Herceptin® (Herceptin®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTrastuzumabTrastuzumab
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  • Herceptin®
    solution PC 
    Hoffmann-La Roche Ltd.     Switzerland
  • Herceptin®
    lyophilizate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
  • Herceptin®
    lyophilizate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspLiofilizate for the preparation of concentrate for the preparation of solution for infusion.
    Composition:

    One multi-dose vial with lyophilizate 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.

    Solvent (bacteriostatic water for injection of 20 ml, containing 1.1% of benzene alcohol as an antimicrobial preservative): benzyl alcohol - 229.9 mg, water for injection - 20.9 ml.

    Description:
    Lyophilizate from white to light yellow color.

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

    Pharmacotherapeutic group:Antineoplastic agent - monoclonal antibodies.
    ATX: & nbsp

    L.01.X.C   Monoclonal antibodies

    L.01.X.C.03   Trastuzumab

    Pharmacodynamics:

    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 IgG1, consisting of human regions (constant sections of heavy chains) and determining the complementarity of mouse regions of the antibody p185 HER2 to HER2.

    Proto-oncogene HER2 or c-yegB2 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 15-20% of patients.

    Total frequency of detection HER2- positive status in the tissue of advanced gastric cancer in screening patients was 15% IHC (immunohistochemical reaction method) 3+ and IGH2 + / FISH+ (hybridization method in situ) or 22.1% when applying the broader definition of IHC + or FISH+. 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. The extracellular domain of the receptor (ECD, p 105) may fall into the bloodstream and be detected in serum samples. 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

    With neoadjuvant-adjuvant therapy, 7.0% of patients who received the drug intravenously appeared antibodies to trastuzumab (regardless of the presence of antibodies initially).

    The clinical significance of these antibodies is unknown. However, these antibodies do not appear to have a negative effect on pharmacokinetics, efficacy (defined as a complete pathological response), or the safety of trastuzumab when administered intravenously.

    Data on immunogenicity in the use of Herceptin ® for the treatment of gastric cancer are absent.

    Pharmacokinetics:

    The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer (MMR) and early stages of breast cancer, as well as in patients with advanced stomach cancer.Special studies on the study of inter-drug interaction were not conducted.

    Mammary cancer

    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 27 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 (CmOh) were 104 mg / l and 189 mg / l, and the minimum concentration (Cmin) - 64.9 mg / l and 47.3 mg / l, respectively. Average Cmin in the equilibrium state on day 21 of cycle 18 (the last cycle with a duration of treatment of 1 year) was 68.9 μg / ml, and CmOh- 225 μg / ml in patients with early 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 were comparable to those in patients with MMR.

    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 ("sluschivayuschiysya" with clot 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 the majority of patients with a high level of "sluschivayuschegosya" with the cell antigen with the introduction of the drug weeklythe 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.

    Common stomach cancer

    Pharmacokinetics of trastuzumab against the background of the equilibrium state

    To evaluate the pharmacokinetics of trastuzumab against a background of the equilibrium state, in patients with advanced gastric cancer after administration of trastuzumab at a loading dose of 8 mg / kg, followed by 6 mg / kg every 3 weeks, a non-linear two-compartment population pharmacokinetic method was used using Phase III data.

    The observed levels of serum trastuzumab concentrations were lower, thus, it was found that the overall clearance of the drug in patients with advanced stomach cancer is higher than in patients with breast cancer who receive trastuzumab in the same dose. The reason for this is unknown.

    At high concentrations, the overall clearance is primarily linear, and the elimination half-life is about 26 days.

    The median of the expected indicator AUC (in the equilibrium state over a 3 week period) is 1213 mg·day / l, median CmOh in the equilibrium state - 132 mg / l, median Cmin - 27.6 mg / l.

    Data on the level of the circulating extracellular domain HER2- receptor ("sluschivayuschiesya" with cells antigen) in the serum of patients with stomach cancer are absent. Pharmacokinetics in specific patient groups

    Individual pharmacokinetic studies in elderly patients and patients with renal or hepatic insufficiency have not been performed.

