Бейодайм®

General characteristics. Structure:

Active ingredient: 420 mg of a pertuzumab

Excipients: A L-histidine, acetic acid ice, sucrose, polysorbate 20, water for injections.

Active ingredient: 440 mg of a trastuzumab.

Excipient: L-histidine hydrochloride, L-histidine, α,α-трегалозы dihydrate, polysorbate 20.

Solvent for the drug Gertseptin® contains: benzyl alcohol, water for injections. Bacteriostatic water for injections (20 ml) contains 1.1% of benzyl alcohol as antimicrobic preservative.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Pertuzumab. Pertuzumab represents the recombinant humanized monoclones which selectively interact with the extracellular HER2 subdomain II (a receptor of an epidermal growth factor of the person of the 2nd type) which is responsible for dimerization. Linkng of a pertuzumab with the subdomain II blocks process a ligand - dependent heterodimerization of HER2 with other proteins of the HER family, including EGFR (a receptor of an epidermal growth factor of the person), HER3 (a receptor of an epidermal growth factor of the person of the 3rd type) and HER4 (a receptor of an epidermal growth factor of the person of the 4th type). Thus, пертузумаб inhibits a ligand - the initiated transfer of intracellular signals on two main alarm ways: a way a mitogen - the activated protein kinase (MAR) and a way of a fosfoinozitid-3-kinase (PI3K). Oppression of these alarm ways is capable to lead to a stunt of cells and apoptosis, respectively. Besides, пертузумаб activation is promoted by the antibody-dependent cellular cytotoxicity (ADCC).

The molecular mass of a pertuzumab makes about 148 kd, and it is expected that, as well as other monoclones, пертузумаб practically does not pass through a blood-brain barrier.

Pertuzumab in the form of the monoagent inhibits proliferation of cells of a tumor of the person. Strengthening of antineoplastic activity of a pertuzumab on models of heterografts with HER2 hyper expression at its use in a combination with trastuzumaby is shown.

Trastuzumab. Trastuzumab represents recombinant DNA derivatives the humanized monoclones which selectively interact with the extracellular domain of receptors of an epidermal growth factor of the person 2 types (HER2). These antibodies represent IgG1 consisting of human regions (constant sites of heavy chains) and HER2 defining a complementarity of mouse sites of an antibody r185 to HER2.

HER2 or with-erB2 protooncogene codes transmembrane retseptoropodobny protein with a molecular weight of 185 kd which is structurally similar to other members of family of receptors of an epidermal growth factor. The hyper expression of HER2 is found in fabric of primary breast cancer (BC) in 25-30% of patients and in fabric of a widespread carcinoma of the stomach in 6.8-42.6% of patients. Gene amplification of HER2 leads to a protein HER2 hyper expression on a membrane of cells of a tumor that in turn causes continuous activation of a receptor of HER2.

Researches show that patients with cancer of a mammary gland at whom amplification or a hyper expression of HER2 in tumor fabric is noted have smaller survival without symptoms of a disease in comparison with patients without amplification or a hyper expression of HER2 in tumor fabric.

Trastuzumab blocks proliferation of tumor cells of the person with a hyper expression of HER2 in vivo and in vitro. In vitro an antibody - dependent cellular cytotoxicity of a trastuzumab is preferential directed to tumor cells with HER2 hyper expression. 

Immunogenicity. Pertuzumab. Approximately anti-therapeutic antibodies (ATA) were found in 6.2% of the patients receiving therapy trastuzumaby in a combination with dotsetaksely and in 2.8% of the patients receiving трастузумаб in a combination with dotsetaksely and pertuzumaby. Communication of antibody formation to a pertuzumab with development of anaphylactic reaction / reaction of hypersensitivity was not authentically established at one of patients.

Trastuzumab. Antibodies to a trastuzumab were found in one of 903 patients from RMZh receiving drug in monotherapy or in a combination with chemotherapy, at the same time the allergy phenomena on трастузумаб at it were absent.

Comparison of frequency of detection of antibodies to a pertuzumab and a trastuzumab and frequencies of detection of antibodies to other biological drugs can be not informative as results of the analysis of an immunogenicity substantially depend on various factors, such as sensitivity and specificity of the analysis, methodology of carrying out the analysis, manipulation with the taken-away samples, sampling time, the accompanying drugs and character of a basic disease.

Pharmacokinetics. Pertuzumab. The pharmacokinetics of a pertuzumab after intravenous administration (in/in) in various doses (from 2 to 25 mg/kg) at patients with different types of a tumor was studied.

The clearance of a pertuzumab did not depend on a dose and the indication.

Pharmacokinetic parameters do not depend on age, sex and an ethnic origin (Japanese and other ethnic groups).

Initial concentration of albumine and size of "the lean body weight" (the size characterizing body weight minus the mass of fatty tissue) exert insignificant impact on clearance of a pertuzumab, at the same time need of dose adjustment of a pertuzumab depending on initial concentration of albumine or body weight is absent.

