Herceptin Lyophilizate for preparation of infusion concentrate, 440mg + diluent 20ml vials 1pc

Composition

Active ingredients:

trastuzumab 440 mg.

Auxiliary substances:

L-histidine hydrochloride – 9.9 mg,

L-histidine-6.4 mg,

α, α-trehalose dihydrate-400 mg,

polysorbate 20-1.8 mg.

Solvent (bacteriostatic water d / i – 20 ml, containing 1.1% benzyl alcohol as an antimicrobial preservative): benzyl alcohol – 229.9 mg, d/i water-20.9 mg

Pharmacological action

Pharmacodynamics

Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively interacts with the extracellular domain of human epidermal growth factor type 2 (HER2) receptors. These antibodies are IgG1 consisting of human regions (constant regions of heavy chains) and determine the complementarity of mouse regions of the p185 HER2 antibody to HER2.

The proto-oncogene HER2 or c-EGB2 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. Overexpression of HER2 is found in the tissue of primary breast cancer (BC) in 25-30% of patients and in the tissue of advanced gastric cancer in 6.8-42.6% of patients. Amplification of the HER2 gene leads to overexpression of the HER2 protein on the tumor cell membrane, which in turn causes permanent activation of the HER2 receptor.

Studies show that breast cancer patients with HER2 amplification or overexpression in the tumor tissue have a lower survival rate without signs of the disease compared to patients without HER2 amplification or overexpression in the tumor tissue.

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

Immunogenicity

Antibodies to trastuzumab were detected in one of 903 breast cancer patients who received the drug alone or in combination with chemotherapy, and she was not allergic to Herceptin®.

Data on immunogenicity in the use of Herceptin® for the treatment of gastric cancer are not available.

Pharmacokinetics

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer and early-stage breast cancer, as well as in patients with advanced gastric cancer. Special studies on the study of inter-drug interaction have not been conducted.

Breast 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 were nonlinear. When the dose was increased, the clearance of the drug decreased.

The elimination half-life (T_1/2)

of T_1/2 is 28-38 days, hence the elimination period after discontinuation of the drug is up to 27 weeks (190 days or 5 half-lives).

Pharmacokinetics of trastuzumab at steady state.

The equilibrium state should be reached in about 25 weeks. When using the population pharmacokinetic method (two-chamber model, model-dependent analysis) to evaluate data from phase I, phase II, and phase III studies in metastatic breast cancer, the median expected AUC at steady state after 3 weeks was 1677 mg×day / l after 3 doses (2 mg/kg) weekly and 1793 mg×day/l after 3 weeks at a dose of 6 mg/kg. The calculated median_cmax was 104 mg / l and 189 mg / L, and cmin was 64.9 mg / L and 47.3 mg/L, respectively. When using a model-independent or “ncamargo” method of analysis (pop-compartmental analysis, NCA), the average C_min in the equilibrium state to the 13th cycle (37 weeks) was 63 mg/l in patients with early-stage breast cancer treated with trastuzumab in a load dose of 8 mg/kg followed by maintenance 6 mg/kg,3 weeks, and was comparable to that in patients with mrmr who received trastuzumab weekly.

Ground clearance

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

Distribution volume

In all clinical trials, the volume of distribution in the central chamber (_VC) was 3.02 liters, in the peripheral chamber (Vp) – 2.68 liters for a typical patient.

Circulating extracellular domain of the HER2 receptor (“peeling” antigen from the cell)

The circulating extracellular domain of the HER2 receptor (an “exfoliating” antigen) was detected in the blood serum of some patients with breast cancer and HER2 overexpression. In 64% of the examined patients, the initial serum samples showed an antigen “exfoliating” from the cell at a concentration of up to 1880 ng / ml (median 11 ng / ml). Patients who had a high level of antigen “exfoliating” from the cell, probably could have a lower_cmin. However, in the majority of patients with elevated levels of “exfoliating” antigen from the cell, when the drug was administered weekly, the target serum concentration of trastuzumab was reached by week 6. There was no significant association between the initial level of the “exfoliating” C-cell antigen and the clinical response.