    Elderly age

    Age does not affect the distribution of trastuzumab.

    Indications:

    Mammary cancer

    Metastatic breast cancer with tumor overexpression HER2:

    - in the form of monotherapy, after one or more chemotherapy regimens;

    - in combination with paclitaxel or docetaxel, in the absence of prior chemotherapy (first-line therapy);

    - in combination with aromatase inhibitors at positive hormonal receptors (estrogen and / or progesterone) in postmenopausal women.

    Early stages of breast cancer with tumor overexpression HER2:

    - in the form of adjuvant therapy after surgical intervention, the completion of chemotherapy (neoadjuvant or adjuvant) and radiotherapytherapy;

    - in combination with paclitaxel or docetaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide;

    - in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin;

    - in combination with neoadjuvant chemotherapy and subsequent adjuvant monotherapy with Herceptin®, with a locally advanced (including inflammatory) disease, or in cases where the tumor size exceeds 2 cm in diameter.

    Common stomach cancer

    Common adenocarcinoma of the stomach or esophageal-gastric transition with tumor overexpression HER2:

    in combination with capecitabine or intravenous fluorouracil and a platinum drug in the absence of prior antitumor therapy for metastatic disease.

    Contraindications:
    Hypersensitivity to trastuzumab, to any component of the drug, incl. to benzyl alcohol contained as a preservative in bacteriostatic water for injection, which is applied to each multi-dose vial of 440 mg, or a mouse protein.
    Pregnancy and the period of breastfeeding.
    Children under 18 years of age (efficacy and safety of use in children not established).
    Severe shortness of breath at rest, caused by metastases to the lungs, or requiring maintenance therapy with oxygen.
    Patients in the early stages of breast cancer with a history of myocardial infarction, angina requiring treatment, chronic heart failure (NYHA functional class IIHA), LVEF <55%, cardiomyopathy, arrhythmia, clinically significant heart disease, uncontrolled arterial hypertension, hemodynamically significant pericardial effusion (efficacy and safety of the drug in these patient groups have not been studied); simultaneous application of the drug with anthracyclines in adjuvant therapy in patients with early stages of breast cancer.
    Carefully:Ischemic heart disease, arterial hypertension, heart failure, concomitant lung disease or lung metastases, previous therapy with cardiotoxic drugs, incl. anthracycline / cyclophosphamide, left ventricular ejection fraction (LVEF) <50%, advanced age.
    Pregnancy and lactation:

    Pregnancy

    Women of childbearing age during treatment with Herceptin® and, at least, within 7 months after the end of treatment, it is necessary to use reliable methods of contraception.

    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 with Herceptin ®, then she should be under close supervision of doctors of different specialties (see also the section "Contraindications"),

    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.

    Breastfeeding period

    Breastfeeding is not recommended during treatment and at least 7 months after the completion of Herceptin® therapy (see also "Contraindications").

    Dosing and Administration:
    Testing for tumor expression of HER2 before starting treatment with Herceptin® is mandatory.

    Treatment with Herceptin® should only be performed under the supervision of a physician with experience in the use of cytotoxic chemotherapy, and the drug should be administered by medical personnel.

    Herceptin® in the dosage form "lyophilizate for the preparation of concentrate for the preparation of a solution for infusion" is administered only by intravenous drip!

    Enter the drug intravenously struyno or bolusno not! AT

    Nimanie!

    Herceptin® is not compatible with a 5% dextrose solution because of the possibility of protein aggregation. Herceptin® can not be mixed or diluted with other medications.

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

    Preparation of the solution

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

    Instructions for preparing the concentrate

    The contents of the Herceptin® vial are dissolved in 20 ml of the supplied with the preparation bacteriostatic water for injection, containing 1.1% of benzyl alcohol as an antimicrobial preservative. This results in a reusable solution concentrate containing 21 mg of trastuzumab in 1 ml and having a pH of 6.0.

