction, observed with a frequency of less than 10%, was left ventricular dysfunction, including symptomatic left ventricular systolic dysfunction (congestive heart failure).

    Since a combination of drugs has been used, it is problematic to establish the causal relationship between the undesirable phenomenon and the specific drug. To describe the frequency of unwanted reactions, the following classification is used: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10000 and <1/1000) and very rarely (<1/10000), including isolated cases.

    Violations from the blood and lymphatic system: very often - neutropenia, anemia, leukopenia, febrile neutropenia (including fatal). Infringements from the immune system, very often hypersensitivity / anaphylactic reactions, infusion reactions / cytokine release syndrome.

    Disorders from the metabolism and nutrition :, very often - a decrease in appetite. Disorders of the psyche: very often - insomnia.

    Disturbances from the nervous system, very often - peripheral neuropathy, headache, dysgeusia (distortion of taste perception), dizziness.

    Disorders from the side of the organ of vision: very often - increased tearing. Heart Disease: often - a violation of the function of the left ventricle, including congestive heart failure.

    Disturbances from the respiratory system, chest and mediastinal organs: very often - shortness of breath, cough; often - pleural effusion; infrequently - interstitial lung disease.

    Disorders from the gastrointestinal tract: very often - diarrhea, nausea, vomiting, constipation, stomatitis, dyspepsia.

    Disturbances from the skin and subcutaneous tissues: very often - alopecia, rash, pathology of the nails, itching, dry skin; often paronychia.

    Disturbances from the musculoskeletal and connective tissues: very often - myalgia, arthralgia.

    General disorders and disorders at the site of administration: very often - increased fatigue, asthenia, peripheral edema, inflammation of the mucous membranes of various locations, pain, increased body temperature, attachment of secondary infections (upper respiratory tract infection, nasopharyngitis); often - chills.

    After docetaxel withdrawal, all adverse reactions were observed with a lower incidence (<10%, except for diarrhea, upper respiratory tract infections, rash, headache and fatigue (> 10%)).

    Infusion reactions, hypersensitivity reactions / anaphylaxis Any adverse reactions that occurred during the infusion or infusion day were attributed to infusion reactions. After the introduction of only the drug Perieta®most infusion reactions were mild or moderate and were observed in approximately 20% of patients. The most frequent infusion reactions (> 1.5%) were nausea, fever, diarrhea, chills, fatigue and headache.

    After simultaneous (in one day) administration of the drug Perieta®, Herceptin ® and docetaxel, starting from the second cycle of therapy, the most frequent (> 1.5%) infusion reactions were alopecia, nausea, decreased appetite, fatigue, constipation, diarrhea, stomatitis and drug hypersensitivity.

    The overall incidence of hypersensitivity / anaphylaxis was 9.1% after a simultaneous (one day) administration of Herceptin and docetaxel and 10.8% after simultaneous administration of Periet®,Herceptin® and docetaxel; of these phenomena, 2.5% and 2% were characterized by the 3rd and 4th degree of severity according to the classification NCI-CTCAE, version 3, respectively. A total of 2 patients after the simultaneous administration of Herceptin® and docetaxel and in 4 patients after simultaneous administration of the drug Perieta®, the drug Herceptin® and docetaxel developed anaphylaxis.

    Most of the hypersensitivity reactions were of mild or moderate severity and were resolved after appropriate treatment. Based on the results of the analysis of hypersensitivity reactions with changing dosage regimens, it was found that hypersensitivity phenomena were associated with docetaxel infusions.

    Deviations from the norm of laboratory indicators

    The frequency of cases of a decrease in the number of neutrophils of the 3rd-4th degree of severity by classification NCI-CTCAE, version 3, was approximately the same with the combination of Herceptin® and docetaxel concurrently with Perieta® and without it.

    Below are the undesirable reactions reported in the application preparation Herceptin® for all approved indications, in regimes other than the mode of application of the Beyodeime® kit in combination with docetaxel.