Advanced gastric cancer

Pharmacokinetics of trastuzumab at steady state To evaluate the pharmacokinetics of trastuzumab at steady state in patients with advanced gastric cancer after use of trastuzumab at a loading dose of 8 mg/kg, followed by use of 6 mg/kg every 3 weeks, a nonlinear two-chamber population pharmacokinetic method was used using data from a phase III study.

The observed serum levels of trastuzumab were lower, so it was found that the total clearance of the drug in patients with advanced gastric cancer is higher than in patients with breast cancer receiving trastuzumab at the same dose. The reason for this is unknown.

At high concentrations, the total clearance is mostly linear, and T_1/2 is about 26 days.

The median estimated AUC (at steady state for a 3-week period) is 1213 mg×day / L, the median_cmax at steady state is 132 mg / L, and the median cmax is 27.6 mg / l.

There are no data on the level of the circulating extracellular domain of the HER2 receptor (an”exfoliating” antigen from the cell) in the serum of patients with gastric cancer.

Pharmacokinetics in special patient groups

Separate pharmacokinetic studies in elderly patients and patients with renal or hepatic insufficiency have not been conducted. Age does not affect the distribution of trastuzumab.

Indications

Breast cancer

Metastatic breast cancer with tumor overexpression of HER2:

• as monotherapy, after one or more chemotherapy regimens;
• in combination with paclitaxel or docetaxel, in the absence of previous chemotherapy (first-line therapy);
• in combination with aromatase inhibitors with positive hormone receptors (estrogen and/or progesterone) in postmenopausal women.

Early stage breast cancer with tumor overexpression of HER2:

• in the form of adjuvant therapy after surgical intervention completion of chemotherapy (neoadjuvant or adjuvant) and radiotherapy;
• in combination with docetaxel or paclitaxel 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 drug Herceptin in patients with locally advanced distributed (including inflammatory) form of the disease or in cases when the tumor size greater than 2 cm in diameter.

Common stomach cancer

Advanced adenocarcinoma of the stomach or esophago-gastric junction with tumor overexpression of HER2:

• in combination with capecitabine or intravenous use of fluorouracil and platinum in the absence of previous antitumor therapy for metastatic disease.

Use during pregnancy and lactation

Women of childbearing age should use reliable methods of contraception during treatment with Herceptin® and for at least 6 months after the end of treatment.

In case of pregnancy, it is necessary to warn the woman about the possibility of harmful effects on the fetus. If a pregnant woman continues to receive therapy with Herceptin®, she should be closely monitored by doctors of various specialties. It is not known whether Herceptin ® affects the reproductive capacity of women. The results of animal experiments showed no signs of impaired fertility or negative effects on the fetus.

Breast-feeding is not recommended during treatment and for at least 6 months after the end of Herceptin therapy.

Benzyl alcohol, contained as a preservative in bacteriostatic water for injection, attached to each multi-dose bottle of 440 mg, has a toxic effect in newborns and children under 3 years of age.

Contraindications

• Severe shortness of breath at rest, caused by metastases in the lungs, or requiring maintenance therapy with oxygen;
• children up to age 18 years (effectiveness and safety of use in children have not been established);
• pregnancy;
• lactation;
• hypersensitivity to trastuzumab or any other component of the drug, including benzyl alcohol contained in the preservative in bacteriostatic water for injection, supplied to each multi-dose vial 440 mg.

With caution: use in patients with coronary heart disease, arterial hypertension, heart failure, concomitant lung diseases or lung metastases, previous therapy with cardiotoxic drugs, including anthracyclines/cyclophosphamide.

Side effects

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

The following classification is used to describe the frequency of adverse reactions in this section:

• very common (≥1/10);
• common (≥1/100, but < 1/10);
• infrequent (≥1/1000, but < 1/100);
• rare (≥1/10,000, but < 1/1000);
• very rare (

Within each group, adverse reactions are presented according to the reduction in severity.