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

    1. Using a sterile syringe, slowly inject 20 ml of bacteriostatic water for injection into 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 pale yellow color. The concentrate of the Herceptin® solution prepared on bacteriostatic water for injection is stable for 28 days at a temperature of 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 the Herceptin ® 440 mg preparation, sterile water for injection (without preservative). The use of other solvents should be avoided.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 volume of the solution:

    - required for administration of a loading dose of trastuzumab of 4 mg / kg body weight, or a maintenance dose of 2 mg / kg, is determined by the following formula:

    body mass (kg) x dose (4 mg / kg loading or 2 mg / kg maintenance)

    Scope (ml) = ---------------------------------------------- -------------------------------------------------- -

    21 (mg / ml, concentration of the prepared solution)

    - required to introduce a loading dose of 8 mg / kg body weight of trastuzumab or a maintenance dose of 6 mg / kg every 3 weeks is determined by the following formula:

    body mass (kg) x dose (8 mg / kg loading or 6 mg / kg maintenance)

    Scope (ml) = ---------------------------------------------- -------------------------------------------------- ---

    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 bag should be turned gently 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 infusion solution occurs 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 disposal of unused product or expired

    The presence of the drug in the environment should be minimized. Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

    Standard dosing regimen

    During each administration of trastuzumab, the patient should be carefully monitored for chills, fever, and other infusion reactions (within 6 hours after the start of the first infusion and within 2 hours after the start of subsequent infusions).An emergency kit should be available, and an infusion should be performed by a medical specialist experienced in the treatment of anaphylaxis.

    In the case of the appearance of infusion reactions, the infusion is interrupted. After the disappearance of symptoms of infusion reactions of mild and moderate severity according to NCI-CTC (the general criteria for the toxicity of the National Cancer Institute in the United States) may be the resumption of infusion. In the case of development of severe life-threatening infusion reactions, consideration should be given to stopping further therapy with Herceptin®.

    Metastatic breast cancer Weekly introduction

    Loading dose: 4 mg / kg body weight as a 90-minute intravenous drip infusion.

    Maintenance dose: 2 mg / kg body weight once a week. The maintenance dose is given 1 week after the loading. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drop infusion.

    Alternative introduction - in 3 weeks

    Loading dose: 8 mg / kg body weight as a 90-minute intravenous drip infusion.

    Maintenance dose: 6 mg / kg body weight every 3 weeks.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.

    Use in combination with paclitaxel or docetaxel

    Paclitaxel or docetaxel were administered the day after the administration of Herceptin® (see the appropriate medical instructions for dosage recommendations), or immediately after the subsequent administration of Herceptin®, if the Herceptin® was well tolerated during the previous administration. Use in combination with an aromatase inhibitor

    Herceptin® and anastrozole were introduced on day 1. Restrictions on the time of administration of Herceptin® and anastrozole but was not (recommendations for dosing, see the instructions for the medical use of anastrozole or other aromatase inhibitors).

    Early stages of breast cancer

    Weekly introduction

    When weekly, Herceptin® is given in loading dose 4 mg / kg body weight, then in supporting 2 mg / kg body weight once a week. The maintenance dose is given 1 week after the loading.The loading dose is administered as a 90-minute intravenous drip infusion. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drop infusion.

    Introduction in 3 weeks

    When administered after 3 weeks loading dose: 8 mg / kg body weight (as a 90-minute intravenous drip infusion).

    Maintenance dose: 6 mg / kg body weight every 3 weeks. 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.

    The use of Herceptin® in the early stages of breast cancer has been studied in combination with chemotherapy according to the schemes described below:

    Use in combination with paclitaxel or docetaxel after chemotherapy for doc-

    sorubicin and cyclophosphamide

    Paclitaxel:

    80 mg / m2 in the form of a long intravenous (IV) infusion, weekly, for 12 weeks

    or

    175 mg / m2 in the form of long-term intravenous infusion, every 3 weeks for 4 cycles (on day 1

    of each cycle).

    Docetaxel:

    100 mg / m2 in the form of intravenous infusion for 1 hour, every 3 weeks, for 4 cycles (starting

    on day 2 in cycle 5, then on day 1 in each subsequent cycle).

