Herceptin, lyophilizate 440 mg +20 ml

Pharmacodynamics

Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively interacts with the extracellular domain of human epidermal growth factor receptor type 2 (HER2). These antibodies are IgG1 antibodies consisting of human regions (constant heavy chain sites) and determinant complementary murine p185 HER2 antibody sites to HER2.

The proto-oncogene HER2 or c-erB2 encodes a transmembrane receptor-like protein with a molecular weight of 185 kDa that is structurally similar to other members of the epidermal growth factor receptor family. Hyperexpression of HER2 is detected 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 membrane of tumor cells, which in turn causes continuous activation of the HER2 receptor.

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

Trastuzumab blocks the proliferation of human tumor cells with HER2 hyperexpression in vivo and in vitro. In vitro antibody-dependent cellular cytotoxicity of trastuzumab predominantly targets tumor cells with HER2 hyperexpression.

Immunogenicity

An antibody to trastuzumab was detected in one of 903 women with breast cancer who received the drug as monotherapy or in combination with chemotherapy, and she was not allergic to Herceptin®.

There are no data on immunogenicity in the use of Herceptin® for the treatment of gastric cancer.

Pharmacokinetics

The pharmacokinetics of trastuzumab have been studied in patients with metastatic and early-stage cancer and in patients with advanced gastric cancer. No special studies on the study of interdrug interactions have been conducted.

Breast cancer

The pharmacokinetics were nonlinear when the drug was administered as short IV infusions at doses of 10, 50, 100, 250 and 500 mg once a week. The clearance of the drug decreased with increasing dose.

The elimination half-life (T_1/2)

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

The pharmacokinetics of trastuzumab on equilibrium.

The equilibrium state should be reached after approximately 25 weeks. Using a population-based 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 equilibrium after 3 weeks was 1677 mg×day/L after administration of 3 doses (2 mg/kg) weekly and 1793 mg×day/L when administered after 3 weeks at a dose of 6 mg/kg. The calculated medians of C_max were 104 mg/L and 189 mg/L, and C_min were 64.9 mg/L and 47.3 mg/L, respectively. Using a model-independent or “non-compartmental” method of analysis (pop-compartmental analysis, NCA), the average C_min in equilibrium by cycle 13 (week 37) was 63 mg/L in patients with early-stage BCM who received trastuzumab at a loading dose of 8 mg/kg, then at a maintenance dose of 6 mg/kg, after 3 weeks, and was comparable to that in patients with mRMJ who received trastuzumab weekly.

Clearance

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

The volume of distribution

In all clinical studies, the central chamber (V_c) volume of distribution was 3.02 L and the peripheral chamber (V_p) was 2.68 L for a typical patient.

The circulating extracellular domain of the HER2-receptor (“sloughing” from the cell antigen)

The circulating extracellular domain of the HER2-receptor (“sloughing” from the cell antigen) was detected in the serum of some patients with breast cancer and HER2 hyperexpression. In 64% of the patients examined, the “sloughing off” antigen was detected in baseline serum samples at a concentration as high as 1880 ng/ml (median, 11 ng/ml). Patients who had high levels of the sloughing off cell antigen probably could have had a lower C_min. However, the majority of patients with elevated sloughing off-cell antigen levels reached their target serum trastuzumab concentration by 6 weeks when the drug was administered weekly. There was no significant association between baseline cell-derived antigen levels and clinical response.

Disseminated gastric cancer

. Pharmacokinetics of trastuzumab at equilibrium state To assess the pharmacokinetics of trastuzumab at equilibrium state in patients with advanced gastric cancer after administration of trastuzumab at a loading dose of 8 mg/kg, followed by administration 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 levels of trastuzumab serum concentrations were lower, thus finding that the overall clearance of the drug was higher in patients with advanced gastric cancer than in breast cancer patients receiving trastuzumab at the same dose. The reason for this is unknown.

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

The median estimated AUC (at equilibrium over a 3 week period) is 1213 mg×day/L, the median C_max at equilibrium is 132 mg/L, and the median C_min is 27.6 mg/L.