Adverse reactions reported with Herceptin® either as monotherapy or in combination with chemotherapy in baseline clinical trials and post-marketing use are listed below. The frequency is indicated in accordance with the maximum found in basic clinical studies.

Infectious and parasitic diseases: often-pneumonia 1 (

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

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

From the immune system: often – hypersensitivity reactions; unknown – anaphylactic reactions 1, anaphylactic shock 1.

From the side of metabolism: often-weight loss, anorexia; unknown-hyperkalemia.

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

From the nervous system: very often – tremor 2, dizziness, headaches; often-peripheral neuropathy, paresthesia, muscle hypertonus, drowsiness, dysgeusia( distortion of taste perception), ataxia; rarely-paresis; unknown-brain edema.

From the side of the organ of vision: very often – conjunctivitis, increased lacrimation; often-dry eyes; unknown-edema of the optic nerve disc, retinal hemorrhage.

Hearing disorders and labyrinth disorders: infrequently-deafness.

From the cardiovascular system: very often – lowering and raising HELL,2, abnormal heart rhythm 2,2 palpitation, atrial flutter, or ventricular 2, reduced ejection fraction of the left ventricle 3, “tides”, and often heart failure (congestive)1 (2%), supraventricular tachyarrhythmia 1,2, cardiomyopathy, hypotension 1,2, vasodilatation; rarely, pericardial effusion; unknown – cardiogenic shock, pericarditis, bradycardia, rhythm “gallop”.

Respiratory, thoracic and mediastinal disorders: very common – wheezing 1,2, shortness of breath 1 (14%), cough, nosebleeds, rhinorrhea; common – bronchial asthma, impaired lung function, pharyngitis; infrequent – pleural effusion 1; rare – pneumonitis; unknown – pulmonary fibrosis 1, respiratory failure 1, lung infiltration 1, acute pulmonary edema 1, acute respiratory distress syndrome 1, bronchospasm 1, hypoxia 1, decreased hemoglobin oxygen saturation 1, laryngeal edema, orthopnea, pulmonary edema.

From the gastrointestinal tract: very often – diarrhea, vomiting, nausea, swelling of the lips 2, abdominal pain; often-pancreatitis, dyspepsia, hemorrhoids, constipation, dry mouth.

From the liver and biliary tract: often-hepatitis, pain in the liver, hepatocellular damage; rarely-jaundice; unknown-liver failure.

From the skin and subcutaneous tissues: very often – erythema, rash, facial edema 2; often-acne, alopecia, dry skin, ecchymosis, hyperhidrosis, macular-papular rash, nail structure disorder, itching; unknown-angioedema, dermatitis, urticaria.

Musculoskeletal and connective tissue disorders: very common – arthralgia, muscle stiffness 2, myalgia; often-arthritis, back pain, ossalgia, muscle spasms, neck pain.

From the side of the kidneys and urinary tract: often-kidney disease; unknown-membranous glomerulonephritis, glomerulonephropathy, renal failure.

Effects on pregnancy, postpartum and perinatal conditions: unknown-oligohydramnion, fatal pulmonary hypoplasia and renal hypoplasia in the fetus.

From the genitals and breast: often-inflammation of the breast/mastitis.

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

Injuries, intoxications, and complications of manipulation: often-bruising.

1 – adverse reactions that were associated with a fatal outcome in the reports.

2-adverse reactions that were mainly reported in association with infusion reactions. The exact percentage is not set.

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

The exact frequency percentage for those terms that were reported together with a fatal outcome with a frequency of “often” or “very often”is shown in parentheses. The percentage indicator refers to the total number of these events with and without a fatal outcome.

The following adverse reactions were reported in baseline clinical trials with a frequency of ≥ 1/10 in any of the therapy groups, with no significant difference between the Herceptin-containing therapy group and the comparison therapy group: lethargy, hypesthesia, limb pain, mouth and pharyngeal pain, lymphedema, weight gain, onychoclasia, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, epigastric pain, gastritis, stomatitis, vertigo, arterial hypertension, hiccups, palmar-plantar syndrome, breast pain, onychorexis, shortness of breath during exercise, and dysuria.

