Gertseptin
Producer: F. Hoffmann-La Roche Ltd., (Hoffman-la Roche Ltd) Switzerland
Code of automatic telephone exchange: L01XC03
Release form: Liquid dosage forms. Lyophilisate for preparation of solution for infusions.
General characteristics. Structure:
Active agent: трастузумаб-150 mg; 440 mg.
Excipients: A L-histidine a hydrochloride - 3,36 mg, a L-histidine - 2,16 mg, α,α-трегалозы a dihydrate - 136,2 mg, polysorbate of 20 - 0,60 mg.
Pharmacological properties:
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
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 phenomena of an allergy to Gertseptin® at her were absent.
Data on an immunogenicity at use of the drug Gertseptin® for cancer therapy of a stomach are absent.
Pharmacokinetics. The pharmacokinetics of a trastuzumab was studied at patients with metastatic RMZh and early stages of RMZh, and also at patients with a widespread carcinoma of the stomach. Special researches on studying of intermedicinal interaction were not conducted.
Breast cancer
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) a median of the expected area under a curve "concentration time" (AUC) in an equilibrium state in 3 weeks made estimates of these researches I of a phase, the II phase and the III phase at metastatic RMZh 1677 ¼ú*ñÑ¡ý/l after introduction of 3 doses (2 mg/kg) weekly and 1793 ¼ú*ñÑ¡ý/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 the 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 to the 6th week. Significant communication between the initial level of the antigen which is "exfoliated" from a cell and the clinical answer was not observed.
Widespread carcinoma of the stomach
Pharmacokinetics of a trastuzumab against the background of an equilibrium state
For assessment of pharmacokinetics of a trastuzumab against the background of an equilibrium state at patients with a widespread carcinoma of the stomach after introduction of a trastuzumab in a load dose of 8 mg/kg, with the subsequent introduction of 6 mg/kg each 3 weeks the nonlinear two-chamber population pharmacokinetic method with use of data of a research III of a phase was applied.
The observed levels of concentration of a trastuzumab in blood serum were lower, thus, it is revealed that the general clearance of drug at patients with a widespread carcinoma of the stomach is higher, than at patients from RMZh receiving трастузумаб in the same dose. The reason of it is unknown.
At high concentration the general clearance has preferential linear character, and the elimination half-life makes about 26 days.
The median of an estimated indicator of AUC (in an equilibrium state within 3 week periods) makes 1213 ¼ú*ßÒÔ¬¿/l, Cmax median in an equilibrium state - 132 mg/l, Cmin median - 27.6 mg/l.
Data on level of the circulating extracellular HER2-domain of a receptor (the antigen which is "exfoliated" from a cell) in serum of patients with a carcinoma of the stomach are absent.
Pharmacokinetics at special groups of patients
Separate pharmacokinetic researches at patients of senile age and patients with a renal or liver failure were not conducted.
Senile age
As it was shown, the age does not influence distribution of a trastuzumab.
Indications to use:
Breast cancer
Metastatic breast cancer with a tumoral hyper expression of HER2:
- in the form of monotherapy, after one or more schemes of chemotherapy;
- in a combination with paklitaksely or dotsetaksely, in case of lack of the previous chemotherapy (the first line of therapy);
- in a combination with aromatase inhibitors at positive hormonal receptors (estrogenic and/or progesteronovy) at women in a postmenopause.
Early stages of a breast cancer with a tumoral hyper expression of HER2:
- in the form of adjuvant therapy after carrying out surgical intervention, end of chemotherapy (neoadjuvant or adjuvant) and radiation therapy;
- in a combination with paklitaksely or the dotsetaksely ambassador of adjuvant chemotherapy doxorubicine and cyclophosphamide;
- in a combination with the adjuvant chemotherapy consisting of a dotsetaksel and a karboplatin.
Widespread carcinoma of the stomach
Widespread adenocarcinoma of a stomach or esophageal and gastric transition with a tumoral hyper expression of HER2:
- in a combination with kapetsitabiny or intravenous administration of a ftoruratsil and drug of platinum in case of lack of the previous antineoplastic therapy concerning a metastatic disease.
Route of administration and doses:
Testing for a tumoral expression of HER2 prior to treatment by the drug Gertseptin® is obligatory.
Герцептин® enter only intravenously kapelno! To administer the drug intravenously struyno or it is bolyusno impossible!