Absorption. Pertuzumab is entered in / century. Other ways of administration of drug were not studied.

Distribution. Later in/in introductions distribution volume in the central camera (VYos) makes 3.07 l and is approximately equal to plasma volume. Vc value and the volume of distribution of a pertuzumab at an equilibrium state (VYoYoSS) demonstrate that distribution happens only in plasma and extracellular liquid.

Metabolism. Metabolism of a pertuzumab was not studied. As well as other antibodies, пертузумаб preferential is exposed to a catabolism.

Removal. The clearance of a pertuzumab makes about 0.239 l/days, the elimination half-life (TYo1/2) is approximately equal to 17.2 days.

Trastuzumab. At administration of drug in the form of short intravenous infusions in a dose of 10, 50, 100, 250 and 500 mg once a week the pharmacokinetics had nonlinear character. At increase in a dose the clearance of drug decreased.

Elimination half-life. The elimination half-life makes 28-38 days, therefore, the removal period after drug withdrawal - up to 27 weeks (190 days or 5 elimination half-lives).

Pharmacokinetics of a trastuzumab against the background of an equilibrium state. The equilibrium state has to be reached approximately in 25 weeks.

When using a population pharmacokinetic method (two-chamber model, model - the dependent analysis) estimates of these researches I of a phase, the II phase and the III phase at metastatic RMZh a median of the expected area under a curve "concentration time" (AUC) in an equilibrium state in 3 weeks made 1677 mg • days/l after introduction of 3 doses (2 mg/kg) weekly and 1793 mg • days/l at introduction in 3 weeks in a dose of 6 mg/kg. The calculated medians of the maximum concentration (Cmax) made 104 mg/l and 189 mg/l, and the minimum concentration (Cmin) – 64.9 mg/l and 47.3 mg/l, respectively. When using model - an independent or "not chamber" method of the analysis (non-compartmental analysis, NCA) average Cmin in an equilibrium state to the 13th cycle (the 37th week) made 63 mg/l at patients with early stages of RMZh receiving трастузумаб in a load dose of 8 mg/kg then in supporting 6 mg/kg, in 3 weeks, and was comparable with that at patients from mRMZh receiving трастузумаб weekly.

Clearance. The typical clearance of a trastuzumab (for the patient with the body weight of 68 kg) made 0.241 l/days.

Distribution volume. In all clinical trials distribution volume in the central camera (Vc) made 3.02 l, in peripheral (Vp) – 2.68 l for the typical patient.

The circulating extracellular HER2-domain of a receptor (which is "exfoliated" from a cell antigen). In blood serum of some patients with RMZh and HER2 the hyper expression found the circulating extracellular HER2-domain of a receptor (which is "exfoliated" from a cell antigen). The antigen which is "exfoliated" from a cell in the concentration reaching 1880 ng/ml (a median of 11 ng/ml) is found in 64% of the inspected patients in initial samples of serum. The patients who had the high level of concentration of the antigen which is "exfoliated" from a cell probably could have lower Cmin. However at most of patients with the increased level of the antigen which is "exfoliated" from a cell at administration of drug weekly target concentration of a trastuzumab in serum was reached by 6th week. Significant communication between the initial level of the antigen which is "exfoliated" from a cell and the clinical answer was not observed.

Pharmacokinetics at special groups of patients. Pertuzumab. Patients of advanced and senile age. Special researches of pharmacokinetics of a pertuzumab at patients elderly (≥65 years) and senile (≥75 years) age were not conducted. By results of the population analysis the age does not exert impact on pharmacokinetic parameters of a pertuzumab.

Patients with a renal failure. Special researches of pharmacokinetics of a pertuzumab at patients with a renal failure were not conducted. By results of the population analysis a renal failure easy (the clearance of creatinine (CC) of 60-90 ml/min.), average (KK of 30-60 ml/min.) and heavy degree (KK <30 ml/min.) does not exert impact on exposure of a pertuzumab. Data for patients with an average and heavy renal failure are limited.

Patients with an abnormal liver function. Studying of pharmacokinetics of a pertuzumab at patients with an abnormal liver function was not carried out.

Trastuzumab. Special researches of pharmacokinetics of a trastuzumab at patients of advanced and senile age and patients with a renal or liver failure were not conducted.

Patients of advanced and senile age. The age does not influence distribution of a trastuzumab.

Indications to use:

Metastatic or local and recurrent, inoperable breast cancer with a tumoral hyper expression of HER2 in a combination with dotsetaksely in the absence of earlier carried out treatment or when progressing a disease after performing adjuvant therapy.

Route of administration and doses:

Prior to treatment by components of the Beyodaym® set it is necessary to hold testing for a tumoral expression of HER2. Obligatory criterion are 3+ points by results of the immunohistochemical analysis (IHC) and/or extent of amplification ≥2.0 by results of hybridization of in situ (ISH). It is necessary to use exact and validirovanny methods of testing. Detailed instructions on conducting HER2 testing and interpretation of its results are provided in application instructions of the validirovanny test systems intended for definition of HER2 of the status.

