Trastuzumab | Herceptin lyophilisate for prigot.r-ra for infusion 150 mg vials 1 pc.
Special Price
$260.68
Regular Price
$273.00
In stock
SKU
BID463670
Latin name
HERCEPTIN
HERCEPTIN
Latin name
HERCEPTIN
Release form
Lyophilisate for solution for infusion.
Packing
1 pc
Pharmacological action of
Pharmacodynamics of
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively interacts with the extracellular domain of human epidermal growth factor 2 receptors (HER2). These antibodies are IgG1 consisting of human regions (constant regions of heavy chains) and determining the complementarity of the murine regions of p185 HER2 anti-HER2 antibody.
The HER2 or c-erB2 proto-oncogen 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 membrane of the tumor cells, which in turn causes constant activation of the HER2 receptor.
Studies show that patients with breast cancer who have amplified or overexpressed HER2 in the tumor tissue have less survival without evidence of disease than patients without amplification or overexpressed HER2 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 primarily directed to tumor cells with HER2 overexpression.
Immunogenicity
Trastuzumab antibodies were detected in one of 903 breast cancer patients who received the drug in monotherapy or in combination with chemotherapy, but did not have any allergies to Herceptin®.
There is no data on the immunogenicity of Herceptin® for gastric cancer.
Pharmacokinetics
The pharmacokinetics of trastuzumab has been studied in patients with metastatic breast cancer and early stages of breast cancer, as well as in patients with advanced gastric cancer. Special studies on the study of drug interactions have not been conducted.
Breast cancer
With the introduction of the drug in the form of short iv infusions at a dose of 10, 50, 100, 250 and 500 mg once a week, the pharmacokinetics was non-linear. With increasing doses, the clearance of the drug decreased.
Elimination half-life (T1 / 2)
T1 / 2 is 28-38 days, therefore, the elimination period after drug withdrawal is up to 27 weeks (190 days or 5 elimination half-lives).
Pharmacokinetics of trastuzumab against equilibrium.
An equilibrium should be reached in about 25 weeks. When using the population pharmacokinetic method (two-chamber model, model-dependent analysis) for evaluating phase I studies, Phase II and phase III with metastatic breast cancer, the median of the expected AUC in equilibrium after 3 weeks was 1677 mg Day / l after 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 Cmax were 104 mg / L and 189 mg / L, and Cmin - 64.9 mg / L and 47.3 mg / L, respectively. When using a model-independent or non-chamber analysis method (non-compartmental analysis, NCA), the average Cmin in equilibrium by cycle 13 (week 37) was 63 mg / L in patients with early breast cancer who received trastuzumab at a loading dose of 8 mg / kg , then in the supporting 6 mg / kg, after 3 weeks, and was comparable to that in patients with breast cancer receiving trastuzumab weekly.
Clearance
The typical clearance of trastuzumab (for a patient weighing 68 kg) was 0.241 l / day.
Distribution volume
In all clinical trials, the distribution volume in the central chamber (Vc) was 3.02 L and in the peripheral (Vp) 2.68 L for a typical patient.
The circulating extracellular domain of the HER2 receptor (cell-desorbing antigen)
In the blood serum of some patients with breast cancer and HER2 hyperexpression, a circulating extracellular domain of the HER2 receptor (cell-descending antigen) was found. In 64% of the examined patients, the antigen peeling from the cell was detected in the initial serum samples at a concentration reaching 1880 ng / ml (median 11 ng / ml). Patients with a high concentration of antigen desquamation from the cell probably could have a lower Cmin. However, in most patients with an increased level of antigen desquamating from the cell with the introduction of the drug, the target serum trastuzumab concentration was reached by week 6. There was no significant relationship between the initial level of antigen peeling from the cell and the clinical response.
Common gastric cancer
Pharmacokinetics of trastuzumab against equilibrium To evaluate the pharmacokinetics of trastuzumab against equilibrium in patients with advanced gastric cancer after administration of trastuzumab at a loading dose of 8 mg / kg, followed by the administration of 6 mg / kg every 3 weeks, a non-linear two-dimensional pharmacokinetic method using data from a phase III study.