There are no data on circulating extracellular domain levels of the HER2 receptor (“sloughing off” antigen from the cell) in the serum of patients with gastric cancer.

Pharmacokinetics in special patient groups

Separate pharmacokinetic studies have not been performed in elderly patients and patients with renal or hepatic impairment. Age has no effect on the distribution of trastuzumab.

Indications

Breast Cancer, Cancer

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 prior chemotherapy (first-line therapy);
• in combination with aromatase inhibitors for positive hormone receptors (estrogen and/or progesterone) in postmenopausal women.

The early stages of breast cancer with tumor overexpression of HER2:

• as adjuvant therapy after surgery, completion of chemotherapy (neoadjuvant or adjuvant) and radiation therapy;
• in combination with paclitaxel or docetaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide;
• in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin® monotherapy if the disease is locally advanced (including inflammatory form) or if the tumor is larger than 2 cm in diameter.

Tumor-spreading gastric cancer

Tumor-spreading adenocarcinoma of the stomach or esophageal-gastric junction with tumor overexpression of HER2:

• in combination with capecitabine or intravenous fluorouracil and platinum drug in the absence of prior anti-tumor therapy for metastatic disease.

Active ingredient

Trastuzumab

Composition

Active substances:

Trastuzumab 440 mg.

Associates:

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, water d/i – 20.9 mg.

How to take, the dosage

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

Herceptin® is only given by IV drip! Herceptin® must not be given by IV drip or bolus!

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

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

Preparation of the solution

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

Instruction for preparation of concentrate

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

Please handle the drug carefully during dissolution. Excessive foaming should be avoided during dissolution as it may make it difficult to draw the correct dose from the vial.

1. With a sterile syringe, slowly squirt 20 ml of bacteriostatic water for injection into the vial of 440 mg Herceptin®, letting the liquid flow directly onto the lyophilisate.
2. Gently swirl the vial to dissolve.

It is not uncommon for a small amount of foam to form while dissolving the product. In order to avoid this it is necessary to let the solution stand for about 5 min. The prepared concentrate should be clear and colorless or pale yellow in color.

The Herceptin® concentrate solution prepared with bacteriostatic water for injection is stable for 28 days at 2-8°C. The prepared concentrate contains a preservative and can therefore be used repeatedly. After 28 days unused residual concentrate should be discarded. Do not freeze!

The sterile water for injection (without preservative) may be used as a solvent for Herceptin® 440 mg. 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 for only 24 hours at 2-8°C and must be discarded after this time. Do not freeze!

Instructions for preparing the solution for infusion

Determine the volume of the solution:

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

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

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

The appropriate volume should be drawn from the bottle with prepared concentrate and injected into an infusion bag with 250 ml of 0.9% sodium chloride solution. Then the infusion bag should be carefully inverted to stir the solution, avoiding foaming. Before infusion, the solution should be checked (visually) for absence of mechanical impurities and color changes. The solution for infusion is administered immediately after its preparation.

In exceptional cases the prepared solution for infusion can be stored for no more than 24 hours at 2-8 ° C, if the concentrate is dissolved and the solution for infusion is prepared under controlled and validated aseptic conditions. In this case, the conditions of storage (storage rules and duration) are the responsibility of the specialist who prepared the solution.

Instructions for the disposal of unused or expired medication

The release of the medication into the environment must be kept to a minimum. The product should not be disposed of with wastewater or with household waste. If possible, special systems should be used to dispose of medication.

The standard dosing regimen

The patient should be closely monitored during each infusion of trastuzumab for chills, fever, and other infusion reactions (within 6 h after the start of the first infusion and within 2 h after the start of subsequent infusions). An emergency kit should be available, and the infusion should be given by a medical professional experienced in the treatment of anaphylaxis.

In case of infusion reactions, the infusion should be interrupted. Once symptoms of mild to moderate infusion reactions have disappeared according to NCI-CTC (National Cancer Institute Common Toxicity Criteria in the United States), the infusion may be resumed. In case of severe life-threatening infusion reactions, discontinuation of further therapy with Herceptin® should be considered.