Beyodaym® set components (Peryeta® and Gertseptin®) enter only intravenously kapelno! To enter Beyodaym® set components intravenously struyno or it is bolyusno impossible!

Beyodaym® set components (Peryeta® and Gertseptin®) can be entered in any sequence. After each infusion of the drug Peryeta® and until administration of the drug Gertseptin® or a dotsetaksel observation of the patient within 30-60 minutes is recommended. Dotsetaksel is recommended to enter after introduction of all components of the Beyodaym® set.
 
Dosing mode. Перьета® (пертузумаб) - a component No. 1. Infusion duration at introduction of the first dose has to make 60 minutes. If the first infusion is transferred well, the subsequent can be carried out for 30-60 minutes. A load dose of the drug Peryeta® - 840 mg in the form of 60-minute intravenous drop infusion. The maintenance dose of the drug Peryeta® - to 420 mg is each 3 weeks in the form of intravenous drop infusion within 30-60 minutes. The maintenance dose is entered in 3 weeks after load.

Герцептин® (трастузумаб) - a component No. 2. A load dose of the drug Gertseptin® - 8 mg/kg of body weight in the form of 90-minute intravenous drop infusion. A maintenance dose of the drug Gertseptin® - 6 mg/kg of body weight each 3 weeks in the form of intravenous drop infusion within 30-90 minutes. The maintenance dose is entered in 3 weeks after load. If the previous load dose was transferred well, the drug can be administered in the form of 30-minute drop infusion.

Dotsetaksel. At use in a combination with the Beyodaym® set the recommended initial dose of a dotsetaksel makes 75 mg/sq.m in the form of intravenous infusion then it is necessary to administer the drug in the same dose each 3 weeks. At good tolerance in the first cycle the dose of a dotsetaksel can be increased to 100 mg/sq.m in the subsequent cycles.

Treatment duration. Treatment should be continued before emergence of signs of progressing of a disease or unacceptable toxicity.

The admission in planned introduction. Перьета® (пертузумаб) - a component No. 1. If having rummaged in planned administration of the drug Peryeta® made less than 6 weeks, it is necessary to administer the drug in a dose of 420 mg in the form of 30-60-minute intravenous drop infusion as soon as possible, without waiting for the following planned introduction.

If having rummaged in administration of the drug Peryeta® made 6 weeks and more, it is necessary to administer the drug in an initial dose of 840 mg in the form of 60-minute intravenous drop infusion. Then, 3 weeks later to continue administration of drug in a maintenance dose of 420 mg each 3 weeks in the form of 30-60-minute intravenous infusion.

Герцептин® (трастузумаб) - a component No. 2. If having rummaged in planned administration of the drug Gertseptin® made less than 6 weeks, it is necessary to administer the drug in a dose of 6 mg/kg as soon as possible, without waiting for the following planned introduction.
If having rummaged in administration of the drug Gertseptin® made 6 weeks and more, it is necessary to administer the drug in a load dose of 8 mg/kg in the form of intravenous drop infusion lasting about 90 minutes. Then, 3 weeks later to continue administration of drug in a maintenance dose of 6 mg/kg each 3 weeks.

Dose adjustment. The dose decline of each of components is not recommended. If treatment is cancelled by one of components of the Beyodaym® set, use of other component of the Beyodaym® set also should be cancelled.

During emergence of the reversible miyelosupressiya caused by chemotherapy therapy by components of the Beyodaym® set can be continued, on condition of careful control of the complications caused by a neutropenia. Instructions on modification of a dose of a dotsetaksel are provided in the instruction on a medical use of a dotsetaksel. At cancellation of a dotsetaksel treatment by components of the Beyodaym® set can be continued before progressing of a disease or development of unacceptable toxicity.

Dysfunction of a left ventricle. Therapy by components of the Beyodaym® set has to be suspended at least for 3 weeks in the following cases:
- decrease in FVLZh to level is lower than 40%;
- FVLZh values of 40-45% at decrease in FVLZh by ≥10% in relation to the values observed before treatment.

It is possible to resume treatment if FVLZh is recovered to level> 45% or 40-45% at decrease on <10% in relation to the values observed before treatment.

If according to repeated assessment in 3 weeks of FVLZh there is no its further decrease, treatment should be cancelled if only the advantage for the specific patient does not surpass risk.

Infusional reactions. The medical specialist having experience of treatment of an anaphylaxis, and also access to funds for rendering the emergency help has to carry out infusions.

At development of infusional reaction it is necessary to reduce the speed of infusion or for a while to stop introduction.

At development of serious reaction of hypersensitivity it is necessary to interrupt immediately infusion and to completely stop therapy.

Special instructions on dosing. Patients of advanced and senile age. Dose adjustment of components of the Beyodaym® set and at patients of senile age is not required from elderly patients.

Patients with a renal failure. Efficiency and safety of components of the Beyodaym® set at patients with a renal failure were not studied.

Patients with an abnormal liver function. Efficiency and safety of components of the Beyodaym® set at patients with an abnormal liver function were not studied.