Information on individual adverse reactions is provided below

Infusion reactions and hypersensitivity reactions

It is estimated that about 40% of patients receiving Herceptin® experience infusion reactions in some form. However, most infusion reactions are mild to moderate in severity (according to the NCI-CTC) and tend to occur at the beginning of treatment, i. e. during the 1st,2nd and 3rd infusions, with subsequent injections occurring less frequently. Reactions include (but are not limited to) the following symptoms: chills, fever, rash, nausea and vomiting, shortness of breath, and headache. Severe anaphylactic reactions requiring immediate additional medical intervention may most often occur during the first or second infusion of Herceptin®, such reactions have been associated with a fatal outcome.

Cardiotoxicity

Cardiotoxicity (heart failure) of NYHA functional class II-IV is a common adverse reaction when using Herceptin® and has been associated with a fatal outcome. In 3 baseline clinical trials using trastuzumab in combination with adjuvant chemotherapy, the incidence of grade 3/4 cardiac dysfunction (symptomatic congestive heart failure) did not differ from that in patients receiving only chemotherapy (i. e. without Herceptin®), and in patients receiving taxanes and Herceptin® sequentially (0.3-0.4%). The frequency was highest in patients who received Herceptin® together with taxanes (2%).

The safety of continuing or resuming therapy with Herceptin® in patients experiencing cardiotoxicity events has not been studied prospectively. However, the majority of patients who experienced heart failure in baseline studies improved with standard therapy, which included diuretics, cardiac glycosides, beta-blockers, and / or ACE inhibitors.

The majority of patients with cardiac symptoms and signs of clinical benefit from Herceptin therapy continued therapy without additional clinically significant cardiac events.

Experience with Herceptin ® in combination with low-dose anthracycline regimens in neoadjuvant therapy is limited.

Hematological toxicity

Febrile neutropenia was very common. Adverse reactions that occur frequently include anemia, leukopenia, thrombocytopenia, and neutropenia. The incidence of hypoprothrombinemia is unknown. The risk of neutropenia may be slightly higher when using trastuzumab in combination with docetaxel after treatment with anthracycline drugs.

Lung disorders

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

Interaction

Specific studies of the drug interaction of Herceptin® in humans have not been conducted.

No clinically significant interactions with concomitant medications (including doxorubicin, paclitaxel, docetaxel, capecitabine, or cisplatin) have been reported in clinical trials.

Herceptin® is not compatible with 5% dextrose solution due to the possibility of protein aggregation.

Herceptin® should not be mixed or dissolved with other medicinal products.

There were no signs of incompatibility between Herceptin® solution and infusion bags made of polyvinyl chloride, polyethylene or polypropylene.

How to take, course of use and dosage

Testing for tumor expression of HER2 before starting treatment with Herceptin® is mandatory.

Herceptin® is administered only intravenously! It is impossible to administer the drug intravenously in a jet or bolus!

Herceptin® is not compatible with 5% dextrose solution due to the possibility of protein aggregation. Herceptin® should not be mixed or diluted with other medicinal products.

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

Preparation of the solution

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

Instructions for preparing the concentrate

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

During dissolution, the drug should be handled carefully. When dissolving, excessive foaming should be avoided, the latter can make it difficult to set the desired dose of the drug from the bottle.

When the drug 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.

Herceptin® solution concentrate 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 therefore can be used repeatedly. After 28 days, the unused concentrate residue should be discarded. Do not freeze!

As a solvent of Herceptin® 440 mg, it is allowed to use sterile water for injection (without preservative). The use of other solvents should be avoided. If sterile water for injection is used as a solvent, the concentrate is physically and chemically stable only for 24 hours at a temperature of 2-8°C and should be discarded after this time. Do not freeze!