    Herceptin® often used in combination with chemotherapy drugs, as well as after the completion of radiation therapy, so it is difficult to determine the cause-effect relationship of unwanted reactions with one of the drugs / radiation therapy used.

    Currently, the most serious and / or frequent adverse reactions reported with the use of Herceptin® are: cardiotoxicity, infusion reactions, hematotoxicity (in particular, neutropenia) and pulmonary disorders.

    To describe the frequency of unwanted reactions in this section, the following classification is used: very often (> 1/10), often (> 1/100, but <1/10), infrequently (> 1/1000, but <1/100), rarely (> 1/10000, but <1/1000), very rarely (<1/10000), is unknown (can not be calculated from available data). Within each group, adverse reactions are presented in accordance with a decrease in severity.

    The frequency is indicated in accordance with the maximum observed in basic clinical trials.

    Infectious and parasitic diseases: often - pneumonia 1 (<1%), neutropenic sepsis, cystitis, Herpes zoster, infection, influenza, nasopharyngitis,sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, erysipelas, phlegmon; infrequently sepsis.

    Benign, malignant and unspecified neoplasms (including cysts and polyps): unknown - progression of malignant neoplasm, progression of neoplasm.

    Violations from the blood and lymphatic system: very often - febrile neutropenia; often - anemia, neutropenia, thrombocytopenia, leukopenia; unknown - hypoprothrombinemia.

    Immune system disorders: often - hypersensitivity reactions; unknown - anaphylactic reactions 1 , anaphylactic shock 1 .

    Disorders from the metabolism: often - weight loss, anorexia; unknown - hyperkalemia.

    Disorders of the psyche: often - anxiety, depression, insomnia, impaired thinking.

    Impaired nervous system: very often - a tremor2, dizziness, headaches; often - peripheral neuropathy, paresthesia, muscle hypertonia, drowsiness, dysgeusia (distortion of taste perception), ataxia; rarely - paresis; unknown - edema of the brain.

    Disorders from the side of the organ of vision: very often - conjunctivitis, increased tearing; often - dry eyes; unknown - edema of the optic disc, hemorrhage in the retina.

    Hearing disorders and labyrinthine disturbances: infrequently, deafness. Disorders from the cardiovascular system: very often - a decrease and increase in blood pressure (BP)2, disturbance of a warm rhythm2, palpitations22, flutter (atria or ventricles)2, reduction of the left ventricular ejection fraction *, "hot flashes"; often - heart failure (stagnant) 1 (2%), supraventricular tachyarrhythmia 1, 2 , cardiomyopathy, arterial hypotension 1, 2 , vasodilation; infrequently - pericardial effusion; unknown - cardiogenic shock, pericarditis, bradycardia, rhythm of "gallop".

    Disturbances from the respiratory system, chest and mediastinal organs: very often - wheezing 1 , dyspnea2 (14%), cough, nosebleeds, rhinorrhea; often - bronchial asthma, pulmonary function, pharyngitis; infrequently - pleural effusion2; rarely - pneumonitis; unknown - pulmonary fibrosis2, respiratory insufficiency2, lung infiltration 1 , acute pulmonary edema 1 , acute respiratory distress syndrome 1 , bronchospasm1 , hypoxia 1 , decreased oxygen saturation of hemoglobin 1 , laryngeal edema, orthopnea, pulmonary edema.

    Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, swelling of the lips2, stomach ache; often - pancreatitis, dyspepsia, hemorrhoids, constipation, dry mouth.

    Disorders from the liver and bile ducts: often - hepatitis, tenderness in the liver, hepatocellular injury; rarely jaundice; unknown - hepatic insufficiency.

    Disturbances from the skin and subcutaneous tissues: very often - erythema, rash, face swelling2; often - acne, alopecia, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, impaired nail structure, itching; unknown - angioedema, dermatitis, urticaria.

    Disturbances from the osteomuscular and connective tissue: very often - arthralgia, muscular stiffness2, myalgia; often - arthritis, back pain, ossalgia, muscle spasms, pain in the neck.