The observed serum trastuzumab concentration levels were lower, thus 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 in the same dose. The reason for this is unknown.
At high concentrations, the overall clearance is mostly linear, and T1 / 2 is about 26 days.
The median of the estimated AUC (in equilibrium over a 3 week period) is 1213 mg day / l, the median Cmax in equilibrium is 132 mg / l, and the median Cmin is 27.6 mg / l.
There are no data on the level of the circulating extracellular domain of the HER2 receptor (cell-disengaging antigen) in the serum of patients with gastric cancer.
Pharmacokinetics in special patient groups
No separate pharmacokinetic studies have been performed in elderly patients or patients with renal or hepatic impairment. Age does not affect the distribution of trastuzumab.
Indications
Breast cancer
Metastatic breast cancer with tumor overexpression HER2: as monotherapy, after one or more
chemotherapy regimens in combination with paclitaxel or docetaxel, in the absence of previous chemotherapy with first-line inhibitor aromatase with positive hormonal receptors (estrogen and / or progesterone) in postmenopausal women.
Early stages of breast cancer with tumor overexpression of HER2: as adjuvant therapy after surgery, completion of chemotherapy (neoadjuvant or adjuvant) and radiation therapy with
in combination with paclitaxel or docetaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide
in combination with adjuvant chemotherapy consisting of docetin adjuvant and carbohydrate adjuvant - a widespread (including inflammatory form) disease or in cases where the size of the tumor exceeds 2 cm in diameter.
Common gastric cancer
Common gastric adenocarcinoma or gastroesophageal junction with tumor overexpression of HER2: in combination with capecitabine or iv fluorouracil and platinum in the absence of previous antitumor therapy for metastatic disease.
Contraindications
Severe shortness of breath at rest caused by lung metastases, or requiring maintenance therapy with oxygen
children under 18 years of age (efficacy and safety of use in children have not been established)
pregnancy
breastfeeding or any other component drug, including to benzyl alcohol, contained as a preservative in bacteriostatic water for injection, attached to each 440 mg multi-dose vial.
Precautions: used for coronary heart disease, arterial hypertension, heart failure, concomitant lung diseases or lung metastases, prior therapy with cardiotoxic drugs, including anthracyclines / cyclophosphamide.
Use during pregnancy and lactation
Women of childbearing age during treatment with HerceptinВ® and at least 6 months after the end of treatment must use reliable methods of contraception.
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 HerceptinВ®, then she should be under close supervision of doctors of various specialties. It is not known whether HerceptinВ® affects fertility in women. The results of animal experiments did not reveal 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 treatment with HerceptinВ®.
Benzyl alcohol, contained as a preservative in bacteriostatic water for injection, supplied with each 440 mg multi-dose vial, has a toxic effect in infants and children up to 3 years old.
Composition
1 vial contains:
Active substances: trastuzumab 150 mg.
Excipients: L-histidine hydrochloride - 3.36 mg, L-histidine - 2.16 mg,?,? - trehalose dihydrate - 136.2 mg, polysorbate 20 - 0.6 mg.
Dosage and Administration
Testing for tumor expression of HER2 prior to 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 drugs.
Herceptin® solution is compatible with infusion bags made of polyvinyl chloride, polyethylene and polypropylene.
Preparation of
solution Preparation of the drug for administration should be carried out under aseptic conditions.
Instruction for the preparation of
concentrate The contents of the Herceptin® vial are diluted in 20 ml of bacteriostatic water for injection, which is supplied with the preparation, containing 1.1% benzyl alcohol as an antimicrobial preservative. The result is a solution concentrate suitable for repeated use, containing 21 mg of trastuzumab in 1 ml and having a pH = 6.0.
During dissolution, the preparation should be carefully handled. When dissolving, excessive foaming should be avoided, the latter can make it difficult to set the right dose of the drug from the bottle.
Using a sterile syringe, slowly inject 20 ml of bacteriostatic water for injection into a 440 mg vial of Herceptin®, directing a stream of liquid directly to the lyophilisate.
To dissolve, gently shake the vial with rotational movements. Do not shake!
