Herceptin - instructions for use, analogs, reviews and release forms (injections in ampoules and vials for injections and infusions, lyophilizate 150 mg and 440 mg) drugs for the treatment of breast and stomach cancer in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Herceptin. Presented are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors of specialists on the use of Herceptin in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Herceptin analogs in the presence of existing structural analogues.Use for the treatment of breast and stomach cancer, in adults, children, as well as in pregnancy and lactation. Composition of the preparation.

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

The proto-oncogene HER2 or c-erB2 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 of HER2 is found in the tissue of primary breast cancer (breast cancer) in 25-30% of patients and in the tissues of advanced stomach 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 a constant activation of the HER2 receptor.

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

Trastuzumab (the active substance of the drug Herceptin) blocks the proliferation of human tumor cells with the overexpression of HER2. The antibody-dependent cellular cytotoxicity of trastuzumab is mainly directed towards tumor cells with overexpression of HER2.

Immunogenicity

Antibodies to trastuzumab were found in one of the 903 women with breast cancer who received the drug in monotherapy or in combination with chemotherapy, and had no allergy to Herceptin.

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

Composition

Trastuzumab + auxiliary substances.

Pharmacokinetics

The pharmacokinetics of trastuzumab have been studied in patients with metastatic breast cancer 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. In the serum of some patients with breast cancer and HER2 overexpression, the circulating extracellular domain of the HER2 receptor ("slipping" from the cell antigen) is found. In 64% of the examined patients, a "slipping" antigen was detected in the initial serum samples at a concentration reaching 1880 ng / ml (median 11 ng / ml). Patients who had a high concentration of "sluschivayuschegosya" with the cell antigen, probably could have a lower Cmin. However, in the majority of patients with an elevated "sluschivayuschegosya" with the cell antigen when the drug was administered weekly, the 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

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 women with breast cancer who receive trastuzumab at the same dose. The reason for this is unknown.At high concentrations, the overall clearance is predominantly linear. Data on the level of the circulating extracellular domain of the HER2 receptor ("sluschivayuschiesya" from the cell 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.

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 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 adjuvant chemotherapy consisting of docetaxel and carboplatin;
in combination with neoadjuvant chemotherapy and subsequent adjuvant monotherapy with Herceptin in a locally advanced (including inflammatory form) disease or in cases where the tumor size exceeds 2 cm in diameter.

Common stomach cancer

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

in combination with capecitabine or iv administration of fluorouracil and a platinum preparation in the absence of prior antitumor therapy for metastatic disease.

Forms of release

Lyophilizate for the preparation of a solution for infusions of 150 mg (injections in ampoules for injections).

Liofilizate for the preparation of concentrate for the preparation of a solution for infusions 440 mg.

Instructions for use and dosing regimen

Intravenously, infusion, at a dose of 4 mg / kg for 90 minutes, then in a maintenance dose of 2 mg / kg for 30 minutes (with poor tolerability for longer) 1 time pera week.

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

Herceptin is administered only by intravenous drip (through droppers)! Enter the drug intravenously struyno or bolusno not!

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

The drug 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 a solution

The contents of the 150-mg Herceptin bottle are dissolved in 7.2 ml of sterile water for injection.

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.

Sterile syringe slowly introduce 7.2 ml of sterile water for injection into the vial with 150 mg drug Herceptin, directing a jet of fluid directly at the lyophilisate.
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 solution should be clear and colorless or have a pale yellow color.

Storage conditions of the prepared solution

A bottle with 150 mg of the drug is used only once.

Solution Herceptin is physically and chemically stable for 24 hours at a temperature of 2-8 degrees Celsius after dissolving with sterile water for injection. Do not freeze!

Instructions for preparing the concentrate

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

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.
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.

Concentrate solution of the drug Herceptin, prepared on bacteriostatic water for injection, is stable for 28 days at a temperature of 2-8 degrees Celsius. The prepared concentrate contains a preservative and can therefore be used repeatedly. After 28 days unused concentrate residue should be discarded. Do not freeze!

As a solvent for Herceptin 440 mg, sterile water for injections is allowed (no 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 temperature2-8 degrees Celsius and should be discarded after this time. Do not freeze!