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.
Solution preparation
Preparation of drug for introduction has to be carried out in aseptic conditions.
Bottle contents from 150 mg of the drug Gertseptin® are parted in 7.2 ml of sterile water for injections.
At dissolution it is necessary to avoid excess foaming, the last can complicate a set of the necessary dose of drug of a bottle.
Instruction for preparation of a concentrate
1. The sterile syringe slowly to enter 7.2 ml of sterile water for injections into a bottle from 150 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 pale yellow color.
Storage conditions of the prepared concentrate
The bottle from 150 mg of drug is used only once.
The drug Gertseptin® solution concentrate physically is also chemically stable during 24 h at a temperature of 2-8 °C after dissolution by sterile water for injections. Not to freeze!
Cultivation of a concentrate should be carried out directly after its preparation. In exceptional cases the concentrate can be stored no more than 24 h at a temperature of 2-8 °C if cultivation of a concentrate happened in the controlled and validirovanny aseptic conditions. At the same time the specialist preparing a concentrate is responsible for storage conditions (rules of storage and duration).
The instruction for preparation of solution for infusion
To determine solution volume:
body weight (kg) x dose (4 mg/kg of load or 2 mg/kg supporting)
Volume (ml) = —————————————————————————————————
21 (mg/ml, concentration of the prepared solution)
body weight (kg) x dose (8 mg/kg of load or 6 mg/kg supporting)
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 infusion can be stored no more than 24 h at a temperature of 2-8 °C if cultivation of a concentrate and preparation of solution for infusion 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 drug or expired
Hit of medicine to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. It is whenever possible necessary to use special systems for utilization of medicines.
Standard mode of dosing
During each introduction of a trastuzumab it is necessary to watch carefully the patient regarding emergence of a fever, fever and other infusional reactions (during 6 h after the beginning of the first infusion and during 2 h after the beginning of the subsequent infusions). Set has to be available to rendering the emergency help, and the medical specialist, experienced in treatment of an anaphylaxis has to carry out infusion.
In case of infusional reactions infusion is interrupted. After disappearance of symptoms infusion resuming is possible.
Metastatic breast cancer
Weekly introduction
Load dose: 4 mg/kg of body weight in the form of 90-minute intravenous drop infusion.
Maintenance dose: 2 mg/kg of body weight once a week. The maintenance dose is entered in 1 week after load. If the previous load dose was transferred well, the drug can be administered in the form of 30-minute drop infusion.
Alternative introduction - in 3 weeks
Load dose: 8 mg/kg of body weight in the form of 90-minute intravenous drop infusion.
Maintenance dose: 6 mg/kg of body weight each 3 weeks. 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.
Use in a combination with paklitaksely or dotsetaksely
In clinical trials paklitakset or dotsetakset were entered next day after administration of the drug Gertseptin® (the recommendation about dosing see in the corresponding instructions on a medical use) or at once after the subsequent administration of the drug Gertseptin® if at the previous introduction of Gertseptin® it was transferred well.
Use in a combination with aromatase inhibitor
In clinical trial of Gertseptin® and анастрозол were entered in day 1. Time limits on administration of the drug Gertseptin® and an anastrazol were not (recommendations about dosing see in the instruction on a medical use of an anastrazol or other inhibitors of aromatase).
Early stages of a breast cancer
Weekly introduction and introduction in 3 weeks
At introduction in 3 weeks a load dose: 8 mg/kg of body weight (in the form of 90-minute intravenous drop infusion).
Maintenance dose: 6 mg/kg of body weight each 3 weeks. 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.
At weekly introduction (in a load dose of 4 mg/kg of body weight, further in the body weight supporting 2 mg/kg once a week) together with the paklitaksely ambassador of chemotherapy doxorubicine and cyclophosphamide. The load dose is entered in the form of 90-minute intravenous drop infusion. If the previous load dose was transferred well, the drug can be administered in the form of 30-minute drop infusion.
Widespread carcinoma of the stomach
Introduction in 3 weeks
Load dose: 8 mg/kg of body weight in the form of 90-minute intravenous drop infusion.
Maintenance dose: 6 mg/kg of body weight each 3 weeks. 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.