When a drug is dissolved, a small amount of foam is often formed. To avoid this, let the solution stand for about 5 minutes. The prepared concentrate should be transparent 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 РC. 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 for Herceptin® 440 mg, sterile water for injection (without preservative) is allowed. 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 РC and should be discarded after this time. Do not freeze!
Instructions for preparing an infusion solution
Determine the volume of solution: required to administer a loading dose of trastuzumab equal to 4 mg / kg 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)
necessary to administer a loading dose of trastuzumab equal to 8 mg / kg body weight, or a maintenance dose equal to 6 mg / kg every 3 weeks, determined by the following formulas :
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 vial with the prepared concentrate, dial the appropriate volume and enter it into the infusion bag with 250 ml of 0.9% sodium chloride solution. Then the infusion bag should be carefully turned over to mix the solution, avoiding foaming. Before administration, the solution should be checked (visually) for any mechanical impurities and discoloration. The solution for infusion is administered immediately after its preparation.
In exceptional cases, the prepared infusion solution can be stored for no more than 24 hours at a temperature of 2-8 РC, if the concentrate was dissolved and the infusion solution was prepared under controlled and validated aseptic conditions. In this case, the storage conditions (storage rules and duration) are the responsibility of the specialist who prepared the solution.
Instructions for disposing of an unused or expired product
The release of a drug into the environment should be minimized. Do not dispose of the product with wastewater or with household waste. If possible, use special systems for the disposal of drugs.
Standard dosing regimen
During each administration of trastuzumab, the patient should be closely 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 done by a medical professional experienced in the treatment of anaphylaxis.
In case of infusion reactions, the infusion is interrupted. After the disappearance of symptoms of infusion reactions of mild to moderate severity according to NCI-CTC (general criteria for toxicity of the National Cancer Institute in the USA), the resumption of infusion is possible. In case of development of severe life-threatening infusion reactions, consideration should be given to discontinuing further therapy with Herceptin®.
Metastatic breast cancer
Weekly administration of
Loading dose: 4 mg / kg body weight as a 90-minute iv drip infusion.
Maintenance dose: 2 mg / kg body weight 1 time per week. A maintenance dose is administered 1 week after exercise. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.
Alternative administration - after 3 weeks
Loading dose: 8 mg / kg body weight as a 90-minute intravenous drip infusion.
Maintenance dose: 6 mg / kg body weight every 3 weeks. A maintenance dose is administered 3 weeks after exercise. 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 was administered the day after the administration of Herceptin® (for dosage recommendations, see the corresponding instructions for medical use) or immediately after the subsequent administration of Herceptin®, if with the previous administration of Herceptin® tolerated well.
Use in combination with the arrdase inhibitor
Herceptin® and anastrozole were administered on day 1. There were no time limits for the administration of the drug Herceptin® and anastrozole (for dosage recommendations, see the medical instructions for use of anastrozole or other aromatase inhibitors).
Early stages of breast cancer
Weekly administration of
With weekly administration, Herceptin® is administered at a loading dose of 4 mg / kg body weight, followed by a maintenance dose of 2 mg / kg body weight 1 time per week.
Maintenance dose is administered 1 week after exercise. The loading dose is administered as a 90-minute intravenous drip infusion. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.
Introduction after 3 weeks
When administered after 3 weeks, loading dose: 8 mg / kg body weight (as a 90-minute iv drip infusion). Maintenance dose: 6 mg / kg body weight every 3 weeks.
Maintenance dose is administered 3 weeks after exercise. 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 schemes described below.
Use in combination with paclitaxel or docetaxel after chemotherapy with doxorubicin and cyclophosphamide
Paclitaxel: 80 mg / m2 as a continuous IV infusion, weekly for 12 weeks or
175 mg / m2 as a continuous IV infusion, every 3 weeks for 4 cycles (on day 1 of each cycle).
Docetaxel: 100 mg / m2 as an iv infusion for 1 hour, every 3 weeks, for 4 cycles (starting on day 2 in cycle 5, then on day 1 in each subsequent cycle).
Herceptin®: starting with the first dose of paclitaxel or docetaxel, Herceptin® was administered according to the weekly schedule during chemotherapy (loading dose of 4 mg / kg, then at a maintenance dose of 2 mg / kg every week).