Patients of children's age. Efficiency and safety of components of the Beyodaym® set at children and teenagers aged up to 18 years were not studied.

Preparation of solution for infusions. Beyodaym® set components (Peryeta® and Gertseptin®) have to be applied only consistently. It is obligatory to carry out cultivation of components in separate infusional packages!

Перьета® (пертузумаб) - a component No. 1. Attention! The drug Peryeta® is not compatible from 5% dextrose solution. Cultivation in such solution results in chemical and physical instability of a pertuzumab. Drug should be dissolved only in 0.9% chloride sodium solution.

The drug Peryeta® cannot be mixed or dissolved together with other medicines. Solution of the drug Peryeta® is compatible to the infusional packages made of polyvinylchloride (PVC), polyethylene and not containing PVC of polyolefin.

Preparation of drug for introduction has to be carried out in aseptic conditions. Перьета® (пертузумаб) does not contain antimicrobic preservatives. In this regard it is necessary to take precautionary measures for preservation of sterility of the prepared solution for infusions.

From a bottle (bottles) it is necessary to select all liquid concentrate and to enter it into an infusional package from 250 ml of 0.9% of solution of sodium of chloride. Concentration of ready solution makes about 3.36 mg/ml (840 mg / 250 ml) for load and 1.68 mg/ml (420 mg / 250 ml) for a maintenance dose.

Then the infusional package needs to be turned carefully for solution hashing, avoiding foaming. Before introduction drug should be checked (visually) regarding lack of mechanical impurity and change of coloring. Solution for infusions is entered immediately after its preparation. 

In exceptional cases the prepared solution of the drug Peryeta® can be stored no more than 24 hours at a temperature of 2-8 °C if preparation of solution for infusions happened in the controlled and validirovanny aseptic conditions. At the same time the specialist preparing solution is responsible for storage conditions (rules of storage and duration).

Герцептин® (трастузумаб) - a component No. 2. Attention! Герцептин® it is not compatible from 5% dextrose solution because of a possibility of aggregation of protein.

Герцептин® it is impossible to mix or part together with other medicines. Solution of the drug Gertseptin® is compatible to the infusional packages made of polyvinylchloride, polyethylene and polypropylene.
Preparation of drug for introduction has to be carried out in aseptic conditions.

Instruction for preparation of a concentrate. Bottle contents with the drug Gertseptin® are dissolved in 20 ml of the bacteriostatic water delivered in set for injections containing 1.1% of benzyl alcohol as antimicrobic preservative. As a result the solution concentrate suitable for repeated use which is containing 21 mg of the drug Gertseptin® in 1 ml and having рН 6.0 turns out.

During dissolution it is necessary to handle drug accurately. At dissolution it is necessary to avoid excess foaming, the last can complicate a set of the necessary dose of drug of a bottle.

1.     The sterile syringe slowly to enter 20 ml of bacteriostatic water for injections into a bottle from 440 mg of the drug Gertseptin®, directing a liquid stream directly to lyophilisate.
2.     For dissolution it is accurate to shake a bottle rotary motions. Not to stir up!
At dissolution of drug a small amount of foam is quite often formed. In order to avoid it it is necessary to allow to solution to stand about 5 minutes. The prepared concentrate has to be transparent and colourless or have light yellow color.

The drug Gertseptin® solution concentrate prepared on bacteriostatic water for injections is stable within 28 days at a temperature of 2-8 °C. The prepared concentrate contains preservative and therefore it can be reused. In 28 days the unused rest of a concentrate should be destroyed. Not to freeze!

As solvent of the drug Gertseptin® use of sterile water for injections is allowed (without preservative). Use of other solvents is not recommended. In case of use as solvent of sterile water for injections, the concentrate physically is also chemically stable only within 24 hours at a temperature of 2-8 °C and has to be destroyed after this time. Not to freeze!

The instruction for preparation of solution for infusion. To determine concentrate volume:
the volume necessary for introduction of a load dose of the drug Gertseptin®, equal 8 mg/kg of body weight, or the maintenance dose equal to 6 mg/kg each 3 weeks, is determined by the following formula:

        body weight (kg) x dose (8 mg/kg of load or 6 mg/kg supporting)
The volume (ml) =------------------------------------------------------------------------------------------
                       21 (mg/ml, concentration of the prepared solution)
 
From a bottle with the prepared concentrate it is necessary to gain the corresponding volume and to enter it into an infusional package from 250 ml of 0.9% of solution of sodium of chloride. Then the infusional package should be turned carefully for solution hashing, avoiding foaming. Before introduction solution should be checked (visually) regarding lack of mechanical impurity and change of coloring. Solution for infusions is entered immediately after its preparation.

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

Instructions for destruction of unused drugs or drugs expired. Hit of medicines to the environment has to be minimized. It is not necessary to utilize drugs by means of sewage or together with household waste. Destruction of unused drugs or drugs expired has to be carried out in compliance with requirements of medical institution. It is whenever possible necessary to use special systems for utilization of medicines.