Metastatic both early stages of RMZh and widespread carcinoma of the stomach
Therapy duration
In clinical trials patients with metastatic RMZh or a widespread carcinoma of the stomach received Gertseptin® before progressing of a disease. Patients with early stages of RMZh have to receive therapy by the drug Gertseptin® during 1 year (18 cycles at the mode in 3 weeks) or prior to a disease recurrence (depending on what will occur quicker).
The admission in planned introduction
If the admission in planned introduction of a trastuzumab made 7 days or less, it is necessary to administer as soon as possible the drug in a usual maintenance dose (the weekly mode: 2 mg/kg of body weight; mode each 3 weeks: 6 mg/kg of body weight), without expecting the following planned introduction. Further to administer the drug in a maintenance dose (the weekly mode: 2 mg/kg of body weight; mode each 3 weeks: 6 mg/kg of body weight) according to the established schedule.
If having rummaged in administration of drug made more than 7 days, it is necessary to enter a load dose of a trastuzumab again (the weekly mode: 4 mg/kg of body weight; mode each 3 weeks: 8 mg/kg of body weight), in the form of 90-minute intravenous drop infusion. Then to continue administration of drug in a maintenance dose (the weekly mode: 2 mg/kg of body weight; mode each 3 weeks: 6 mg/kg of body weight).
Dose adjustment
In clinical trials the dose of the drug Gertseptin® was not reduced. During emergence of the reversible miyelosupressiya caused by chemotherapy the therapy course can be continued by the drug Gertseptin® after a dose decline of chemotherapy or its temporary cancellation (according to the corresponding recommendations in application instructions of a paklitaksel, dotsetaksel or inhibitor of aromatase), on condition of careful control of the complications caused by a neutropenia.
Special instructions on dosing
Patients of senile age
Data confirm lack of change of distribution of the drug Gertseptin® depending on age. In clinical trials the dose by the patient of senile age was not reduced.
Children
Efficiency and safety of use for children are not established.
Features of use:
Treatment by the drug Gertseptin® should be carried out only under observation of the oncologist.
HER2 testing has to be held in specialized laboratory which can provide quality control of the procedure of testing.
Герцептин® it has to be used at patients with metastatic RMZh or early stages of RMZh only in the presence of a tumoral hyper expression of HER2 determined by method of immunohistochemical reaction (IGH), or gene amplification of HER2 determined by method of hybridization of in situ (FISH or SISH). It is necessary to use exact and validirovanny methods of definition.
Герцептин® it has to be used at patients with a metastatic carcinoma of the stomach only in the presence of the tumoral hyper expression of HER2 determined by the IGH method as IGH2+ and confirmed with results of SISH or FISH, or IGH3+. It is necessary to use exact and validirovanny methods of definition.
Now there are no data from clinical trials on the patients receiving Gertseptin® repeatedly after use in adjuvant therapy.
Infusional reactions, reactions similar on allergic and hypersensitivity
Infrequently at administration of the drug Gertseptin® there were serious infusional undesirable reactions: short wind, hypotension, rattles in lungs, hypertensia, a bronchospasm, a supraventricular tachyarrhythmia, decrease in saturation of hemoglobin oxygen, an anaphylaxis, a respiratory distress, a small tortoiseshell and a Quincke's disease. Most of them arose during infusion or during 2.5 h from the beginning of the first introduction. At emergence of infusional reaction it is necessary to stop introduction. It is necessary to watch carefully the patient before elimination of all symptoms. At most of patients elimination of symptoms was observed and further they received drug Gertseptin® infusions.
Effective therapy of serious reactions consists in use of inhalation of oxygen, beta адреностимуляторов, glucocorticosteroids. In rare instances these reactions were associated with a fatal outcome. The risk of development of lethal infusional reactions is higher at patients with the asthma at rest caused by metastasises in lungs or associated diseases therefore such patients should not carry out therapy by the drug Gertseptin®.
Cases at which after initial improvement the aggravation of symptoms, and also cases with the delayed prompt aggravation of symptoms was observed were reported. The lethal outcome arose within hours or one week after infusion. Seldom or never patients had symptoms of infusional reactions or pulmonary symptoms (in more than 6 h later began administrations of the drug Gertseptin®). It is necessary to warn patients about the possible delayed development of this symptoms and about need of immediate contact with the attending physician in case of their emergence.