Metastatic breast cancer

Weekly administration

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

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

An alternative administration after 3 weeks

The loading dose: 8 mg/kg body weight as a 90-minute IV infusion.

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

Paclitaxel or docetaxel in combination

Paclitaxel or docetaxel were administered the day after Herceptin® administration (for dosing recommendations, see appropriate medical instructions) or immediately after subsequent administration of Herceptin® if Herceptin® was well tolerated on the preceding administration.

The use in combination with an aromatase inhibitor

Herceptin® and anastrozole were administered on day 1. There were no time restrictions on the administration of Herceptin® and anastrozole (see the instructions for medical use for anastrozole or other aromatase inhibitors for dosing recommendations).

Early-stage breast cancer

Weekly administration

In weekly administration, Herceptin® is given at a loading dose of 4 mg/kg body weight, followed by a maintenance dose of 2 mg/kg body weight once weekly.

The maintenance dose is given 1 week after the loading dose. The loading dose is administered as a 90-minute IV infusion. If the preceding loading dose is well tolerated, the drug may be administered as a 30-minute drip infusion.

Injection after 3 weeks

Injection after 3 weeks, the loading dose: 8 mg/kg body weight (as a 90-minute IV infusion). Maintenance dose: 6 mg/kg body weight every 3 weeks.

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

The use of Herceptin® in early 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/m² as a prolonged IV infusion, weekly, for 12 weeks or
175 mg/m² as a prolonged IV infusion, every 3 weeks for 4 cycles (on day 1 of each cycle).

Docetaxel:

• 100 mg/m² as an IV 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 regimen during chemotherapy (loading dose 4 mg/kg, then at a maintenance dose of 2 mg/kg each week).

Thereafter, Herceptin® monotherapy was continued according to the weekly regimen after use in combination with paclitaxel or according to administration 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 Herceptin® were to be administered on the same day, paclitaxel or docetaxel was administered first.

The use in combination with docetaxel and carboplatin

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

• docetaxel at a dose of 75 mg/m² as an IV infusion for 1 h, followed by carboplatin at a dose to achieve a target AUC of 6 mg/mL/min, as an IV infusion, for 30-60 min.

Herceptin®:

• Herceptin® together with chemotherapy was administered according to a weekly regimen (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 administration after 3 weeks. The total duration of therapy with Herceptin® from the first administration was 1 year, regardless of the number of doses received or missed. 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 a 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;
• further, paclitaxel 150 mg/m^sup>2, every 3 weeks, for 4 cycles;
• further, 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 a regimen every 3 weeks. The total duration of therapy with Herceptin® was 1 year.

Spreadable gastric cancer

Injection after 3 weeks

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

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

Metastatic and early-stage BC and advanced gastric cancer

The duration of therapy

The treatment with Herceptin® in patients with metastatic BC or advanced gastric cancer is until disease progression. Patients with early-stage breast cancer should receive therapy with Herceptin® for 1 year or until disease relapse (whichever occurs first).

Missing a scheduled administration

If a missed scheduled administration of trastuzumab is 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; every 3 weeks: 6 mg/kg body weight) without waiting for the next scheduled administration. Then administer the drug in a maintenance dose (weekly regimen: 2 mg/kg body weight; regimen every 3 weeks: 6 mg/kg body weight) according to the previously established schedule.

If the break in drug administration is more than 7 days, a loading dose of trastuzumab should be administered again (weekly regimen: 4 mg/kg body weight; regimen every 3 weeks: 8 mg/kg body weight), as a 90-minute intravenous drip infusion. Thereafter, continue the drug in a maintenance dose (weekly regimen: 2 mg/kg body weight; regimen every 3 weeks: 6 mg/kg body weight).

Dose adjustment

. During reversible chemotherapy-induced myelosuppression, therapy with Herceptin® may be continued after reduction in the dose of chemotherapy or temporary withdrawal (as recommended in the paclitaxel, docetaxel or aromatase inhibitor guidelines for use), provided that complications due to neutropenia are carefully controlled./p>

Special Dosing Instructions

Patients in the Elderly

Dose reduction of Herceptin® in elderly patients is not necessary.