Instructions for preparing the infusion solution

Determine the volume of the solution:

• the required loading dose of trastuzumab equal to 4 mg / kg of body weight, or a maintenance dose equal to 2 mg/kg, is determined by the following formula::

Volume (ml) = body weight (kg)×dose (4 mg/kg loading or 2 mg/kg maintenance)/21 (mg / ml, concentration of the prepared solution);

• required for the use of a loading dose of trastuzumab equal to 8 mg/kg body weight, or a maintenance dose equal to 6 mg/kg every 3 weeks, is determined by the following formula:

Volume (ml) = body weight (kg)×dose (8 mg/kg loading or 6 mg/kg maintenance)/21 (mg / ml, concentration of the prepared solution).

From the bottle with the prepared concentrate, you should dial the appropriate volume and enter it into an infusion bag with 250 ml of 0.9% sodium chloride solution. Then the infusion bag should be carefully turned over to mix the solution, avoiding foaming. Before use, the solution should be checked (visually) for the absence of mechanical impurities and discoloration. The infusion solution 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 the concentrate was dissolved and the infusion solution was prepared under controlled and validated aseptic conditions. In this case, the specialist who prepared the solution is responsible for the storage conditions (storage rules and duration).

Instructions for disposing of an unused or expired product

The release of the medicinal product into the environment should be kept to a minimum. Do not dispose of the product using waste water or together with household waste. If possible, it is necessary to use special systems for disposing of medicines.

Standard dosage regimen

During each use 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 the infusion should be administered by a medical professional experienced in the treatment of anaphylaxis.

In case of infusion reactions, the infusion is interrupted. After the symptoms of mild to moderate infusion reactions disappear, according to the NCI-CTC (General Toxicity criteria of the National Cancer Institute in the USA), it is possible to resume the infusion. In the event of severe life-threatening infusion reactions, discontinuation of further Herceptin therapy should be considered.

Metastatic breast cancer

Weekly introduction

Loading dose: 4 mg / kg of body weight in the form of a 90-minute intravenous drip infusion.

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

Alternative use-after 3 weeks

Loading dose: 8 mg / kg of body weight in the form of a 90-minute intravenous drip infusion.

Maintenance dose: 6 mg / kg body weight every 3 weeks. The maintenance dose is administered 3 weeks after the exercise dose. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.

Use in combination with paclitaxel or docetaxel

Paclitaxel or docetaxel were administered on the day following Herceptin use (see dosage recommendations). in the relevant instructions for medical use) or immediately after the subsequent use of Herceptin®, if Herceptin® was well tolerated during the previous use.

Use in combination with an aromatase inhibitor

Herceptin® and Anastrozolee were administered on day 1. There were no time limits for the use of Herceptin® and Anastrozolee (see the instructions for medical use of Anastrozolee or other aromatase inhibitors for dosage recommendations).

Early stages of breast cancer

Weekly introduction

With weekly use, Herceptin® is administered at a loading dose of 4 mg/kg of body weight, then at a maintenance dose of 2 mg/kg of body weight once a week.

The maintenance dose is administered 1 week after the exercise dose. The loading dose is given as a 90-minute intravenous drip infusion. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.

Introduction in 3 weeks

When administered after 3 weeks, the loading dose is 8 mg / kg of body weight (in the form of a 90-minute intravenous drip infusion). Maintenance dose: 6 mg / kg body weight every 3 weeks.

The maintenance dose is administered 3 weeks after the exercise dose. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.

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

Use in combination with paclitaxel or docetaxel after chemotherapy with doxorubicin and cyclophosphamide

Paclitaxel:

• 80 mg / m%^% 2 as a long-term IV infusion, weekly, for 12 weeks or
• 175 mg / m%^%2 as a long-term IV infusion, every 3 weeks for 4 cycles (on day 1 of each cycle).

Docetaxel:

• 100 mg / m%^%2 as an intravenous infusion for 1 h, 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 according to a weekly schedule during chemotherapy (a loading dose of 4 mg / kg, then at a maintenance dose of 2 mg/kg each week).