    Disorders from the kidneys and urinary tract: often - kidney disease; it is not known - membranous glomerulonephritis, glomerulonephropathy, renal failure.

    Influence on the course of pregnancy, postpartum and perinatal conditions: unknown - oligohydramnion, fatal hypoplasia of the lungs and kidney hypoplasia in the fetus. Violations of the genitals and breast: often - inflammation of the breast / mastitis.

    General disorders and disorders at the site of administration: very often - asthenia, chest pain, chills, weakness, flu-like syndrome, infusion reactions, pain, fever; often - peripheral edema, malaise, mucositis, swelling.

    Trauma, intoxication and complications of manipulation: often - a bruise.

    1 - undesirable reactions, which in the reports were associated with a fatal outcome.

    2 - undesirable reactions, which were mainly reported in association with infusion reactions (exact percentage not established).

    * - adverse reactions were observed with combination therapy after anthracyclines and in combination with taxanes.

    The exact percentage of the frequency is given in parentheses for those terms that are reported together with a fatal outcome with frequency "often" or "very often". Percentage refers to the total number of these phenomena with a fatal outcome and without it.

    The following undesired reactions were reported in basic clinical trials with a frequency> 1/10 in any of the treatment groups, with no significant difference between the therapy group containing trastuzumab, and the comparison therapy group: lethargy, hypoesthesia, pain in the extremities, pain in the mouth and pharynx, conjunctivitis, lymphedema, weight gain, onychoclasis, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, epigastric pain, gastritis, stomatitis , vertigo, arterial hypertension, hiccups, palmar dyspnea syndrome, pain in the mammary glands area, onychorexis, dyspnea with exercise and dysuria.

    Below you will find information on individual adverse reactions.

    Infusion reactions and hypersensitivity reactions

    It is estimated that about 40% of patients receiving Herceptin ® receive infusion reactions in one form or another. However, most infusion reactions are mild and moderate in severity (according to NCI-CTC) and tend to occur at the beginning of treatment, i.e. at the time of 1,2 and the third infusion, with subsequent administrations occur less frequently. 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 are associated with a fatal outcome.

    Cardiotoxicity

    Cardiotoxicity (heart failure) II-IV functional class for NYHA (classification of the New York Association of Cardiologists) is a frequent undesirable reaction with the use of Herceptin ® and was associated with a fatal outcome.

    In 3 basic clinical trials using the Herceptin drug in combination with adjuvant chemotherapy, the incidence of cardiac dysfunction of 3/4 degree (symptomatic congestive heart failure) did not differ from that in patients receiving chemotherapy alone (ie, without Herceptin®), and in patients receiving taxanes and the Herceptin ® preparation sequentially (0.3-0.4%). The frequency was greatest in patients receiving Herceptin together with taxanes (2.0%).

    The safety of continuation or resumption of therapy with Herceptin in patients who experienced cardiotoxicity was not studied prospectively. However, the condition of the majority of patients experiencing heart failure in baseline studies improved with standard therapy, which included beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

    Most patients with cardiac symptoms and signs of clinical benefit from trastuzumab continued the therapy without the occurrence of additional clinically significant cardiac events.

    Experience in the use of the drug Gerceptin® in combination with low-dose regimens of anthracyclines in neoadjuvant therapy is limited.

    Hematological toxicity

    Very often there was febrile neutropenia. Undesirable reactions that occur frequently include anemia, leukopenia, thrombocytopenia and neutropenia. The frequency of hypoprothrombinemia is unknown. The risk of neutropenia may be slightly higher with the use of Herceptin ® in combination with docetaxel after therapy with anthracycline-based drugs.

    Disorders from the side of the lungs

    With the use of the drug Herceptin ® associated with serious adverse events from the lungs (including fatal outcome). These reactions include, but are not limited to: pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure.

    Overdose:

    The maximum tolerated dose of Perieta ®(pertuzumab) not installed. Single doses exceeding 25 mg / kg (1,727 mg) have not been studied.