Interaction

No specific drug interaction studies of Herceptin® in humans have been conducted.

In clinical studies no clinically significant interactions with concomitantly used drugs (including doxorubicin, paclitaxel, docetaxel, capecitabine or cisplatin) have been observed.

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

Herceptin® should not be mixed or dissolved with other drugs.

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

Special Instructions

The treatment with Herceptin® should only be performed under the supervision of an oncologist. HER2 testing should be performed by a specialized laboratory that can provide quality control of the testing procedure.

Herceptin® should only be used in patients with metastatic or early-stage breast cancer when tumor HER2 hyperexpression as determined by immunohistochemical reaction (IHC) or HER2 gene amplification as determined by in situ hybridization (FISH or SISH). Accurate and validated detection methods should be used.

Herceptin® should only be used in patients with metastatic gastric cancer when tumor HER2 overexpression determined by IHC as IHC2+ and confirmed by SISH or FISH or IHC3+. Accurate and validated detection methods should be used.

There are currently no data from clinical studies of patients who received Herceptin® repeatedly after use in adjuvant therapy.

Infusion reactions and hypersensitivity reactions

Infrequent serious infusion adverse reactions have occurred with Herceptin®: shortness of breath, arterial hypotension, wheezing in the lungs, arterial 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 h from the beginning of the first infusion. If an infusion reaction occurs, the infusion should be stopped. The patient should be closely monitored until all symptoms have resolved. Effective therapy of severe reactions consists in the use of oxygen inhalation, beta-adrenergic stimulants, GCS. In case of severe and life-threatening infusion reactions, discontinuation of further therapy with Herceptin® should be considered.

In rare cases, these reactions have been associated with a fatal outcome. The risk of fatal infusion reactions is higher in patients with dyspnea at rest caused by pulmonary metastases or comorbidities, so these patients should not be treated with Herceptin®.

There have been reported cases in which deterioration has occurred after initial improvement, as well as cases with delayed rapid deterioration. Lethal outcome occurred within hours or one week after infusion. In very rare cases, patients have had symptoms of infusion reactions or pulmonary symptoms (more than 6 hours after initiation of Herceptin®). Patients should be warned about the possible delayed development of these symptoms and the need to contact their physician immediately if they occur.

Lung disorders

Serious lung events, sometimes accompanied by death, have been reported with Herceptin® in the post-registration period. In addition, cases of interstitial lung disease (ILD), including pulmonary infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure were observed. Risk factors associated with IBD include: previous or concomitant therapy with other anti-neoplastic drugs known to be associated with IBD (taxanes, gemcitabine, vinorelbine, and radiation therapy). These phenomena may occur either during the infusion (as manifestations of infusion reactions) or delayed. The risk of severe pulmonary reactions is higher in patients with metastatic lung lesions, comorbidities accompanied by dyspnea at rest. Therefore, such patients should not receive Herceptin®. Caution should be exercised, especially in patients receiving concomitant therapy with taxanes, because of the development of pneumonitis.

Cardiotoxicity

General guidelines

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

Patients planning to receive Herceptin®, especially those previously treated with anthracyclines and cyclophosphamide, should first undergo a thorough cardiology work-up, including history taking, physical examination, ECG, echocardiography and/or radioisotopic ventriculography or MRI.

The possible benefits and risks of Herceptin® should be carefully compared before starting treatment with Herceptin®.

Because the T_1/2 of Herceptin® is about 28-38 days, the drug may remain in the blood up to 27 weeks after completion of therapy. Patients who receive anthracyclines after completing Herceptin® treatment may have an increased risk of cardiotoxicity. Whenever possible, physicians should avoid prescribing anthracycline-based chemotherapy for 27 weeks after completion of Herceptin® therapy. Careful monitoring of cardiac function should be performed when using anthracyclines.