    Herceptin®:

    starting with the first dose of paclitaxel or docetaxel, Herceptin® was administered weekly according to the chemotherapy schedule (loading dose of 4 mg / kg, then at a maintenance dose of 2 mg / kg every week).

    In the future, monotherapy with Herceptin® continued according to the weekly schedule after application in combination with paclitaxel or as administered 3 weeks after use in combination with docetaxel. The total duration of therapy with Herceptin® from the first administration was 1 year, regardless of the number of doses received or missed. If paclitaxel or docetaxel and the drug Herceptin® should have been administered on the same day, then paclitaxel or docetaxel was introduced first.

    The use in combination with docetaxel and carboplatinum

    Docetaxel / Carboplatin (every 3 weeks for 6 cycles, starting from day 2 of the first cycle, then on day 1 in each subsequent cycle):

    docetaxel at a dose of 75 mg / m as an IV infusion for 1 hour, followed by carboplatin in a dose to achieve the target AUC - 6 mg / ml / min, as an IV infusion, for 30-60 minutes. Gereceptan®:

    Herceptin® together with chemotherapy was administered according to a weekly schedule (loading dose of 4 mg / kg, then in a maintenance dose of 2 mg / kg every week). After chemotherapy, Herceptin® monotherapy continued according to the administration 3 weeks later. Total duration of therapy with Herceptin® from the time of the first administration was 1 year, regardless of the number of doses received or missed. If docetaxel, carboplatin and Herceptin® were to be introduced into one

    day, it was first introduced docetaxel, followed by carboplatin, then Herceptin®.

    Neoadjuvant - adjuvant therapy

    Herceptin® was administered according to the regimen every 3 weeks in combination with a neoadjuvant

    chemotherapy (10 cycles):

    doxorubicin 60 mg / m2 and paclitaxel 150 mg / m2, every 3 weeks, for 3 cycles;

    Further paclitaxel 150 mg / m2, every 3 weeks, for 4 cycles;

    Further cyclophosphamide, methotrexate and fluorouracil on days 1 and 8, every 4 weeks, for 3 cycles.

    After the operative intervention, adjuvant monotherapy with Herceptin® continued according to the regimen every 3 weeks.The total duration of therapy with Herceptin ® was 1 year.

    Common stomach cancer

    Introduction in 3 weeks

    Loading dose: 8 mg / kg body weight as a 90-minute intravenous drip infusion.

    Maintenance dose: 6 mg / kg body weight every 3 weeks. 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.

    Metastatic and early stages of breast cancer and common stomach cancer

    Duration of therapy

    Treatment with Herceptin ® in patients with metastatic breast cancer or advanced stomach cancer is carried out before the disease progresses. Patients with early breast cancer should receive therapy with Herceptin ® for 1 year or until the disease recurs (depending on what happens sooner). Treatment with Herceptin® in patients with early stages of breast cancer over one year is not recommended.

    Skipping in the planned introduction

    If the admission in the planned administration of trastuzumab is 7 days or less, the drug should be administered as soon as possible in the usual maintenance dose (weekly schedule:

    - mg / kg of body weight; mode every 3 weeks: 6 mg / kg body weight), without waiting for the next scheduled administration. Next, administer the drug in a maintenance dose (weekly: 2 mg / kg body weight, every 3 weeks: 6 mg / kg body weight) according to the previously established schedule.

    If the break in the introduction of the drug is more than 7 days, you must re-enter the loading dose of trastuzumab (weekly regimen: 4 mg / kg body weight, regimen every

    - weeks: 8 mg / kg body weight) as a 90-minute intravenous drip infusion. Then continue the administration of the drug in a maintenance dose (weekly regimen: 2 mg / kg body weight, every 3 weeks: 6 mg / kg body weight).

    Correction of dose

    During the period of reversible myelosuppression caused by chemotherapy, the course of therapy with Herceptin® can be continued after a reduction in the dose of chemotherapy or its temporary withdrawal (according to the relevant recommendations in the instructions for the use of paclitaxel, docetaxel or aromatase inhibitor), provided that the complications due to neutropenia are closely monitored.