    In case of overdose, patients should be closely monitored in order to detect signs or symptoms of adverse reactions and to prescribe appropriate symptomatic treatment.

    In clinical studies of overdose cases of Herceptin® (trastuzumab) was not observed. Introduction of Herceptin® in single doses more than 10 mg / kg has not been studied. Herceptin® in doses <10 mg / kg was tolerated well.

    Interaction:

    Peoueta ® (pertuzumab)

    No evidence of pharmacokinetic interaction of pertuzumab with trastuzumab, docetaxel, gemcitabine, erlotinib, capecitabine was found.

    Herceptin ® (trastuzumab)

    Special studies of medicinal interactions of the drug Herceptin® in humans were not conducted. In clinical trials, no clinically relevant interactions with concomitantly used drugs (including doxorubicin, paclitaxel, docetaxel, capecitabine or cisplatin) was not observed.

    The effect of trastuzumab on the pharmacokinetics of other antitumour drugs Pharmacokinetic data obtained in women with HER2- positive metastatic breast cancer, it is suggested that the exposure of paclitaxel and doxorubicin and their major metabolites (6-alpha-hydroxypaclitaxel and doxorubicinol) does not change in the presence of trastuzumab when administered at a loading dose (8 mg / kg or 4 mg / kg IV) then in a maintenance dose (6 mg / kg every 3 weeks or 2 mg / kg every week in / in). Nevertheless, trastuzumab can increase the overall exposure of one of the metabolites of doxorubicin (7-deoxy-13-dihydrocoxorubicinone), the biological activity of this metabolite and the clinical significance of increasing its exposure are unknown.

    The data obtained in the study of the use of trastuzumab (4 mg / kg in the loading dose and 2 mg / kg once a week, iv, in the supporting) and docetaxel (60 mg / g) in Japanese patients with HER2- positive metastatic breast cancer suggest that simultaneous administration of trastuzumab does not affect the pharmacokinetics of a single-dose docetaxel.

    The results of studying the pharmacokinetics of capecitabine andcisplatin when used in combination with or without trastuzumab in Japanese male and female patients with advanced stomach cancer suggest that exposure of biologically active metabolites of capecitabine (for example, fluorouracil) did not change with simultaneous use of cisplatin or cisplatin and trastuzumab. However, higher concentrations of capecitabine and a longer half-life with trastuzumab have been reported. The data also indicate that the pharmacokinetics of cisplatin did not change with the simultaneous use of capecitabine or capecitabine in combination with trastuzumab.

    Effect of antitumor drugs on the pharmacokinetics of trastuzumab When comparing simulated serum concentrations of trastuzumab with monotherapy (at a loading dose of 4 mg / kg and supporting 2 mg / kg every week, iv) and trastuzumab concentrations when used in combination with docetaxel in Japanese patients with HER2- positive metastatic breast cancer showed no evidence of an effect of docetaxel on the pharmacokinetics of trastuzumab.Comparison of pharmacokinetic parameters in patients with HER2- positive metastatic breast cancer with trastuzumab concurrently with paclitaxel and with trastuzumab as monotherapy showed that individual and mean values ​​of the minimum serum trastuzumab concentration varied both within the same group and between groups, but no apparent effect of concurrent administration of paclitaxel on no pharmacokinetics of trastuzumab were observed.

    Co-administration with anastrozole does not affect the pharmacokinetics of trastuzumab.
    Special instructions:

    In the patient's medical records, the trade name of the Beyondime® kit should be indicated. Replacement of components of the kit (Perieta ® (pertuzumab) or Herceptin ® (trastuzumab)) on any other similar biological medicinal products requires agreement with the attending physician. The information presented in this manual refers only to the components of Perieta ® (pertuzumab) and Herceptin ® (trastuzumab).

    Treatment with components of the Beyondime ® kit should only be performed under the supervision of an oncologist.