The phenomena from lungs
At use of the drug Gertseptin® in the post-registration period the heavy phenomena from lungs which sometimes were followed lethal by an outcome were registered. Besides, cases of the intersticial pulmonary disease (IPD), including pulmonary infiltrates, an acute respiratory distress syndrome, pneumonia, a pneumonitis, a pleural exudate, a respiratory distress, an acute fluid lungs and pulmonary insufficiency were observed. The risk factors associated with IBL include: earlier carried out or accompanying therapy by other anti-neoplastic drugs which, as we know, are connected with IBL (taxons, gemcitabine, винорельбин and radiation therapy). These phenomena can arise as during infusion (as manifestations of infusional reactions), and is delayed. The risk of heavy reactions from lungs is higher at patients with the metastatic damage of lungs, associated diseases which are followed by an asthma at rest. Therefore such patients should not receive the drug Gertseptin®. It is necessary to be careful, especially at the patients receiving the accompanying therapy by taxons because of development of a pneumonitis.
Cardiotoxicity
The heart failure (the II-IV functional class on NYHA) noted after therapy by the drug Gertseptin® as monotherapy or in a combination with paklitaksely or dotsetaksely, especially after the chemotherapy containing anthracyclines (doxorubicine or эпирубицин), can be moderate severity or a heavy current and in some cases can lead to a lethal outcome.
Patients to whom purpose of the drug Gertseptin® is planned especially those from them which received drugs of an anthracycline row and cyclophosphamide earlier, have to undergo the careful cardiological inspection including collecting the anamnesis, physical survey, an electrocardiography, an echocardiography and/or a radio isotope ventrikulografiya or the magnetic and resonant tomography (MRT) in the beginning.
Prior to treatment by the drug Gertseptin® it is necessary to compare carefully possible advantage and risk of its appointment.
Герцептин® it is not necessary to appoint together with anthracyclines except for well controlled clinical trials in which monitoring of function of heart is carried out. Patients who received anthracyclines earlier have an increased risk of development of cardiotoxicity at therapy by the drug Gertseptin® though this risk is lower, than at combined use. As the elimination half-life of the drug Gertseptin® makes about 28-38 days, drug can be in blood up to 27 weeks after completion of therapy. At patients who receive anthracyclines after completion of treatment by the drug Gertseptin® increase in risk of cardiotoxicity is possible. Whenever possible doctors have to avoid purpose of chemotherapy on the basis of anthracyclines within 27 weeks after completion of therapy by the drug Gertseptin®. At use of drugs of an anthracycline row it is necessary to carry out careful monitoring of function of heart.
At patients with early stages of RMZh receiving Gertseptin® after chemotherapy on the basis of anthracyclines increase in frequency of the symptomatic and asymptomatic undesirable phenomena from heart in comparison by that was observed, receiving chemotherapy dotsetaksely and karboplatiny (the modes which are not containing a praparata of an anthracycline row). At the same time the difference was more in cases of combined use of the drug Gertseptin® and taxons, than at consecutive use.
Irrespective of the used mode, the majority of the symptomatic cardial phenomena arose in the first 18 months of treatment. In one of 3 conducted basic researches (with a median of the period of the subsequent observation of 5.5 years) long increase in cumulative frequency of the symptomatic cardial phenomena or phenomena connected with decrease in the fraction of emission of a left ventricle (FELV) was observed: at 2.37% of the patients receiving Gertseptin® together with taxons after therapy by anthracyclines in comparison with 1% of patients in groups of comparison (in group of therapy by anthracyclines and cyclophosphamide further taxons and in group of therapy by taxons, karboplatiny and the drug Gertseptin®).
As patients at early stages of RMZh with the established congestive heart failure in the anamnesis, not controlled arrhythmias of high risk, the stenocardia demanding drug treatment, clinically significant heart diseases, symptoms of a transmural myocardial infarction according to the ECG which is badly controlled by arterial hypertension did not take part in clinical trial, information on a ratio advantage/risk at such patients is absent and therefore treatment by drug is not recommended to such patients.
It is necessary to consider carrying out standard cardiological inspection at patients with standard risk factors of cardiovascular diseases (for example, obesity, a lipidemia, smoking, arterial hypertension, etc.) after initial screening.
During treatment by the drug Gertseptin® it is necessary to investigate function of heart each 3 months. Monitoring of function of heart can help with identification of patients with myocardium dysfunction.