Further monotherapy with Herceptin® was continued according to the weekly schedule after use in combination with paclitaxel or according to the introduction 3 weeks after use in combination with docetaxel. Total duration of therapy with Herceptin® from the moment of first use was 1 year, regardless of the number of received or missed doses. If paclitaxel or docetaxel and Herceptin® were to be administered on the same day, paclitaxel or docetaxel was administered first.

Use in combination with docetaxel and carboplatin

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 75 mg/m2 as an intravenous infusion for 1 hour, followed by carboplatin to achieve the target AUC of 6 mg/ml/min, as an intravenous infusion for 30-60 minutes.

Herceptin®:

• Herceptin® was administered together with chemotherapy according to a weekly schedule (a loading dose of 4 mg / kg, then at a maintenance dose of 2 mg / kg each week). After chemotherapy, Herceptin ® monotherapy was continued according to the use after 3 weeks. Total duration of therapy with Herceptin® from the moment of first use was 1 year, regardless of the number of received or missed doses. If docetaxel, carboplatin and Herceptin® were to be administered on the same day, docetaxel was administered first, followed by carboplatin, then Herceptin®.

Neoadjuvant-adjuvant therapy Herceptin® was administered according to the regimen every 3 weeks in combination with neoadjuvant chemotherapy (10 cycles):

• doxorubicin 60 mg / m2 and paclitaxel 150 mg / m2, every 3 weeks, for 3 cycles;
• then-paclitaxel 150 mg / m2, every 3 weeks, for 4 cycles;
• then-cyclophosphamide, methotrexate and fluorouracil on days 1 and 8, every 4 weeks, for 3 cycles.

After surgery, adjuvant monotherapy with Herceptin® was 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 of body weight in the form of a 90-minute intravenous drip infusion.

Maintenance dose: 6 mg / kg body weight every 3 weeks. The maintenance dose is administered 3 weeks after the exercise dose. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.

Metastatic and early-stage breast cancer and advanced gastric cancer

Duration of therapy

Treatment with Herceptin® in patients with metastatic breast cancer or advanced gastric cancer is performed before the disease progresses. Patients with early-stage breast cancer should be treated with Herceptin® for 1 year or until the disease recurs (whichever is faster).

Skipping a routine introduction

If the scheduled use of trastuzumab is missed for 7 days or less, the drug should be administered as soon as possible at the usual maintenance dose (weekly regimen: 2 mg/kg body weight; regimen every 3 weeks: 6 mg/kg body weight), without waiting for the next scheduled use. Then enter the drug in a maintenance dose (weekly mode: 2 mg/kg of body weight; mode every 3 weeks: 6 mg/kg of body weight) in accordance with the previously established schedule.

If the break in use of the drug is more than 7 days, it is necessary to re-enter the loading dose of trastuzumab (weekly regimen: 4 mg/kg of body weight; regimen every 3 weeks: 8 mg/kg of body weight), in the form of a 90-minute intravenous drip infusion. Then continue the use of the drug at a maintenance dose (weekly regimen: 2 mg / kg of body weight; regimen every 3 weeks: 6 mg/kg of body weight).

Dose adjustment

When reversible chemotherapy-induced myelosuppression occurs, Herceptin® therapy may be continued after a reduction in the dose of chemotherapy or temporary discontinuation (as recommended in the instructions for use of paclitaxel, docetaxel, or an aromatase inhibitor), provided that neutropenia-related complications are carefully monitored

Special dosage instructions

Elderly patients

There is no need to reduce the dose of Herceptin® in elderly patients.

Overdose

No cases of overdose of the drug were observed in clinical studies. use of Herceptin® in single doses greater than 10 mg / kg has not been studied. Herceptin ® in doses < 10 mg / kg was well tolerated.

Special instructions

Treatment with Herceptin® should only be carried out under the supervision of an oncologist. HER2 testing should be performed in a specialized laboratory that can provide quality control of the testing procedure.