The necessity of a standard cardiac examination in patients with suspected cardiovascular disease during the pre-treatment evaluation should be evaluated.

In all patients, cardiac function should be monitored during treatment (e.g., every 12 weeks).

Monitoring can identify patients who develop cardiac dysfunction.

Patients with asymptomatic impaired heart function may benefit from more frequent monitoring (e.g., every 6-8 weeks). If left ventricular function impairment persists and is not symptomatic, it is appropriate to consider discontinuing the drug if there is no clinical benefit from its use. Caution should be exercised during treatment of patients with symptomatic heart failure, arterial hypertension or documented history of coronary artery disease, and early breast cancer patients with left ventricular ejection fraction ≤55%.

If LVEF falls to values below 50% and by 10 points relative to the value before therapy, treatment should be suspended and the LVEF should be reassessed at least 3 weeks later. If LVEF has not improved or has continued to decline, discontinuation of the drug should be considered if the benefit in this patient does not outweigh the risk. Such patients should be evaluated and monitored by a cardiologist.

If symptomatic heart failure develops with Herceptin® therapy, appropriate standard drug therapy should be given. Consideration should be given to discontinuing Herceptin® when clinically significant heart failure develops unless the benefit to the individual patient outweighs the risk.

The safety of continuing or resuming Herceptin® therapy in patients who develop cardiotoxicity has not been studied in prospective clinical trials. Most patients improved with standard drug therapy in baseline studies. Diuretics, cardiac glycosides, beta-adrenoblockers and/or ACE inhibitors were used as standard therapy. In the presence of clinical benefit from Herceptin®, most patients with adverse cardiac reactions continued therapy without additional clinically significant cardiac reactions.

Metastatic breast cancer

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

The risk of cardiotoxicity in patients with metastatic breast cancer is increased with prior therapy with anthracyclines, but is lower compared to that with concomitant use of anthracyclines and Herceptin®.

Early-stage breast cancer

Patients with early-stage breast cancer should have a cardiac evaluation before starting treatment, every 3 months during therapy, and every 6 months after completion of therapy for 24 months from the last dose of the drug. Longer follow-up after treatment with Herceptin® in combination with anthracyclines is recommended, with a frequency of examinations once per year for 5 years from the last dose of Herceptin® or thereafter if there is a prolonged decrease in LVEF.

Adjuvant therapy

The use of Herceptin® in combination with anthracyclines in adjuvant therapy is not recommended. Patients with early breast cancer who received Herceptin® after anthracycline-based chemotherapy had an increased incidence of symptomatic and asymptomatic cardiac adverse events compared to those who received docetaxel and carboplatin chemotherapy (nonanthracycline regimens). The difference was greater when Herceptin® and taxanes were used together than when they were used sequentially.

Because early-stage cancer patients with a history of established congestive heart failure, uncontrolled high-risk arrhythmias, angina requiring drug therapy, clinically significant heart defects, signs of transmural myocardial infarction on ECG, and poorly controlled hypertension were not enrolled in the clinical trial, information on the benefit/risk ratio in these patients is not available, and therefore treatment with the drug is not recommended in these patients.

Neoadjuvant-adjuvant therapy

Introductive therapy For patients with early-stage breast cancer who are eligible for neoadjuvant-adjuvant therapy, the use of Herceptin® in combination with anthracyclines is recommended only if they have not previously received chemotherapy and only when using low-dose anthracycline regimens (maximum total doxorubicin dose 180 mg/msup>2 or epirubicin 360 mg/m²).

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

Because patients with NYHA functional class II-IV heart failure, LVEF of 180 mm Hg or diastolic > 100 mm Hg), clinically significant heart defects and uncontrolled high risk arrhythmias have not been enrolled in a clinical trial, treatment with Herceptin® is not recommended for these patients.

Trastuzumab has limited experience with low-dose anthracycline regimens. When Herceptin® was used in conjunction with neoadjuvant chemotherapy that included three cycles of neoadjuvant doxorubicin (total doxorubicin dose 180 mg/m²), the incidence of symptomatic heart function impairment was low (1.7%).