    Beyondime ® should only be used in the presence of tumor overexpression HER2, determined by the method of immunohistochemical reaction (IHC), or amplification of the gene HER2, determined by the hybridization method in situ (FISH or CISH).

    HER2 testing should be carried out in a specialized laboratory that can provide quality control testing procedures.

    Peoueta ® (pertuzumab)

    Cardiotoxicity

    Against the background of the use of drugs that block activity HER2, including Perieta ®, there was a decrease in LVEF. The use of Perietta ® and Herceptin ® in combination with docetaxel was not accompanied by an increase in the incidence of symptomatic left ventricular systolic dysfunction or a decrease in LVEF compared with the use of only Herceptin ® and docetaxel. However, in patients who have previously received anthracyclines or radiotherapy for the thoracic region, the risk of reducing LVEF may be higher.

    The efficacy and safety of Perieta ® was not investigated in patients with LVEF <50%; chronic heart failure in history; with a previously observed decrease in LVEF to <50% during adjuvant therapy with Herceptin ®1; for conditions that are capable of disturbing left ventricular function, such as uncontrolled hypertension, recent myocardial infarction, severe heart rhythm disorders requiring drug therapy or previous treatment with anthracyclines with a cumulative dose of doxorubicin or an equivalent drug> 360 mg / m2.

    LVEF should be assessed prior to the use of Perieta® and should be assessed regularly (eg every 3 months) on the background of treatment in order to ensure that LVEF is within the normal range established in this institution. If LVEF is less than 40% or 40-45% with a decrease of> 10% from baseline before treatment, the use of Perieta ® and Herceptin ® should be discontinued. If, after a reassessment of approximately 3 weeks, LVEF does not improve or further decline occurs, consideration should be given to the abolition of Peritet ® and Herceptin ®, unless it is decided that the benefits of using the drug for a particular patient are greater than the risk.

    Infusion reactions and hypersensitivity reactions

    With the use of Perieta ®, infusion reactions and hypersensitivity reactions may develop. When Periet® is administered, the patient should be carefully monitored during the first infusion and within 60 minutes after the end, as well as during subsequent infusions and within 30 minutes after the end. If a clinically significant reaction to infusion develops, slow the infusion rate or interrupt it and take appropriate therapeutic measures. Careful observation of the patient and evaluation of his condition are recommended until the symptoms are completely resolved. In patients with severe infusion reactions, the need for a complete discontinuation of Perieta ® should be assessed, taking into account the degree of severity, the reaction observed, and the nature of the response to treatment prescribed in connection with the adverse reaction.

    Febrile neutropenia

    In patients treated with Perieta®, Herceptin® and docta cele, the risk of febrile neutropenia is increased compared to patients receiving only Herceptin® and docetaxel, especially during the first 3 cycles of therapy.

    The minimum values ​​of the number of neutrophils are similar in patients treated with Perieta ®, Herceptin ® docetaxel, and in patients who received only Herceptin ® and docetaxel.

    Thus, a higher incidence of febrile neutropenia in patients receiving Perieta ® may be associated with a higher incidence of mucositis and diarrhea in these patients, and the possibility of symptomatic treatment of mucositis and diarrhea should be considered. During the baseline clinical trial, no cases of febrile neutropenia were reported after exclusion from the docetaxel treatment regimen. Herceptin® (trastuzumab)

    Cardiotoxicity

    Patients receiving Herceptin ® as a monotherapy or in combination with paclitaxel or docetaxel, especially after chemotherapy involving anthracyclines (doxorubicin or epirubicin), have an increased risk of developing chronic heart failure (CHF) (II-IV functional class for NYHA) or asymptomatic cardiac dysfunction. The severity of these phenomena can vary from medium to severe. These phenomena can lead to death.In addition, caution should be exercised in the treatment of patients with high cardiovascular risk, for example, in elderly patients with hypertension, documented coronary heart disease, chronic heart failure, left ventricular ejection fraction (LVEF) <55%.