Features of use:

Side effects:

Diarrhea, alopecia and neutropenia were the most frequent undesirable reactions (observed more than at 50% of patients), connected using the drug Peryeta® in a combination with the drug Gertseptin® and dotsetaksely.

The most often observed (> 10%) undesirable reactions of the 3-4th severity on classification of National institute of cancer of National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE), version 3, were the neutropenia, a febrile neutropenia and a leukopenia.

Dysfunction of a left ventricle, including symptomatic systolic dysfunction of a left ventricle (congestive heart failure) was the heaviest and clinically significant undesirable reaction observed with a frequency less than 10%.

As the combination of drugs was used, it is problematic to establish precisely cause and effect interrelation between the undesirable phenomenon and specific drug. For the description of frequency of undesirable reactions the following classification is used: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10000 and <1/1000) and is very rare (<1/10000), including isolated cases.

Disturbances from blood and lymphatic system: very often – a neutropenia, anemia, a leukopenia, a febrile neutropenia (including with a lethal outcome).

Disturbances from immune system: very often – hypersensitivity / anaphylactic reactions, infusional reactions / a syndrome of release of cytokines.

Disturbances from a metabolism and food: very often – a loss of appetite.

Disturbances of mentality: very often – sleeplessness.

Disturbances from a nervous system: very often – peripheral neuropathy, a headache, a dysgeusia (distortion of flavoring perceptions), dizziness.

Disturbances from an organ of sight: very often – the raised slezootdeleniye.

Disturbances from heart: often – dysfunction of a left ventricle, including congestive heart failure.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often – short wind, cough; often – a pleural exudate; infrequently – an intersticial pulmonary disease.

Disturbances from digestive tract: very often – diarrhea, nausea, vomiting, a lock, stomatitis, dyspepsia.

Disturbances from skin and hypodermic fabrics: very often – an alopecia, rash, pathology of nails, an itch, a xeroderma; often – paronychias.

Disturbances from skeletal and muscular and connecting fabric: very often – a mialgiya, an arthralgia.

The general frustration and disturbances in an injection site: very often – increased fatigue, an adynamy, peripheral hypostases, an inflammation of mucous membranes of various localization, pain, fervescence, accession of consecutive infections (upper respiratory tract infections, a nasopharyngitis); often – a fever.
 
After cancellation of a dotsetaksel all undesirable reactions were observed with a smaller frequency (<10%, except for diarrhea, upper respiratory tract infections, rash, a headache and fatigue (˃10%)).

Infusional reactions, reactions hypersensitivity/anaphylaxis. Any side reactions which development happened in the course of infusion or in day of infusion were referred to infusional reactions. After administration only of the drug Peryeta® the majority of infusional reactions had easy or moderate severity and were observed approximately at 20% of patients. (> 1.5%) nausea, fervescence, diarrhea, a fever, fatigue and a headache were the most frequent infusional reactions.

After simultaneous (in one day) administrations of the drug Peryeta®, the drug Gertseptin® and a dotsetaksel, since the second cycle of therapy (> 1.5%) infusional reactions the alopecia, nausea, a loss of appetite, increased fatigue, a lock, diarrhea, stomatitis and medicinal hypersensitivity were the most frequent.

The general frequency of the phenomena of a hypersensitivity/anaphylaxis made 9.1% after simultaneous (in one day) administrations of the drug Gertseptin® and a dotsetaksel and 10.8% after simultaneous administration of the drug Peryeta®, the drug Gertseptin® and a dotsetaksel; from these phenomena of 2.5% and 2% were characterized by the 3rd and 4th severity on NCI-CTCAE classification, version 3, respectively. In total at 2 patients after simultaneous administration of the drug Gertseptin® and a dotsetaksel and at 4 patients after simultaneous administration of the drug Peryeta®, the drug Gertseptin® and a dotsetaksel the anaphylaxis developed.

The majority of reactions of hypersensitivity were easy or moderate severity and were allowed after the corresponding treatment. By results of the analysis of reactions of hypersensitivity at change of the modes of dosing of drugs, it is established that the phenomena of hypersensitivity were connected with infusions of a dotsetaksel.

Aberrations of laboratory indicators. Frequency of cases of decrease in number of neutrophils of the 3-4th severity on NCI-CTCAE classification, version 3, was approximately identical at use of a combination of the drug Gertseptin® and a dotsetaksel along with the drug Peryeta® and without it.
 
Undesirable reactions about which it was reported at use of the drug Gertseptin® according to all approved indications, in the modes other than the mode of use of the Beyodaym® set in a combination with dotsetaksely are given below.

The drug Gertseptin® is often used in a combination with chemotherapeutic drugs, and also after completion of radiation therapy therefore definition of relationship of cause and effect of undesirable reactions with one of the applied drugs / radiation therapy is complicated.

Now the most serious and/or frequent undesirable reactions about which it was reported when using drug Gertseptin® are: cardiotoxicity, infusional reactions, a gematotoksichnost (in particular, a neutropenia) and disturbances from lungs.