    When decrease in the left ventricular ejection fraction (LVEF) for >10 units from the original AND below the value of 50% treatment should be suspended. A reassessment of LVEF should be performed after approximately 3 weeks. If there is no improvement in LVEF or its further decline, or if symptoms of chronic heart failure (CHF) appear, consideration should be given to discontinuing Herceptin® treatment, unless the benefit for a particular patient is greater than the risk. All these patients should be referred to a cardiologist for a survey and be monitored.

    Special instructions for dosing

    Elderly patients

    The dose reduction of Herceptin® in elderly patients is not required (see the section "Pharmacological properties", subsection "Pharmacokinetics in special patient groups").

    Side effects:

    Currently, the most serious and / or frequent adverse reactions reported with Herceptin® are: cardiac dysfunction, infusion reactions, hematotoxicity (in particular neutropenia), infections and lung 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 the available data). Within each group, adverse reactions are presented in accordance with a decrease in severity.

    Below are the undesirable reactions reported in the use of Herceptin ® in both monotherapy and in combination with chemotherapy in basic clinical trials and in post-marketing use. The frequency is indicated in accordance with the maximum observed in basic clinical trials.

    Infectious and parasitic diseases: often - pneumonia+, neutropenic sepsis, cystitis, Herpes zoster, infections, 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 the neoplasm;

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

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

    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 tremor1, 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)1, disturbance of a warm rhythm1, palpitations1, flutter (atria or ventricles)1, reduction of the left ventricular ejection fraction *, "hot flashes"; often - heart failure (chronic)+, supraventricular tachyarrhythmia+1, cardiomyopathy, arterial hypotension+1 vasodilation; infrequently - pericardial effusion; unknown - cardiogenic shock, pericarditis, bradycardia, rhythm of "gallop".

    Disturbances from the respiratory system, chest and mediastinal organs: very often - rales + 1, dyspnea+1, cough, nosebleeds, rhinorrhea; often - bronchial asthma, pulmonary function, pharyngitis; infrequently - pleural effusion+; rarely - pneumonitis; unknown - pulmonary fibrosis +, respiratory failure, lung infiltration +, acute pulmonary edema +, acute respiratory distress syndrome, bronchospasm +, hypoxia +, decreased hemoglobin oxygen saturation +, laryngeal edema, orthopnea, pulmonary edema.

    Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, swelling of the lips1, abdominal pain, indigestion, constipation; often - pancreatitis, hemorrhoids, dry mouth.

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

    Disorders from the rut and subcutaneous tissues: very often - erythema, rash, face swelling1, alopecia, a violation of the structure of the nails; often - acne, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, itching, onychoclasia, dermatitis, urticaria; Unknown angioedema.

    Disturbances from the osteomuscular and connective tissue: very often about - arthralgia, muscular stiffness1, myalgia; often - arthritis, back pain, ossalgia, muscle spasms, neck pain, pain in the limbs.

    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 hypoplasia and / or impaired renal function 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, mucositis; often - peripheral edema, malaise, swelling.

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

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

    1 - undesirable reactions, which were mainly reported in association with infusion reactions. The exact percentage is not established.

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

    Below you will find information on individual adverse reactions.

    Heart Dysfunction

    Chronic 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. The following signs and symptoms of cardiac dysfunction were observed in patients treated with Herceptin®: dyspnea, orthopnea, increased cough, pulmonary edema, gallop rhythm, or a decrease in the left ventricular ejection fraction.

    In 3 basic clinical trials using trastuzumab in combination with adjuvant chemotherapy, the incidence of cardiac dysfunction of 3/4 degree (namely symptomatic chronic heart failure) did not differ from that in patients receiving chemotherapy alone (i.e.without the drug Herceptin®), and in patients,

    who received taxanes and Herceptin® consistently (0.3-0.4%). The frequency was greatest in patients receiving Herceptin® together with taxanes (2.0%). Experience with Herceptin ® in combination with low-dose anthracycline regimens in neoadjuvant therapy is limited.