For patients with early stages of RMZh assessment of function of heart should be carried out initially and to repeat each 3 months during therapy, each 6 months after the end of therapy within 24 months after the last administration of drug. Also further monitoring of function of heart is recommended to the patients receiving the chemotherapy containing drugs of an anthracycline row: annually within 5 years after the last introduction or longer if the continuing decrease in FVLZh is observed.
At asymptomatic dysfunction of heart to carry out monitoring of a state reasonablly more often (for example, each 6-8 weeks). In the presence of the continuing decrease in FVLZh, even for lack of clinical symptoms, it is necessary to consider expediency of interruption of therapy by the drug Gertseptin® provided that at the specific patient it does not give overt clinical effect. At treatment of patients with already available symptomatic heart failure, arterial hypertension or the established coronary heart disease, and at patients with early stages of RMZh and FVLZh <55% it is necessary to show extra care.
At decrease in FVLZh of a reference value and it is lower than 50% for 10 points, therapy by the drug Gertseptin® it is necessary to interrupt and conduct repeated research FVLZh in 3 weeks if FVLZh did not improve, therapy should be cancelled if only the advantage of its use for the specific patient significantly does not exceed risk.
It is necessary to direct such patients to the cardiologist for inspection and observation.
At emergence of symptoms of heart failure during therapy the drug Gertseptin® it is necessary to appoint standard therapy. At patients with clinically significant symptoms of heart failure therapy with the drug Gertseptin® needs to be interrupted if only the advantage of its use for the specific patient significantly does not exceed risk.
Safety of continuation or resuming of therapy was not studied by the drug Gertseptin® at the patients who tested the cardiotoxicity phenomena in prospective researches. However, the condition of most of patients at whom heart failure in basic researches developed improved when performing the standard medicamentous therapy including diuretic, cardiac glycosides and/or inhibitors of an angiotensin-converting enzyme. Most of patients with cardial symptoms at which treatment by the drug Gertseptin® effectively, continued therapy by the drug Gertseptin® without heart aggravation of symptoms.
Women of childbearing age during treatment by the drug Gertseptin® and, at least, within 6 months after the end of treatment need to use reliable methods of contraception.
In case of approach of pregnancy it is necessary to warn the woman about a possibility of harmful effects on a fruit. If the pregnant woman receives therapy by the drug Gertseptin®, then it has to be under careful observation of doctors of different specialties. It is unknown whether Gertseptin® influences reproductive ability at women. Results of experiments on animals did not reveal signs of disturbance of fertility or a negative impact on a fruit.
Feeding by breast milk is not recommended during treatment and, at least, within 6 months after the end of therapy by the drug Gertseptin®.
The sterile water for injections which is used for cultivation of contents of a bottle from 150 mg of the drug Gertseptin® does not contain benzyl alcohol.
Influence on ability to drive the car and work with mechanisms
Researches on studying of influence of drug on ability to drive the car and to work with mechanisms were not conducted. In case of symptoms of infusional reactions patients should not drive the car or to work with mechanisms to full permission of symptoms.
Side effects:
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 the pulmonary undesirable phenomena.
For the description of frequency of undesirable reactions in this section the following classification is used: very often (> 1/10), it is frequent (> 1/100, 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.
Undesirable reactions about which it was reported at use of the drug Gertseptin® both in monotherapy, and in a combination with chemotherapy in basic clinical trials and at post-marketing use are given below.
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, decrease in number leukocytes/leukopenia; it is unknown - a prothrombinopenia.
Disturbances from immune system: often - hypersensitivity; it is unknown - anaphylactic reactions †, an acute anaphylaxis †.
Disturbances from a metabolism and food: often - decrease in body weight, anorexia; it is unknown - a giperkalemiya.
Disturbances of mentality: often - alarm, a depression, sleeplessness, disturbance of thinking.
Disturbances from a nervous system: very often - tremor1, dizziness, headaches; often - a peripheral neuropathy, paresthesias, a muscle hyper tone, drowsiness, a dysgeusia, an ataxy; seldom - paresis; it is unknown - wet brain.
Disturbances from an organ of sight: often - a xerophthalmus, the raised slezootdeleniye; it is unknown - a papilledema, a retinal apoplexy.
Disturbances from an acoustic organ and labyrinth disturbances: infrequently - deafness.