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

Herceptin® should be used in patients with metastatic gastric cancer only if there is a tumor overexpression of HER2, defined by IHC as IHC 2+ and confirmed by SISH or FISH results, or IHC 3+. Accurate and validated detection methods should be used.

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

Infusion reactions and hypersensitivity reactions

Infrequently, serious infusion-related adverse reactions have occurred with Herceptin®: shortness of breath, hypotension, wheezing in the lungs, hypertension, bronchospasm, supraventricular tachyarrhythmia, decreased hemoglobin oxygen saturation, anaphylaxis, respiratory distress syndrome, urticaria and angioedema. Most of them occurred during the infusion or within 2.5 hours of the first use. If an infusion reaction occurs, the injection should be stopped. The patient should be carefully monitored until all symptoms are resolved. Effective therapy for serious reactions is the use of oxygen inhalation, beta-adrenostimulants, and corticosteroids. Discontinuation of further Herceptin therapy should be considered in the event of severe and life-threatening infusion reactions.

In rare cases, these reactions were associated with a fatal outcome. The risk of fatal infusion reactions is higher in patients with rest dyspnea caused by lung metastases or concomitant diseases, so such patients should not be treated with Herceptin®.

Cases have been reported in which the condition worsened after the initial improvement, as well as cases with a delayed rapid deterioration of the condition. Death occurred within hours or one week after the infusion. In very rare cases, patients developed symptoms of infusion reactions or pulmonary symptoms (more than 6 hours after the start of Herceptin®use). Patients should be warned about the possible delayed development of these symptoms and the need for immediate contact with the attending physician if they occur.

Lung disorders

When using Herceptin® in the post-marketing period, severe pulmonary events were recorded, which were sometimes accompanied by a fatal outcome. Interstitial lung disease (ILD) has also been reported, including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure. Risk factors associated with IHD include: previous or concomitant therapy with other anti-neoplastic drugs known to be associated with IHD (taxanes, gemcitabine, vinorelbine, and radiation therapy). These phenomena can occur both during the infusion (as a manifestation of infusion reactions), and delayed. The risk of severe reactions from the lungs is higher in patients with metastatic lung damage, concomitant diseases, accompanied by shortness of breath at rest. Therefore, such patients should not receive Herceptin®. Caution should be exercised, especially in patients receiving concomitant taxane therapy, due to the development of pneumonitis.

Cardiotoxicity

General instructions

Heart failure (NYHA functional class II-IV) reported after Herceptin ® therapy as monotherapy or in combination with paclitaxel or docetaxel, especially after chemotherapy containing anthracyclines (doxorubicin or epirubicin), can be moderate or severe and in some cases can lead to death.

Patients who are scheduled to receive Herceptin®, especially those who have previously received anthracycline-type drugs and cyclophosphamide, should first undergo a thorough cardiac examination, including anamnesis, physical examination, ECG, echocardiography and/or radioisotope ventriculography or MRI.

Before starting treatment with Herceptin®, it is necessary to carefully compare the possible benefits and risks of its use.

Since the T_1/2 of Herceptin® is approximately 28-38 days, the drug can be present in the blood for up to 27 weeks after the end of therapy. Patients who receive anthracyclines after completing treatment with Herceptin® may have an increased risk of cardiotoxicity. If possible, doctors should avoid prescribing anthracycline-based chemotherapy for up to 27 weeks after completing Herceptin therapy. When using anthracycline drugs, careful monitoring of heart function should be carried out.

It is necessary to evaluate the need for a standard cardiological examination in patients who are suspected of having cardiovascular diseases during the examination before starting treatment.

All patients should have their heart function monitored 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, more frequent monitoring may be useful (for example, every 6-8 weeks). If there is a prolonged deterioration in left ventricular function that does not manifest itself symptomatically, it is advisable to consider discontinuing the drug if there is no clinical benefit from its use. Caution should be exercised when treating patients with a history of symptomatic heart failure, hypertension, or documented coronary artery disease, as well as patients with early-stage breast cancer with a left ventricular ejection fraction < 55%.