    Patients who are scheduled to administer Herceptin®, especially those who previously received anthracycline-based drugs and cyclophosphamide, must first pass a thorough cardiological examination, including a history, physical examination, electrocardiography, echocardiography (ECG) and / or radioisotope ventriculography or magnetic resonance imaging (MRI). Pre-treatment cardiac examination should be repeated every 3 months during therapy and every 6 months after it is completed within 24 months of the administration of the last dose of the drug.

    Before starting treatment with Herceptin ®, you must carefully compare the possible benefits and risks of its use.

    Since the half-life of Herceptin® is about 28-38 days, the drug can be in the blood up to 27 weeks after completion of therapy.Patients who receive anthracyclines after completing treatment with Herceptin ® may increase the risk of cardiotoxicity. Where possible, physicians should avoid the appointment of anthracycline-based chemotherapy within 27 weeks after completion of therapy with Herceptin ®. With the use of anthracycline drugs, careful monitoring of heart function should be carried out.

    It should be assessed the need for a standard cardiac examination in patients with suspected cardiovascular disease.

    All patients should monitor cardiac function during treatment (with a recommended frequency of every 3 months). As a result of monitoring, it is possible to identify patients who have developed cardiac dysfunction.

    In patients with asymptomatic cardiac dysfunction, more frequent monitoring may be useful (for example, every 6-8 weeks). With prolonged worsening of left ventricular function, which is not manifested symptomatically, it is advisable to consider abolishing therapy if the clinical benefit from its use is absent.

    The safety of continuation or resumption of therapy with Herceptin in patients who developed a violation of the function of the heart has not been studied. In the course of therapy with Herceptin ® in various regimens of therapy (except for the combination with Perieta ® and docetaxel, the left ventricular ejection fraction (LVEF) decreased by> 10 units from the original I and below the value of 50%, treatment should be suspended. LVEF should be performed after about 3 weeks, if there is no improvement in LVEF or its further decline, or if symptoms of chronic heart failure (CHF) appear, it is necessary to consider discontinuing and treatment with Herceptin ®, unless the benefit for a particular patient is greater than the risk.All these patients should be referred to a cardiologist for examination and under observation.

    If symptomatic heart failure develops with Gerceptin ®, it is necessary to conduct appropriate standard medical therapy for CHF. In the majority of patients with CHF or asymptomatic cardiac dysfunction in basicstudies showed improvement in the background against standard drug therapy for CHF (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers). In the presence of clinical benefit from the use of Herceptic, the majority of patients with adverse cardiac reactions continued therapy without manifesting additional clinically relevant reactions.

    Features of metastatic breast cancer It is not recommended to use Herceptin ® together in combination with anthracyclines for the treatment of metastatic breast cancer.

    The risk of developing cardiotoxicity in patients with metastatic breast cancer is youwe with previous treatment with anthracyclines, however, it is lower compared to that with simultaneous use of anthracyclines and Herceptin ®

    Infusion reactions and hypersensitivity reactions

    Serious infusional undesirable reactions occurred infrequently with the administration of Herceptin®: shortness of breath, arterial hypotension, wheezing in the lungs, arterial hypertension, bronchospasm, supraventricular tachyarrhythmia,reduction of hemoglobin oxygen saturation, anaphylaxis, respiratory distress syndrome, urticaria and angioedema. Most of them occurred during infusion or within 2.5 hours from the start of the first injection. When an infusion reaction occurs, the administration should be stopped. Care must be taken to monitor the patient until all symptoms are eliminated. Effective therapy of serious reactions consists in the use of beta-adrenostimulants, glucocorticosteroids and inhalation of oxygen. In case of development of severe and life-threatening infusion reactions, consideration should be given to stopping further therapy.

    In rare cases, these reactions were associated with a fatal outcome. The risk of developing lethal infusion reactions is higher in patients with dyspnea at rest caused by metastases to the lungs or concomitant diseases, so one should not take therapy for such a patient.