    When using Herceptin ® for one year after the completion of adjuvant chemotherapy, heart failure III-IV functional class for NYHA was observed in 0.6% of patients with median follow-up of 12 months and in 0.89% of patients with median follow-up of 8 years. The incidence of mild symptomatic and asymptomatic left ventricular dysfunction was 6.35%. Severe CHF was reversible in 70% of cases (reversibility was determined by at least two consecutive increases in LVEF> 50% after the event). The mild symptomatic and asymptomatic left ventricular dysfunction was reversible in 83.1% of cases. Approximately 10% of the events associated with cardiac dysfunction occurred after the completion of Herceptin ® therapy.

    In basic clinical studies with metastatic breast cancer, the frequency of cardiacdysfunction with intravenous administration of the drug Herceptin ® in combination with paclitaxel ranged from 9% to 12% compared with 1% -4% for monotherapy with paclitaxel. For monotherapy with Herceptin ®, the frequency was 6% -9%. The highest incidence of cardiac dysfunction was observed in patients receiving Herceptin® concomitantly with anthracyclines / cyclophosphamide (27%), which is significantly higher than for the treatment with anthracyclines / cyclophosphamide (7% -10%). In a prospective cardiac monitoring study, the incidence of symptomatic CHF was 2.2% in patients receiving Herceptin ® and docetaxel, compared with 0% in patients who received monotherapy with docetaxel. In the majority of patients (79%) with cardiac dysfunction, there was an improvement after standard CHF treatment.

    Infusion reactions and hypersensitivity reactions

    It is estimated that about 40% of patients receiving Herceptin ® experience 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.during the 1st, 2nd and 3rd infusions, with subsequent injections occur less frequently. Reactions include the following symptoms: chills, fever, shortness of breath, arterial hypotension, wheezing in the lungs, bronchospasm, tachycardia, decreased oxygen saturation of hemoglobin, respiratory distress syndrome, rash, nausea, vomiting and headache.

    The frequency of infusion reactions of all degrees of severity varies and depends on the indication, methodology of information collection, and also whether Herceptin® together with chemotherapy or used in monotherapy.

    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. In some cases, anaphylactoid reactions were observed.

    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 trastuzumab 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 effects 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

    insufficiency.

    Overdose:
    In clinical studies, no overdose of the drug was observed. The administration of Herceptin® in single doses greater than 10 mg / kg has not been studied. Herceptin® in doses <10 mg / kg was tolerated well.
    Interaction:

    Special studies of drug interactions of the drug Herceptin ® in humans have not been conducted.

    In clinical trials, 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, suggest that 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) and 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 loading dose and 2 mg / kg once a week, iv, in the supporting) and docetaxel (60 mg / m2) 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 and cisplatin 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 maintaining 2 mg / kg every week, iv) and trastuzumab concentrations when used in combination with docetaxel in Japanese patients 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 the use of Herceptin ® concurrently with paclitaxel and with the use of Herceptin ® as a monotherapy,that the individual and mean values ​​of the minimum serum concentration of the Herceptin® drug varied both within the same group and between groups, but there was no apparent effect of simultaneous administration of paclitaxel to the pharmacokinetics of trastuzumab.

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

    Herceptin® is not compatible with a 5% dextrose solution because of the possibility of protein aggregation. Herceptin® can not be mixed or dissolved with other medications.

    Signs of incompatibility between the solution of Herceptin ® and infusion packets made of polyvinyl chloride, polyethylene or polypropylene were not observed.

    Special instructions:

    In the patient's medical records, the trade name of the drug should be indicated. Replacement of the drug with any other biological medicinal product requires agreement with the attending physician.

    HER2 testing should be carried out in a specialized laboratory that

    can provide quality control testing procedures.

    Herceptin® should be used in patients with metastatic breast cancer or early breast cancer only if there is a tumor overexpression HER2, determined by the method of immunohistochemical reaction (IHC), or amplification of the gene HER.2, determined by the hybridization method in situ (FISH or CISH). Accurate and validated methods should be used.