Subsequently, Herceptin® monotherapy continued according to the weekly schedule after administration in combination with paclitaxel or according to the administration 3 weeks after administration in combination with docetaxel. The total duration of Herceptin® therapy from the moment of the first injection 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, then 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 at a dose of 75 mg / m2 in the form of iv infusion for 1 h, followed by carboplatin in a dose to achieve the target AUC - 6 mg / ml / min, in the form of an intravenous infusion, for 30-60 minutes.
Herceptin®: Herceptin® together with chemotherapy was administered according to a weekly schedule (loading dose of 4 mg / kg, then in a maintenance dose of 2 mg / kg every week). After chemotherapy, Herceptin® monotherapy continued according to the administration after 3 weeks. The total duration of Herceptin® therapy from the moment of the first injection 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, then docetaxel was the first to be administered, 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
further - paclitaxel 150 mg m2, every 3 weeks, for 4
cycles, followed by cyclophosphamide, methotrexate and fluorouracil on days 1 and 8, every 4 weeks, for 3 cycles.
After surgery, adjuvant monotherapy with Herceptin® continued according to the regimen every 3 weeks. The total duration of Herceptin® therapy was 1 year.
Common gastric cancer
Introduction after 3 weeks
Loading dose: 8 mg / kg body weight as a 90-minute iv drip infusion.
Maintenance dose: 6 mg / kg body weight every 3 weeks. A maintenance dose is administered 3 weeks after exercise. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.
Metastatic and early stages of breast cancer and advanced gastric cancer
Duration of therapy
Treatment with Herceptin® in patients with metastatic breast cancer or advanced gastric cancer is carried out before the disease progresses. Patients with early breast cancer should receive Herceptin® therapy for 1 year or until the disease recurs (whichever is faster).
Skip in planned administration
If the skip in scheduled administration of trastuzumab was 7 days or less, the drug should be administered as soon as possible in 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 introduction. Next, administer the drug in a maintenance dose (weekly regimen: 2 mg / kg body weight regimen every 3 weeks: 6 mg / kg body weight) in accordance with the previously established schedule.
If the break in the administration of the drug was more than 7 days, it is necessary to re-enter the loading dose of trastuzumab (weekly regimen: 4 mg / kg body weight regimen every 3 weeks: 8 mg / kg body mass), as a 90-minute intravenous drip infusion . Then continue the administration of the drug in a maintenance dose (weekly regimen: 2 mg / kg body weight regimen every 3 weeks: 6 mg / kg body mass).
dose adjustment During the period of occurrence of reversible myelosuppression caused by chemotherapy, Herceptin® therapy can be continued after the chemotherapy dose is reduced or temporarily withdrawn (according to the relevant recommendations in the instructions for use of paclitaxel, docetaxel or aromatase inhibitor), provided that complications are carefully monitored , due to neutropenia
Special instructions for dosing
Elderly patients
Reducing the dose of the drug Herceptin® in elderly patients is not required.
Side effects of
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 often ( 1/10)
often ( 1/100, but <1/10)
infrequently ( 1/1000, but <1/100)
rarely ( 1/10 000, but <1/1000)
very rarely (<1/10 000), unknown (cannot be calculated based on available data).
Within each group, adverse reactions are presented in accordance with a decrease in severity.
The following are the adverse reactions that have been reported with Herceptin®, both in monotherapy and in combination with chemotherapy in basic clinical trials and in post-marketing use. The frequency is indicated in accordance with the maximum found in basic clinical studies.
Infectious and parasitic diseases: often - pneumonia1 (< 1%), neutropenic sepsis, cystitis, Herpes zoster, infections, flu, nasopharyngitis, sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, erysipelas, phlegmon infrequently - sepsis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): unknown - progression of a malignant neoplasm, progression of a neoplasm.
From the blood and lymphatic system: very often - febrile neutropenia often - anemia, neutropenia, thrombocytopenia, leukopenia is unknown - hypoprothrombinemia.
On the part of the immune system: often - hypersensitivity reactions unknown - anaphylactic reactions1, anaphylactic shock1.