Side effect

neutropenic sepsis;
cystitis;
infection;
flu;
nasopharyngitis;
sinusitis;
skin infections;
rhinitis;
upper respiratory tract infection;
urinary tract infections;
face;
phlegmon;
sepsis;
progression of malignant neoplasm;
anemia, neutropenia, thrombocytopenia, leukopenia;
anaphylactic reactions;
anaphylactic shock;
decreased body weight;
anorexia;
anxiety;
depression;
insomnia;
violation of thinking;
tremor;
dizziness;
headache;
peripheral neuropathy;
paresthesia;
muscular hypertonia;
drowsiness;
dysgeusia (distortion of taste perception);
ataxia;
paresis;
edema of the brain;
conjunctivitis;
increased tear;
dry eyes;
edema of the optic disc;
hemorrhage into the retina;
deafness;
decrease and increase of blood pressure;
heart rhythm disorder;
palpitation;
flutter of the atria or ventricles;
reduction of the left ventricular ejection fraction;
"tides";
heart failure (stagnant);
supraventricular tachyarrhythmia;
cardiomyopathy;
arterial hypotension;
vasodilation;
pericardial effusion;
cardiogenic shock;
pericarditis;
bradycardia;
cough;
nose bleed;
rhinorrhea;
pneumonia;
bronchial asthma;
pharyngitis;
pneumonitis;
acute pulmonary edema;
bronchospasm;
hypoxia;
laryngeal edema;
orthopnea;
pulmonary edema;
diarrhea, constipation;
vomiting, nausea;
swelling of the lips;
stomach ache;
pancreatitis;
dyspepsia;
hemorrhoids;
dry mouth;
jaundice;
erythema;
rash;
swelling of the face;
dry skin;
ecchymosis;
hyperhidrosis;
angioedema;
dermatitis;
hives;
arthralgia;
myalgia;
arthritis;
back pain;
muscle spasms;
pain in the neck;
kidney disease;
membranous glomerulonephritis;
glomerulonephropathy;
kidney failure;
fatal hypoplasia of the lungs and kidney hypoplasia in the fetus;
inflammation of the breast / mastitis;
asthenia;
pain in the chest;
chills;
weakness;
fever;
peripheral edema.

Contraindications

severe dyspnea at rest caused by metastases to the lungs, or requiring maintenance therapy with oxygen;
children under 18 years of age (efficacy and safety of use in children not established);
pregnancy;
the period of breastfeeding;
increased sensitivity to trastuzumab or any other 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 440 mg.

Application in pregnancy and lactation

Women of childbearing age during treatment with Herceptin and at least 6 months after the end of treatment should 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. It is not known whether Herceptin affects fertility in women. The results of experiments on animals showed no signs of impaired fertility or a negative effect on the fetus.

Breastfeeding is not recommended during treatment and at least 6 months after the end of Herceptin therapy.

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

Use in children

The effectiveness and safety of the drug in children under 18 years of age have not been established.

Benzyl alcohol, which is part of bacteriostatic water as a preservative, has a toxic effect on newborns and children under 3 years.

Application in elderly patients

A decrease in the dose of Herceptin in elderly patients is not required.

special instructions

Treatment with Herceptin should be done only under the supervision of an oncologist. HER2 testing should be conducted 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 of HER2 determined by the immunohistochemical reaction (IHC) method or amplification of the HER2 gene determined by hybridization (FISH or SISH). Accurate and validated methods should be used.

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

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

Infusion reactions and hypersensitivity reactions

Serious infusion unwanted reactions occurred infrequently with the administration of Herceptin: shortness of breath, arterial hypotension, wheezing in the lungs, arterial hypertension, bronchospasm, supraventricular tachyarrhythmia, decreased oxygen saturation of hemoglobin, anaphylaxis, respiratory distress syndrome, hives and angioedema. Most of them occurred during infusion or within 2.5 hours from the start of the first injection. If an infusion reaction occurs, the injection should be stopped. Care should be taken to monitor the patient until all symptoms are eliminated. Effective therapy for serious reactions consists in the use of inhalation of oxygen, beta-adrenostimulators, GCS.In case of development of severe and life-threatening infusion reactions, 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 metastases to the lungs or concomitant diseases, therefore 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 the drug Herceptin in the postregistered period, severe phenomena from the side of the lungs were registered, 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 anti-neoplastic drugs known to be associated with IBL (taxanes, gemcitabine, vinorelbine and radiation therapy). These phenomena can occur both during infusion (both manifestations of infusion reactions) and delayed. 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.

Cardiotoxicity

General instructions

Heart failure (NYHA class 2-4 functional class), observed after therapy with Herceptin as monotherapy or in combination with Paclitaxel or docetaxel, especially after chemotherapy,containing anthracyclines (doxorubicin or epirubicin) may be of moderate severity or severe course and in some cases may lead to death.

Patients who are scheduled to receive Herceptin, especially those who have previously received anthracycline and cyclophosphamide, should first undergo a thorough cardiac examination, including a history, 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 T1 / 2 of the drug Herceptin is about 28-38 days, the drug can be in the blood up to 27 weeks after the completion of therapy. Patients who receive anthracyclines after completion of treatment with Herceptin may have an increased risk of cardiotoxicity. 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 who, when examined before treatment, are suspected of having cardiovascular diseases.

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.

Patients with asymptomatic cardiac dysfunction may find it useful to monitor more often (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. Caution should be exercised during treatment of patients with symptomatic heart failure, arterial hypertension or documented coronary artery lesions in history, as well as patients with early stages of breast cancer with a fraction of left ventricular ejection of less than 55%.