    Herceptin® should be used in patients with metastatic stomach cancer only in the presence of tumor overexpression HER2, determined by the IHC method as IGX2 + and confirmed by the results SISH or FISH, or IGHZ +. Accurate and validated methods should be used.

    Currently, there are no data from clinical studies on patients who received Herceptin® repeatedly after use in adjuvant therapy.

    Heart Dysfunction

    General instructions

    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, care should be taken 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 to undergo a thorough cardiological examination, which includes the collection of anamnesis, physical examination, electrocardiography (ECG), echocardiography and / or radioisotope ventriculography (MUGA) or magnetic resonance imaging (MRI). Monitoring can identify patients with cardiac dysfunction. The initial 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 trastuzumab 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 completion of treatment with Herceptin ® may have an increased risk of heart dysfunction. 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 (for example, every 12 weeks). As a result of monitoring, it is possible to identify patients who have developed cardiac dysfunction.

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

    The safety of the continuation or resumption of therapy with Herceptin® in patients who developed a violation of the function of the heart has not been studied. When the left ventricular ejection fraction (LVEF) decreases >10 units from the original AND below the value of 50% treatment should be suspended. A reassessment of LVEF should be performed after approximately 3 weeks. If there is no improvement in LVEF or its further decline, or if symptoms of chronic heart failure (CHF) appear, consideration should be given to discontinuing Herceptin® treatment, unless the benefit for a particular patient is greater than the risk. All of these papatients should be referred to a cardiologist for a survey and be monitored.

    If symptomatic heart failure develops with the Herceptin ® therapy, appropriate standard medical therapy for CHF should be performed.

    In the majority of patients with heart failure or asymptomatic heart dysfunction, baseline studies showed improvement in the background of 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 Herceptin®, the majority of patients with adverse cardiac reactions continued therapy without manifestation of additional clinically significant reactions from the heart.

    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 heart dysfunction in patients with metastatic breast cancer increased with prior anthracycline therapy, but it is lower compared to that with concomitant use of anthracyclines and Herceptin®.

    Early stages of breast cancer

    Patients with early-stage breast cancer should be cardiological examination before treatment, every 3 months during treatment and every 6 months after its closure within 24 months after the last dose of drug.Longer monitoring is recommended after treatment with Herceptin® in combination with anthracyclines at a frequency of 1x per year for 5 years after the last dose of Herceptin®, or further if there is a continuous decrease in LVEF.

    Treatment with Herceptin ® is not recommended for patients in the early stages of breast cancer (adjuvant and neoadjuvant therapy) with: a history of myocardial infarction; angina pectoris requiring treatment; CHF (II-IV functional class for NYHA) in the anamnesis or at present; LVEF is below 55%; other cardiomyopathies; arrhythmias requiring treatment; clinically significant heart defects; poorly controlled hypertension, with the exception of arterial hypertension, amenable to standard drug therapy; hemodynamically significant pericardial effusion, since the efficacy and safety of the drug in these patients have not been studied.

    Adjuvant therapy

    It is not recommended to use Herceptin ® together in combination with anthracyclines in adjuvant therapy. In patients with early stages of breast cancer,who received Herceptin® after anthracycline-based chemotherapy, there was an increase in the incidence of symptomatic and asymptomatic cardiovascular adverse events compared with those receiving chemotherapy with docetaxel and carboplatin (regimes not containing anthracycline-based drugs). The difference was greater in cases of combined use of Herceptin® and taxanes than with sequential use.

    Regardless of the regime used, most symptomatic cardiac events occurred in the first 18 months of treatment. One of 3 baseline studies (with a median follow-up period of 5.5 years) showed a prolonged increase in the cumulative incidence of symptomatic cardiac events or events associated with a decrease in LVEF: 2.37% of patients receiving Herceptin® together with taxanes after anthracycline therapy, compared with 1% of patients in comparison groups (in the group of therapy with anthracyclines and cyclophosphamide, then taxanes, and in the group of therapy with taxanes, carboplatin and Herceptin ®).