For the description of frequency of undesirable reactions in this section the following classification is used: very often (³1/10), it is frequent (³1/100, but <1/10), infrequently (≥1/1000, but <1/100), is rare (≥1/10000, but <1/1000), is very rare (<1/10000), it is unknown (it cannot be calculated on the basis of the available data). Within each group undesirable reactions are presented according to decrease in gravity.

Frequency is specified according to most meeting in basic clinical trials.

Infectious and parasitic diseases: often – pneumonia † (<1%), neytropenichesky sepsis, cystitis, Herpes zoster, infections, flu, a nasopharyngitis, sinusitis, skin infections, rhinitis, upper respiratory tract infections, infections of urinary tract, an ugly face, phlegmon; infrequently – sepsis.

The high-quality, malignant and not specified new growths (including cysts and polyps): it is unknown – progressing of a malignant new growth, progressing of a new growth.

Disturbances from blood and lymphatic system: very often – a febrile neutropenia; often – anemia, a neutropenia, thrombocytopenia, a leukopenia; it is unknown – a prothrombinopenia.

Disturbances from immune system: often – hypersensitivity reactions; it is unknown – anaphylactic reactions †, an acute anaphylaxis †.

Disturbances from a metabolism: often – decrease in body weight, anorexia; it is unknown – a hyperpotassemia.

Disturbances of mentality: often – alarm, a depression, sleeplessness, disturbance of thinking.

Disturbances from a nervous system: very often – tremor1, dizziness, headaches; often – peripheral neuropathy, paresthesias, a muscle hyper tone, drowsiness, a dysgeusia (distortion of flavoring perceptions), an ataxy; seldom – paresis; it is unknown – wet brain.

Disturbances from an organ of sight: very often – conjunctivitis, the raised slezootdeleniye; often – a xerophthalmus; it is unknown – a papilledema, a retinal apoplexy.

Disturbances from an acoustic organ and labyrinth disturbances: infrequently – deafness.

 

Disturbances from cardiovascular system: very often – decrease and increase in the arterial pressure (AP) 1, disturbance cordial ritma1, serdtsebiyeniye1, trembling (auricles or ventricles) 1, decrease in fraction of emission of a left ventricle *, "inflows"; often – heart failure (congestive) † (2%), a supraventricular tachyarrhythmia †1, a cardiomyopathy, arterial hypotension †1, a vazodilatation; infrequently – a pericardiac exudate; it is unknown – cardiogenic shock, a pericardis, bradycardia, a rhythm of "gallop".

Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often – rattles †1, an asthma † (14%), cough, nasal bleeding, a rhinorrhea; often – bronchial asthma, dysfunction of lungs, pharyngitis; infrequently – a pleural exudate †; seldom – a pneumonitis; it is unknown – pulmonary fibrosis †, respiratory insufficiency †, infiltration of lungs †, an acute fluid lungs †, an acute respiratory distress syndrome †, a bronchospasm †, a hypoxia †, decrease in saturation of hemoglobin oxygen †, hypostasis of a throat, an orthopnea, lung hypostasis.

Disturbances from digestive tract: very often – diarrhea, vomiting, nausea, hypostasis gub1, abdominal pains; often – pancreatitis, dyspepsia, hemorrhoids, a lock, dryness in a mouth.

Disturbances from a liver and biliary tract: often – hepatitis, morbidity in a liver, hepatocellular damage; seldom – jaundice; it is unknown – a liver failure.

Disturbances from skin and hypodermic fabrics: very often – an erythema, rash, hypostasis litsa1; often – an acne, an alopecia, a xeroderma, an ecchymoma, a hyperhidrosis, makulo-papular rash, disturbance of structure of nails, an itch; it is unknown – a Quincke's disease, dermatitis, a small tortoiseshell.

Disturbances from musculoskeletal and connecting fabric: very often – an arthralgia, muscular skovannost1, a mialgiya; often – arthritis, dorsodynias, an ossalgiya, spasms of muscles, pain in a neck.

Disturbances from kidneys and urinary tract: often – a disease of kidneys; it is unknown – a hymenoid glomerulonephritis, a glomerulonefropatiya, a renal failure.

Influence on the course of pregnancy, puerperal and perinatal states: it is unknown – олигогидрамнион, a fatal hypoplasia of lungs and a hypoplasia of kidneys at a fruit.

Disturbances from generative organs and a mammary gland: often – an inflammation of milk gland / mastitis.

The general frustration and disturbances in an injection site: very often – an adynamy, stethalgias, a fever, weakness, a grippopodobny syndrome, infusional reactions, pains, fever; often – peripheral hypostases, an indisposition, mukozit, hypostases.
Injuries, intoxications and complications of manipulations: often – a bruise.

† – undesirable reactions which in messages were associated with a lethal outcome.
1 – undesirable reactions which were generally reported in association with infusional reactions (the exact percentage quantity is not established).
* – undesirable reactions were observed at a combination therapy after anthracyclines and in a combination with taxons.