If LVEF falls below 50% and by 10 points relative to the value before the start of therapy, treatment should be suspended and reassessment of LVEF no later than 3 weeks later.If LVEF has not improved or its decline has continued, consideration should be given to the withdrawal of the drug if the benefit from its use in this patient does not exceed the risk. Such patients should be examined by a cardiologist and under his supervision.

If symptomatic heart failure develops with the Herceptin therapy, appropriate standard medical therapy should be performed. Consideration should be given to the cancellation of Herceptin in the development of clinically significant heart failure, if the benefit of using the drug in a particular patient does not exceed the risk.

The safety of the continuation or resumption of therapy with Herceptin in patients who developed cardiotoxicity has not been studied in prospective clinical trials. Most patients showed improvement in the background of standard drug therapy in basic clinical trials. 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, the majority of patients with adversereactions from the heart 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 cardiotoxicity in patients with metastatic breast cancer is elevated with prior therapy with anthracyclines, but it is lower compared to that with concomitant use of anthracyclines and Herceptin.

Early stages of breast cancer

Patients with early breast cancer should undergo a cardiac examination before treatment, every 3 months during therapy and every 6 months after the end of treatment, within 24 months of the administration of the last dose of the 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.

Adjuvant therapy

It is not recommended to use the drug Herceptin in combination with anthracyclines in adjuvant therapy. In patients with early 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). However, the difference was greater in cases of joint use of the drug Herceptin and taxanes than in the case of sequential application.

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).

Since patients in the early stages of breast cancer with established congestive heart failure in history, uncontrolled high-risk arrhythmias, angina pectoris requiring medical treatment, clinically significant heart defects, signs of transmural myocardial infarction according to ECG data poorly controlled by arterial hypertension did not participate in the clinical study, then information on the benefit / risk ratio in such patients is not available, and therefore treatment with the drug is not recommended for such patients.

Neoadjuvant-adjuvant therapy

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

In patients who received low doses of anthracyclines and Herceptin as part of neoadjuvant therapy, additional cytotoxic chemotherapy is not recommended after surgical intervention.

Since patients with heart failure 2-4 functional class according to NYHA, LVEF less than 55% according to radioisotope ventriculography or echocardiography, history of established congestive heart failure, stenocardia requiring medication, signs of transmural myocardial infarction according to ECG, poorly controlled by hypertension (systolic pressure more than 180 mm Hg or diastolic more than 100 mm Hg), clinically significant heart defects and uncontrolled arrhythmias are high th risk did not take part in a clinical trial, treatment with Herceptin in these patients is not recommended.

The experience with trastuzumab in conjunction with low-dose regimens for anthracycline therapy is limited. When using Herceptin together with neoadjuvant chemotherapy, which included three cycles of neoadjuvant doxorubicin (total dose of doxorubicin 180 mg / m2), the incidence of symptomatic cardiac dysfunction was low (1.7%).

Neoadjuvant-adjuvant therapy with Herceptin is not recommended for patients over the age of 65 because the clinical experience of such patients is limited.

Additional Information

When prescribing Herceptin to a patient with hypersensitivity to benzyl alcohol, the drug must be dissolved with water for injection, with only one dose taken from each multi-dose vial. The remaining drug should be discarded.

Impact on the ability to drive vehicles and manage mechanisms

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.

Drug Interactions

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

In clinical trials, no clinically relevant interactions with concomitant medications (including doxorubicin, paclitaxel, docetaxel, capecitabine, or cisplatin) have not been reported.

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.

No evidence of the incompatibility between the solution preparation and infusion bags made of polyvinyl chloride, polyethylene or polypropylene was not observed.

Analogues of medicinal Herceptin

Herceptin has no structural analogs for the active substance.

Analogues on the curative effect (remedies for the treatment of breast cancer):

Abitaxel;
Avastin;
Alkeran;
Arglabin;
Arimidex;
Aromasine;
Biel;
Buserelin depot;
Velba;
Vinblastine;
Vinelbin;
Vincristine;
Gemzar;
Hemita;
Hydrea;
Hormoplex;
Depostat;
Doxorubifer;
Doxorubicin;
Zitazonium;
Zoladex;
Intaksel;
Carboplatin;
Kelix;
Xeloda;
Leukeran;
Mawerex;
Methotrexate;
Mitoxantrone;
Mitotax;
Navelbin;
Novanthron;
Novofen;
Nolvadex;
Omnadren;
Oncotron;
Orimeten;
Paclitaxel;
Paxen;
Provera;
Sinestrol;
Tayverb;
Tamoxen;
Tamoxifen;
Tautax;
Testosterone propionate;
Fazlodex;
Fareston;
Photosens;
Ftorafur;
Fluorouracil;
Halavan;
Holoksan;
Cyclophosphane;
Egistrazole;
Aldesine;
Episondan;
The Estrolet;
Ethinylestradiol;
Etoposide.

If there are no analogues of the medication for the active substance, you can go to the links below for diseases,from which the corresponding preparation helps, and to look at the available analogs for therapeutic effects.

Used for the treatment of diseases: cancer, oncology, mammary cancer, stomach cancer