    There have been reported cases in which, after initial improvement, there was a worsening of the condition, as well as cases with delayed rapid deterioration of the condition. Lethal outcome occurred within hours or one week after infusion.In very rare cases, patients showed symptoms of infusion reactions or pulmonary symptoms (6 hours or more after the onset of Herceptin® administration). Patients should be warned about the possible delayed development of these symptoms and the need for immediate contact with the doctor in case they occur.

    Disorders from the side of the lungs

    With the use of Herceptin ® in the postgravitational period, severe lung events were recorded, which were sometimes accompanied by a fatal outcome. In addition, cases of interstitial lung disease (IBL) have been reported, including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure. The risk factors associated with IBL include: previous or concomitant therapy with other anti-neoplastic drugs known to be associated with IBL (taxanes, gemcitabine, vinorelbine and radiation therapy). These phenomena can occur both during infusion (both manifestations of infusion reactions) and delayed.The risk of severe reactions from the lungs is higher in patients with metastatic lung involvement, concomitant diseases accompanied by dyspnea at rest. Therefore, such patients should not receive Herceptin ®. Care should be taken, especially in patients receiving concomitant taxane therapy, because of the development of pneumonitis.

    When using Herceptin ® in patients with hypersensitivity to benzyl alcohol the drug must be dissolved with water for injection, with only one dose taken from each multi-dose vial. The remaining preparation should be disposed of (recycling recommendations see above).

    Gasoline alcohol, contained as a preservative in bacteriostatic water for injections, applied to each multi-dose bottle of Herceptin ®, has a toxic effect in newborns and children under 3 years.

    Effect on the ability to drive transp. cf. and fur:

    Effect of therapy on the components of the Beyodeim set ® the ability to drive and work with machinery has not been studied. When developing some unwanted reactions, in particular dizziness, one should refrain from managing vehicles and mechanisms.In case of symptoms of infusion reactions, patients should not drive the car or work with the mechanisms until the symptoms are completely resolved.

    Form release / dosage:Perieta® (pertuzumab), a concentrate for the preparation of a solution for infusions 420 mg / 14 ml; Herceptin® (trastuzumab), lyophilizate for the preparation of concentrate for the preparation of a solution for infusion 440 mg (vials).
    Packaging:

    Perieta ® (pertuzumab) - component number 1: 420 mg / 14 ml of perthuzumab in a bottle of colorless glass (hydrolytic class 1 EF), sealed with a stopper of butyl rubber laminated with fluoropolymer, crimped with an aluminum cap and covered with a brown plastic lid.

    Herceptin ® (trastuzumab) - component number 2: on 440 mg trastuzumab in a bottle of colorless glass (hydrolytic class 1 EF), sealed with a stopper of butyl rubber, crimped with an aluminum cap and covered with a plastic lid of a light green color. Bacteriostatic water for injection (solvent for Herceptin®) - component No. 3: 20 ml of bacteriostatic water for injection into a bottle of colorless glass (hydrolytic class 1 EF), sealed with a butyl rubber stopper, crimped with an aluminum cap and closed with a white plastic lid.

    1 bottle with Perieta ® (component No.1), 1 bottle with Herceptin ® (component No. 2) and 1 bottle of bacteriostatic water for injection - solvent for the preparation of Herceptin ® (component No. 3) is placed in a cardboard tray which, together with the instruction for the use of the Beyodeime® kit, is placed in a pack of cardboard for consumer packagings of subgroups of chromosome GOST 7933-89 or imported with partitions inside.

    For the purpose of controlling the first opening, stickers with the logo of JSC "ORTAT" are glued on the pack.

    Storage conditions:Store at 2-8 ° C in a dark place.
    Keep out of the reach of children.
    Shelf life:2 years. Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-002670
    Date of registration:22.10.2014 / 09.09.2015
    Expiration Date:22.10.2019
    Date of cancellation:2018-04-09
    The owner of the registration certificate:R-PHARM, CJSC R-PHARM, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspORTAT, CJSCORTAT, CJSC
    Information update date: & nbsp09.04.2018
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