If LVEF falls to values below 50% and 10 points relative to the value before starting therapy, treatment should be suspended and LVEF should be re-evaluated no later than 3 weeks later. If LVEF has not improved or continued to decline, discontinuation of the drug should be considered if the benefit of its use in this patient does not outweigh the risk. Such patients should be examined by a cardiologist and be under his supervision.

If symptomatic heart failure develops during therapy with Herceptin®, appropriate standard medical therapy should be performed. Discontinuation of Herceptin® should be considered if clinically significant heart failure develops, if the benefit of using the drug in a particular patient does not outweigh the risk.

The safety of continuing or resuming Herceptin therapy in patients who have developed cardiotoxicity has not been studied in prospective clinical trials. The majority of patients showed improvement in their condition against the background of standard drug therapy in basic clinical studies. Diuretics, cardiac glycosides, beta-blockers, and/or ACE inhibitors were used as standard therapy. If there is a clinical benefit from the use of Herceptin®, most patients with adverse reactions from the heart continued therapy without showing additional clinically significant reactions from the heart.

Metastatic breast cancer

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

The risk of cardiotoxicity in patients with metastatic breast cancer is increased with previous 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 receive a cardiac evaluation before starting treatment, every 3 months during therapy, and every 6 months after the end of therapy for 24 months from the last dose of the drug. Longer monitoring is recommended after treatment with Herceptin® in combination with anthracyclines, with a frequency of examinations once a year for 5 years from the last dose of Herceptin® or further, if there is a prolonged decrease in LVEF.

Adjuvant therapy

It is not recommended to use Herceptin ® in combination with anthracyclines as part of adjuvant therapy. Patients with early-stage breast cancer who received Herceptin® after anthracycline-based chemotherapy experienced an increased incidence of symptomatic and asymptomatic cardiac adverse events compared to those who received docetaxel and carboplatin chemotherapy (regimens that do not contain anthracycline drugs). At the same time, the difference was greater in cases of concomitant use of Herceptin® and taxanes than in cases of sequential use.

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

Since patients in the early stages of breast cancer with an established history of congestive heart failure, uncontrolled high-risk arrhythmias, angina requiring medication, clinically significant heart defects, signs of transmural myocardial infarction according to ECG data, poorly controlled arterial hypertension did not participate in the clinical study, there is no information about the benefit/risk ratio in such patients, and therefore treatment with the drug is not recommended for such patients.

Neoadjuvant-adjuvant therapy

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

In patients receiving low-dose anthracyclines and Herceptin® as part of neoadjuvant therapy, additional cytotoxic chemotherapy after surgery is not recommended.

Since patients with NYHA Functional Class II-IV heart failure, LVEF 180 mm Hg or diastolic > 100 mm Hg), clinically significant heart defects, and high-risk uncontrolled arrhythmias did not participate in the clinical trial, treatment with Herceptin® is not recommended for such patients.

Experience with trastuzumab in combination with low-dose anthracycline regimens is limited. When Herceptin® was used in combination with neoadjuvant chemotherapy, which included three cycles of neoadjuvant doxorubicin (total dose of doxorubicin 180 mg/m2), the frequency of symptomatic cardiac dysfunction was low (1.7%).

Neoadjuvant-adjuvant therapy with Herceptin® is not recommended in patients over the age of 65 years, as clinical experience in such patients is limited.

Additional information

When prescribing Herceptin® to a patient with hypersensitivity to benzyl alcohol, the drug should be dissolved with water for injection, and only one dose can be selected from each multi-dose bottle. The remaining drug should be discarded.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Studies on the effect of the drug on the ability to drive a car and work with mechanisms have not been conducted. If symptoms of infusion reactions occur, patients should not drive or operate machinery until the symptoms are fully resolved.

Form of production

Lyophilizate for preparation of concentrate for preparation of infusion solution

Storage conditions

At a temperature of 2-8 °C

Shelf life

4 years

Active ingredient

Trastuzumab

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Breast Cancer, Cancer