From the side of metabolism: often - weight loss, anorexia is unknown - hyperkalemia.
From the psyche: often - anxiety, depression, insomnia, impaired thinking.
From the side of the nervous system: very often - tremor2, dizziness, headaches often - peripheral neuropathy, paresthesia, muscle hypertonicity, drowsiness, dysgeusia (distortion of taste perception), ataxia rarely - paresis is unknown - cerebral edema.
From the side of the organ of vision: very often - conjunctivitis, increased lacrimation often - dry eyes are unknown - swelling of the optic disc, retinal hemorrhage.
On the part of the organ of hearing and labyrinth disorders: infrequently - deafness.
From the side of the cardiovascular system: very often - a decrease and increase in blood pressure, heart rhythm disturbance2, palpitations2, atrial or ventricular flutter2, a decrease in the ejection fraction of the left ventricle3, hot flashes often - heart failure (congestive) 1 (2%), supraventricular tachyarrhythmia 1.2, cardiomyopathy, arterial hypotension 1.2, vasodilation infrequently - pericardial effusion is unknown - cardiogenic shock, pericarditis, bradycardia, gallop rhythm.
From the respiratory system, chest and mediastinal organs: very often - wheezing1,2, shortness of breath1 (14%), cough, nosebleeds, rhinorrhea often - bronchial asthma, impaired lung function, pharyngitis infrequently - pleural effusion1 rarely - pneumonitis is unknown - pulmonary fibrosis1, respiratory failure1, lung infiltration1, acute pulmonary edema1, acute respiratory distress syndrome1, bronchospasm1, hypoxia1, decreased oxygen saturation of hemoglobin1, laryngeal edema, orthopnea, pulmonary edema.
From the gastrointestinal tract: very often - diarrhea, vomiting, nausea, swelling of the lips2, abdominal pain often - pancreatitis, dyspepsia, hemorrhoids, constipation, dry mouth.
From the side of the liver and biliary tract: often - hepatitis, pain in the liver, hepatocellular damage rarely - jaundice is unknown - liver failure.
On the part of the skin and subcutaneous tissues: very often - erythema, rash, facial edema2 often - acne, alopecia, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, impaired nail structure, itching unknown - angioedema, dermatitis, urticaria.
From the musculoskeletal system and connective tissue: very often - arthralgia, muscle stiffness2, myalgia often - arthritis, back pain, ossalgia, muscle cramps, neck pain.
From the side of the kidneys and urinary tract: often - kidney disease is unknown - membranous glomerulonephritis, glomerulonephropathy, renal failure.
Effect on pregnancy, postpartum and perinatal conditions: unknown - oligohydramnios, fatal hypoplasia of the lungs 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, pains, fever, often peripheral edema, malaise, mucositis, edema.
Injuries, intoxications and complications of manipulations: often - a bruise.
1 - unwanted reactions that have been associated with death in messages.
2 - adverse reactions, which were mainly reported in association with infusion reactions. The exact percentage has not been established.
3 - adverse reactions were observed with combination therapy after anthracyclines and in combination with taxanes.
The exact percentage of the frequency for those terms that were reported along with a fatal outcome with frequency often or very often is given in parentheses. Percentage refers to the total number of these phenomena with and without a fatal outcome.
The following adverse reactions have been reported in baseline clinical studies with a frequency of 1/10 in any of the treatment groups, without a significant difference between the treatment group containing Herceptin® and the comparison therapy group: lethargy, hypesthesia, pain in the extremities, pain in the mouth and throat, lymphedema, weight gain, onychoclasia, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, epigastric pain, gastritis, stomatitis, vertigo, arterial hypertension, hiccups, palmar-plantar syndrome, pain in the mammary gland, onychorexis, dyspnea during physical exertion and dysuria.
Information on selected adverse reactions is given below
Infusion and hypersensitivity reactions
It is estimated that about 40% of patients receiving Herceptin® experience some form of infusion. However, most infusion reactions are mild and moderate in severity (according to NCI-CTC) and tend to occur at the beginning of treatment, i.e. during the 1st, 2nd and 3rd infusions, with subsequent injections occur less frequently. Reactions include (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, most likely to occur during the first or second infusion of the drug Herceptin®, such reactions were associated with a fatal outcome.