Disturbances from heart: very often - decrease and increase in AD1, disturbance cordial ritma1, serdtsebiyeniye1, trepetaniye1, decrease in fraction of emission *; often - heart failure (congestive) † (2%), a supraventricular tachyarrhythmia †1, a cardiomyopathy; infrequently - a pericardiac exudate; it is unknown - cardiogenic shock, a pericardis, bradycardia, the present cantering rhythm.
Disturbances from vessels: often - hypotension †1, a vazodilatation.
Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often - rattles †1, an asthma † (14%); often - asthma, cough, nasal bleeding, dysfunction of lungs, pharyngitis, a rhinorrhea; infrequently - a pleural exudate †; seldom - a pneumonitis; it is unknown - pulmonary fibrosis †, a respiratory distress †, respiratory insufficiency †, infiltration of lungs †, an acute fluid lungs †, an acute respiratory distress a 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, makulopapulezny rash, disturbance of structure of nails, an itch; it is unknown - a Quincke's disease, dermatitis, a small tortoiseshell.
Disturbances from skeletal and muscular 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, fatal a 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, a pyrexia; 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.
†-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 specified 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> 1/10 in any of groups of therapy without significant difference between group of the therapy containing Gertseptin®, and group of therapy of comparison: a lethargy, a giposteziya, extremity pains, mouth and drink pain, conjunctivitis, a limfoyedema, increase in body weight, nail toxicity, musculoskeletal pain, pharyngitis, bronchitis, discomfort in breasts, pain in epigastriums, gastritis, stomatitis, вертиго, inflows, hypertensia, 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, reactions similar on allergic and hypersensitivity
It is counted that about 40% of the patients receiving Gertseptin® will experience infusional reactions in this or that form. However the majority of infusional reactions are easy and moderate on severity (on NCI-CTC classification) 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 a trastuzumab 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 Gertseptin® is consecutive (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 who tested the cardiotoxicity phenomena. However the condition of most of the patients who tested heart failure in basic researches improved at purpose of standard therapy which included diuretics, cardiac glycosides, beta-blockers and/or inhibitors of an angiotensin-converting enzyme.
Most of patients with cardial symptoms and signs of clinical advantage of therapy by the drug Gertseptin® continued therapy without emergence of additional clinically significant cardial phenomena.
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 a trastuzumab in a combination with the dotsetaksely ambassador of therapy by drugs of an anthracycline row.
Pulmonary phenomena
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 a syndrome, pneumonia, a pneumonitis, a pleural exudate, a respiratory distress, an acute fluid lungs and pulmonary insufficiency.
Interaction with other medicines:
Special researches of medicinal interactions of the drug Gertseptin® 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.
Герцептин® it is not compatible from 5% dextrose solution because of a possibility of aggregation of protein.
Герцептин® it is impossible to mix or dissolve together with other medicines.
Incompatibility signs between the solution of the drug Gertseptin® and infusional packages made of polyvinylchloride, polyethylene or polypropylene was not observed.
Contraindications:
Hypersensitivity to a trastuzumab or any other component of drug.
Pregnancy and period of breastfeeding.
Children's age (efficiency and safety of use for children are not established).
The heavy asthma at rest caused by metastasises in lungs, or demanding a maintenance therapy oxygen.
With care to apply at:
Coronary heart disease, the arterial hypertension, heart failure, associated diseases of lungs or metastasises in lungs preceding therapy by cardiotoxic medicines, including anthracyclines / cyclophosphamide.
Overdose:
In clinical trials of cases of overdose of drug it was not observed. Administration of the drug Gertseptin® in single doses more than 10 mg/kg was not studied. The drug Gertseptin® in doses <10 mg/kg was transferred well.
Storage conditions:
To store at a temperature of 2-8 °C. To store in the place, unavailable to children.
Issue conditions:
According to the recipe
Packaging:
Lyophilisate for preparation of solution for infusions, 150 mg
On 150 mg of a trastuzumab in the bottles made of colourless glass of a hydrolytic class I, corked by traffic jams from butyl rubber, closed by aluminum caps and plastic covers. On 1 bottle together with the application instruction place in a cardboard pack.
Lyophilisate for preparation of a concentrate for preparation of solution for infusions of 440 mg
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.
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.
1 bottle with drug and 1 bottle with solvent together with the application instruction is placed in a cardboard pack.