    The identified risk factors for the development of cardiovascular adverse events with adjuvant therapy with Herceptin® are: age> 50 years, low baseline LVEF (<55%) before and after initiation of paclitaxel treatment, a 10-15 unit LVEF reduction preceding or concomitant with antihypertensive preparations. The risk of cardiac dysfunction in patients treated with Herceptin® after the completion of adjuvant chemotherapy was associated with a higher total dose of anthracyclines before treatment with Herceptin® and with a body mass index (BMI)> 25 kg / m2.

    Neoadjuvant-adyovant therapy

    For patients with early breast cancer who can be given neoadjuvant-adjuvant therapy, the use of Herceptin® with anthracyclines is recommended only if they have not previously received chemotherapy and only with low-dose regimens of anthracycline therapy (the maximum total dose of doxorubicin is 180 mg / m2 or epirubicin 360 mg / m2).

    In patients who have received a full course of low-dose anthracyclines and Herceptin® as part of neoadjuvant therapy, additional cytotoxic chemotherapy is not recommended after surgical intervention.In all other cases, the decision on the need for additional cytotoxic chemotherapy is taken on the basis of individual factors. The experience with trastuzumab in conjunction with low-dose regimens for anthracycline therapy is limited to two studies. When using Herceptin ® together with neoadjuvant chemotherapy, which included three to four cycles of neoadjuvant therapy with anthracyclines (total dose of doxorubicin 180 mg / m2 or epirubicin 300 mg / m2), the incidence of symptomatic cardiac dysfunction was low (1.7%).

    Clinical experience in patients older than 65 years is limited.

    Infusion reactions and hypersensitivity reactions

    With the introduction of Herceptin® there were serious infusion unwanted reactions: dyspnea, arterial hypotension, wheezing in the lungs, arterial hypertension, bronchospasm, supraventricular tachyarrhythmia, decreased oxygen saturation of hemoglobin, anaphylaxis, respiratory distress syndrome, urticaria and angioedema. Premedication can be used to reduce the risk of these phenomena.Most of these reactions occurred during infusion or within 2.5 hours from the onset of the first administration. If an infusion reaction occurs, the injection should be stopped and the patient carefully monitored until all symptoms are eliminated. To stop these symptoms, analgesics / antipyretics, such as paracetamol, or antihistamines, such as diphenhydramine. Most patients, after resolving the symptoms of infusion reactions, were able to continue therapy with Herceptin®.

    Effective therapy of serious reactions consists in the use of beta-adrenostimulators, glucocorticosteroids, oxygen inhalation. If severe and life-threatening infusion reactions develop, consideration should be given to stopping further therapy with Herceptin®.

    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 lung metastases or concomitant diseases, so such patients should not be treated with Herceptin®.

    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 (after more than 6 hours 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 effusions, acute pulmonary edema, and respiratory failure. Risk factors associated with IBL include: previous or concomitant therapy with other antitumor drugs that are known to be associated with IBL (taxanes, gemcitabine, vinorelbine and radiation therapy). These phenomena can occur as manifestations of infusion reactions, and deferred. 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. Benzyl alcohol, contained as a preservative in bacteriostatic water for injection, which is applied to each multi-dose vial of 440 mg, has a toxic effect in newborns and children under 3 years of age.

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

    Effect on the ability to drive transp. cf. and fur:Studies to study the effect of the drug on the ability to drive a car and work with mechanisms have not been carried out.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:
    Liofilizate for the preparation of concentrate for the preparation of a solution for infusions 440 mg.
    Packaging:
    According to 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 closed with a plastic lid of a light green color.
    By 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 covered with a white plastic cover.
    1 bottle with the drug (lyophilizate) and 1 bottle of solvent together with the instruction for use are placed in a cardboard box.
    Storage conditions:Store at 2-8 ° C. Keep out of the reach of children.
    Shelf life:4 years. Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:П N012038 / 01
    Date of registration:09.07.2010
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp21.09.2015
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