In brackets the exact percentage indicator of frequency for those terms which were reported together with a fatal outcome with a frequency "often" is presented or "it is very frequent". The percentage indicator belongs to total number of these phenomena with a fatal outcome and without it.

The following undesirable reactions were reported in basic clinical trials with a frequency of ³1/10 in any of groups of therapy, without significant difference between group of the therapy containing трастузумаб and group of therapy of comparison: a lethargy, a hypesthesia, extremity pains, mouth and drink pain, conjunctivitis, a limfedema, increase in body weight, an onikhoklaziya, musculoskeletal pain, pharyngitis, bronchitis, discomfort in breasts, pain in epigastriums, gastritis, stomatitis, вертиго, arterial hypertension, a hiccups, a palmar and bottom syndrome, pain in mammary glands, онихорексис, an asthma at an exercise stress and a dysuria.

Below information on separate undesirable reactions is provided. Infusional reactions and reactions of hypersensitivity. It is counted that about 40% of the patients receiving the drug Gertseptin® experience infusional reactions in this or that form. However the majority of infusional reactions are easy and moderate on severity (according to NCI-CTC) and tend to arise in an initiation of treatment, i.e. during the 1, 2 and 3 infusion, at the subsequent introductions arise less often. Reactions include (but are not limited) the following symptoms: fever, fever, rash, nausea and vomiting, short wind and headache. The heavy anaphylactic reactions demanding immediate additional medical interventions most often can arise during the first or second infusion of the drug Gertseptin®, such reactions were associated with a lethal outcome.

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

In 3 basic clinical trials of use of the drug Gertseptin® in a combination with adjuvant chemotherapy the frequency of cardiac dysfunction 3/4 degrees (symptomatic congestive heart failure) did not differ from that at the patients receiving only chemotherapy (i.e. without the drug Gertseptin®), and at the patients receiving taxons and the drug Gertseptin® consistently (0.3-0.4%). Frequency was the greatest at the patients receiving Gertseptin® together with taxons (2.0%).

Safety of continuation or resuming of therapy was prospektivno not studied by the drug Gertseptin® at the patients testing the cardiotoxicity phenomena. However the condition of most of the patients testing heart failure in basic researches improved at purpose of standard therapy which included beta adrenoblockers and inhibitors of an angiotensin-converting enzyme or blockers of receptors of angiotensin.

Most of patients with cardial symptoms and signs of clinical advantage of therapy trastuzumaby continued therapy without emergence of additional clinically significant cardial phenomena.

Experience of use of the drug Gertseptin® in a combination with the low-dose modes of anthracyclines in neoadjuvant therapy is limited.

Hematologic toxicity. Very often there was a febrile neutropenia. The undesirable reactions arising often include anemia, a leukopenia, thrombocytopenia and a neutropenia. Frequency of emergence of a prothrombinopenia is unknown. The risk of a neutropenia can be slightly higher at use of the drug Gertseptin® in a combination with the dotsetaksely ambassador of therapy by drugs of an anthracycline row.

Disturbances from lungs. Using the drug Gertseptin® the heavy undesirable phenomena from lungs are associated (including with a fatal outcome). These reactions include (but are not limited): infiltrates in lungs, an acute respiratory distress syndrome, pneumonia, a pneumonitis, a pleural exudate, an acute fluid lungs and respiratory insufficiency.

Interaction with other medicines:

Перьета® (пертузумаб). Signs of pharmacokinetic interaction of a pertuzumab with trastuzumaby, dotsetaksely, gemcitabine, erlotiniby, kapetsitabiny are not revealed.

Герцептин® (трастузумаб). Special researches of medicinal interactions of the drug Gertseptin® at the person were not conducted. In clinical trials no clinically significant interactions with at the same time used drugs (including doxorubicine, paklitakset, dotsetakset, капецитабин or Cisplatinum) were noted.

Influence of a trastuzumab on pharmacokinetics of other antineoplastic drugs. The pharmacokinetic data obtained at women with HER2-positive metastatic RMZh assume that exposure paklitakset also doxorubicine and their main metabolites (6 - alpha гидроксипаклитаксел and доксорубицинол) does not change in the presence of a trastuzumab at introduction in a load dose (8 mg/kg or 4 mg/kg in/in), and then in a maintenance dose (to 6 mg/kg there are each 3 weeks or 2 mg/kg every week in/in).

Nevertheless, трастузумаб can increase the general exposure of one of metabolites of doxorubicine (7-dezoksi-13-digidrodoksorubitsinon), biological activity of this metabolite and clinical value of increase in its exposure are unknown.

Also dotsetakset the data obtained when studying use of a trastuzumab (4 mg/kg in a load dose and 2 mg/kg weekly, in/in, in supporting) (60 mg/sq.m) at the Japanese patients with HER2-positive metastatic RMZh, allow to assume that simultaneous introduction of a trastuzumab does not exert impact on pharmacokinetics of once entered dotsetaksel.