Neoadjuvant-adjuvant therapy with Herceptin® is not recommended for patients over 65 years of age because of limited clinical experience in these patients.

If Herceptin® is prescribed to a patient with hypersensitivity to benzyl alcohol, the drug must be dissolved with water for injection and only one dose may be withdrawn from each multi-dose vial. The remaining drug should be discarded.

Impact on the ability to drive vehicles and other mechanisms requiring high concentration

There have been no studies of the drug effect on the ability to drive and operate machinery. If symptoms of infusion reactions occur, patients should not drive or operate machinery until symptoms have resolved.

Contraindications

• Severe dyspnea at rest caused by pulmonary metastases or requiring oxygen support therapy;
• children under 18 years of age (efficacy and safety in children not established);
• pregnancy;
• breastfeeding period;
• high sensitivity to trastuzumab or any other component of the drug, includingч. benzyl alcohol as a preservative in the bacteriostatic water for injection that accompanies each 440 mg multi-dose vial.

With caution: use in CHD, arterial hypertension, heart failure, comorbid lung disease or pulmonary metastases, prior therapy with cardiotoxic drugs including anthracyclines/cyclophosphamide.

Side effects

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

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

• very frequently (≥1/10);
• frequently (≥1/100, but < 1/10);
• infrequently (≥1/1000, but < 1/100);
• very rare ( < 1/10,000), unknown (cannot be calculated from available data).

Within each group, adverse reactions are presented according to decreasing severity.

The adverse reactions reported with Herceptin® both in monotherapy and in combination with chemotherapy in baseline clinical trials and in post-marketing use are presented below. The frequency is given according to the maximum frequency encountered in the baseline clinical trials.

Infectious and parasitic diseases: Frequent – pneumonia¹ ( < 1%), neutropenic sepsis, cystitis, Herpes zoster, infections, influenza, nasopharyngitis, sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, rye, phlegmon; infrequent – sepsis.

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

The blood and lymphatic system: very common – febrile neutropenia; common – anemia, neutropenia, thrombocytopenia, leukopenia; unknown – hypoprothrombinemia.

The immune system: frequent – hypersensitivity reactions; unknown – anaphylactic reactions¹, anaphylactic shock¹.

Metabolism: often – weight loss, anorexia; unknown – hyperkalemia.

Psychiatric disorders: often – anxiety, depression, insomnia, impaired thinking.

Nervous system disorders: very common – tremor², dizziness, headaches; common – peripheral neuropathy, paresthesia, muscle hypertonicity, somnolence, dysgeusia (distortion of taste perception), ataxia; rarely – paresis; unknown – cerebral edema.

An organ of vision: very common – conjunctivitis, increased lacrimation; common – dry eyes; unknown – edema of the optic disk, retinal hemorrhage.

Hearing organ and labyrinth disorders: infrequent – deafness.

Cardiovascular system disorders: very common – decreased and increased BP² , heart rhythm disturbance² , palpitations², atrial or ventricular flutter², decreased left ventricular ejection fraction³, “flushes”; Frequent – heart failure (congestive)¹ (2%), supraventricular tachyarrhythmia^1,2, cardiomyopathy, arterial hypotension^1,2, vasodilation; infrequent – pericardial effusion; unknown – cardiogenic shock, pericarditis, bradycardia, “gallop” rhythm.

Respiratory system, thoracic and mediastinal organs: very common – wheezing^1,2, dyspnea¹ (14%), cough, nasal bleeding, rhinorrhea; common – bronchial asthma, impaired lung function, pharyngitis; infrequent – pleural effusion¹; rare – pneumonitis; unknown – pulmonary fibrosis¹, respiratory failure¹, pulmonary infiltration¹, acute pulmonary edema¹, acute respiratory distress syndrome¹, bronchospasm¹, hypoxia¹, decreased hemoglobin oxygen saturation¹, laryngeal edema, orthopnea, pulmonary edema.

Gastrointestinal disorders: very common – diarrhea, vomiting, nausea, lip swelling², abdominal pain; common – pancreatitis, dyspepsia, hemorrhoids, constipation, dry mouth.