Results of studying of pharmacokinetics of a kapetsitabin and Cisplatinum when using in a combination with trastuzumaby or without it at the Japanese male and female patients with a widespread carcinoma of the stomach assume that exposure of biologically active metabolites of a kapetsitabin (for example, ftoruratsit) did not change at simultaneous use of Cisplatinum or Cisplatinum and trastuzumab. However higher concentration of a kapetsitabin and longer period of its semi-removal at a combination with trastuzumaby were registered. Data also specify that the pharmacokinetics of Cisplatinum did not change at simultaneous use of a kapetsitabin or kapetsitabin in a combination with trastuzumaby.

Influence of antineoplastic drugs on pharmacokinetics of a trastuzumab. When comparing of the simulated serumal concentration of a trastuzumab at its monotherapy (in a load dose of 4 mg/kg and supporting 2 mg/kg every week, in/in) and concentration of a trastuzumab at its use in a combination with dotsetaksely at the Japanese patients with HER2-positive metastatic RMZh of any signs testimonial of influence of a dotsetaksel on pharmacokinetics of a trastuzumab, it is not found.

Comparison of pharmacokinetic indicators at patients with HER2-along with paklitaksely and at use of a trastuzumab as monotherapy showed to positive metastatic RMZh at use of a trastuzumab that individual and average values of the minimum serumal concentration of a trastuzumab varied both within one group, and between groups, however any obvious effect of simultaneous introduction of a paklitaksel on pharmacokinetics of a trastuzumab was not observed.

Combined use with anastrozoly does not influence pharmacokinetics of a trastuzumab.

Contraindications:

Hypersensitivity to a pertuzumab, a trastuzumab, benzyl alcohol or to any excipient which is a part of components of the Beyodaym® set.

Pregnancy and period of breastfeeding. Children's age up to 18 years (efficiency and safety of use are not established). Values of fraction of emission of a left ventricle of heart (FVLZh) before treatment <50%.

Congestive heart failure in the anamnesis.

Uncontrollable arterial hypertension.

Recently postponed myocardial infarction.

The serious violations of a cordial rhythm demanding medicinal therapy at the time of purpose of the Beyodaym® set except for fibrillation of auricles and Bouveret's supraventricular disease.

The previous treatment by anthracyclines with a cumulative dose of doxorubicine or equivalent drug> 360 mg/sq.m.

Abnormal liver functions (efficiency and safety of use were not studied).

The heavy asthma at rest caused by metastasises in lungs or demanding a maintenance therapy oxygen.
 
With care. Decrease in FVLZh to level <50% against the background of the previous adjuvant therapy by the drug Gertseptin®; FVLZh values <55%; the previous treatment by cardiotoxic medicines, including anthracyclines/cyclophosphamide or the previous radiation therapy on area of a thorax; coronary heart disease, arterial hypertension, heart failure, associated diseases of lungs or metastasises in lungs; states which are capable to break function of a left ventricle; renal failures.

Overdose:

The maximum tolerable dose of the drug Peryeta® (пертузумаб) is not established. The single doses exceeding 25 mg/kg (1727 mg) were not studied.

In case of overdose it is necessary to watch attentively patients for the purpose of detection of signs or symptoms of undesirable reactions and purpose of the corresponding symptomatic treatment.

In clinical trials of cases of overdose of the drug Gertseptin® (трастузумаб) it was not observed. Administration of the drug Gertseptin® in single doses more than 10 mg/kg was not studied. Герцептин® in doses of ≤10 mg/kg it was transferred well.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging.

To store at a temperature of 2-8 °C in the place protected from light. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Перьета® (пертузумаб) – a component No. 1: on 420 mg / 14 ml of a pertuzumab in the bottle of colourless glass (a hydrolytic class 1 EF) corked by a stopper from the butyl rubber laminated by a ftorpolimer, which is pressed out by an aluminum cap and closed by a plastic cover of brown color.

Герцептин® (трастузумаб) – a component No. 2: on 440 mg of a trastuzumab in the bottle of colourless glass (a hydrolytic class 1 EF) corked by a stopper from butyl rubber, which is pressed out by an aluminum cap and closed by a plastic cover of light green color.

Bacteriostatic water for injections (solvent for the drug Gertseptin®) – a component No. 3: on 20 ml of bacteriostatic water for injections in the bottle of colourless glass (a hydrolytic class 1 EF) corked by a stopper from butyl rubber, which is pressed out by an aluminum cap and closed by a plastic cover of white color.

1 bottle with the drug Peryeta® (component No. 1), 1 bottle with the drug Gertseptin® (component No. 2) and 1 bottle with bacteriostatic water for injections – solvent for the drug Gertseptin® (component No. 3) is placed in the cardboard pallet which together with the application instruction of the Beyodaym® set place in a pack from a cardboard for a retail container of subgroups chrome-ersatz in accordance with GOST 7933-89 or import with partitions inside.
For the purpose of control of the first opening on a pack paste self-adhesive stickers with a logo of CJSC ORTAT.