Hepatic and biliary tract disorders: frequent – hepatitis, pain in the liver area, hepatocellular damage; rarely – jaundice; unknown – liver failure.

Skin and subcutaneous tissue: very common – erythema, rash, facial edema²; common – acne, alopecia, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, nail structure disorders, itching; unknown – angioedema, dermatitis, urticaria.

Musculoskeletal and connective tissue disorders: very common – arthralgia, muscle stiffness², myalgia; common – arthritis, back pain, ossalgia, muscle spasms, pain in the neck.

Renal and urinary tract disorders: frequent – renal disease; unknown – membranous glomerulonephritis, glomerulonephropathy, renal failure.

Impact on the course of pregnancy, postpartum and perinatal conditions: unknown – oligohydramnios, fatal pulmonary hypoplasia and fetal renal hypoplasia.

Gender and mammary gland disorders: often – mammary gland inflammation/mastitis.

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

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

¹ – adverse reactions reportedly associated with death.

² – adverse reactions that were mostly reported in association with infusion reactions. The exact percentage has not been determined.

³ – Adverse reactions were observed with combination therapy after anthracyclines and in combination with taxanes.

The exact percentages in parentheses represent the exact frequency for those terms reported together with fatal outcomes with a frequency of “often” or “very often.” The percentage refers to the total number of these occurrences with and without fatalities.

The following adverse reactions were reported in baseline clinical trials with an incidence of ≥1/10 in either therapy group, with no significant difference between the Herceptin®-containing therapy group and the comparison therapy group lethargy, hypoesthesia, limb pain, mouth and throat pain, lymphedema, weight gain, onychoclasia, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, epigastric pain, gastritis, stomatitis, vertigo, hypertension, hiccups, palmar-subcutaneous syndrome, breast pain, onychorexis, breathlessness with exercise and dysuria.

The following is information on individual adverse reactions

Infusion reactions and hypersensitivity reactions

It is estimated that about 40% of patients receiving Herceptin® experience some form of infusion reaction. However, most infusion reactions are mild to moderate in severity (according to NCI-CTC) and tend to occur early in treatment, i.e., during the 1st, 2nd and 3rd infusions, occurring less frequently with subsequent infusions. 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®, and such reactions have been associated with death.

Cardiotoxicity

Cardiotoxicity (heart failure) of NYHA functional class II-IV is a frequent adverse reaction with Herceptin® and has been associated with fatal outcome. In 3 baseline clinical trials of trastuzumab in combination with adjuvant chemotherapy, the incidence of grade 3/4 cardiac dysfunction (symptomatic congestive heart failure) was not different between patients receiving chemotherapy alone (i.e., without Herceptin®) and 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 who experienced cardiotoxicity has not been prospectively studied. However, the majority of patients who experienced heart failure in the baseline studies improved with standard therapy which included diuretics, cardiac glycosides, beta-adrenoblockers and/or ACE inhibitors.

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

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

Hematologic toxicity

Febrile neutropenia occurred very frequently. Undesirable reactions occurring frequently include anemia, leukopenia, thrombocytopenia and neutropenia. The incidence of hypoprothrombinemia is unknown. The risk of neutropenia may be slightly higher when trastuzumab is used in combination with docetaxel after therapy with anthracyclines.

Lung disorders

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

Overdose

No cases of drug overdose have been observed in clinical trials. Administration of Herceptin® in single doses greater than 10 mg/kg has not been studied. Herceptin® in doses ≤10 mg/kg was well tolerated.

Pregnancy use

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

In case of pregnancy, the woman should be warned about the possibility of harmful effects on the fetus. If the 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 fertility in women. The results of animal experiments showed no evidence of impaired fertility or negative effects on the fetus.

Breastfeeding is not recommended during treatment and for at least 6 months after completion of Herceptin® therapy.

The benzyl alcohol contained as a preservative in the bacteriostatic water for injection included with each 440 mg multi-dose vial has toxic effects in infants and children less than 3 years of age.