Cardiotoxicity
Cardiotoxicity (heart failure) NYHA Functional Class II-IV is a common adverse reaction with Herceptin® and has been associated with a fatal outcome. In 3 basic clinical trials of the use of trastuzumab in combination with adjuvant chemotherapy, the frequency of cardiac dysfunction of 3/4 degree (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 greatest in patients receiving Herceptin® together with taxanes (2%).
The safety of continuing or resuming therapy with Herceptin® in patients experiencing cardiotoxicity has not been studied prospectively. However, the status of most patients who experienced heart failure in baseline studies improved with standard therapy, which included diuretics, cardiac glycosides, beta-blockers, and / or ACE inhibitors.
Most 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.
Hematologic toxicity
Very often febrile neutropenia occurred. Adverse reactions that frequently occur 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
Herceptin® is associated with severe adverse events in the lungs (including fatal outcomes). These reactions include (but are not limited to): lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure.
Drug Interaction
No specific human drug interaction studies have been conducted with Herceptin® in humans.
In clinical studies, no clinically relevant interaction with concomitantly administered drugs (including doxorubicin, paclitaxel, docetaxel, capecitabine or cisplatin) was noted.
Herceptin® is not compatible with 5% dextrose solution due to the possibility of protein aggregation.
Herceptin® cannot be mixed or dissolved with other medicines.
No incompatibilities were observed between the solution of Herceptin® and infusion bags made of polyvinyl chloride, polyethylene or polypropylene.
overdose
No clinical overdose of drug was observed. The administration of the drug Herceptin® in single doses greater than 10 mg / kg has not been studied. Herceptin® at doses of 10 mg / kg was well tolerated.
Storage conditions
Keep out of the reach of children at temperatures from 2 ° to 8 РC.
Expiration
4 years.
Deystvuyuschee substances
Trastuzumab
dosage form
dosage form
solution infusion
F. Hoffmann-La Roche Ltd, Switzerland p19hoff77
HERCEPTIN
Release form
Lyophilisate for solution for infusion.
Packing
1 pc
Pharmacological action of
Pharmacodynamics of
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that selectively interacts with the extracellular domain of human epidermal growth factor 2 receptors (HER2). These antibodies are IgG1 consisting of human regions (constant regions of heavy chains) and determining the complementarity of the murine regions of p185 HER2 anti-HER2 antibody.
The HER2 or c-erB2 proto-oncogen 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 membrane of the tumor cells, which in turn causes constant activation of the HER2 receptor.
Studies show that patients with breast cancer who have amplified or overexpressed HER2 in the tumor tissue have less survival without evidence of disease than patients without amplification or overexpressed HER2 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 primarily directed to tumor cells with HER2 overexpression.
Immunogenicity
Trastuzumab antibodies were detected in one of 903 breast cancer patients who received the drug in monotherapy or in combination with chemotherapy, but did not have any allergies to Herceptin®.
There is no data on the immunogenicity of Herceptin® for gastric cancer.
Pharmacokinetics
The pharmacokinetics of trastuzumab has been studied in patients with metastatic breast cancer and early stages of breast cancer, as well as in patients with advanced gastric cancer. Special studies on the study of drug interactions have not been conducted.
Breast cancer
With the introduction of the drug in the form of short iv infusions at a dose of 10, 50, 100, 250 and 500 mg once a week, the pharmacokinetics was non-linear. With increasing doses, the clearance of the drug decreased.
Elimination half-life (T1 / 2)
T1 / 2 is 28-38 days, therefore, the elimination period after drug withdrawal is up to 27 weeks (190 days or 5 elimination half-lives).
Pharmacokinetics of trastuzumab against equilibrium.
An equilibrium should be reached in about 25 weeks. When using the population pharmacokinetic method (two-chamber model, model-dependent analysis) for evaluating phase I studies, Phase II and phase III with metastatic breast cancer, the median of the expected AUC in equilibrium after 3 weeks was 1677 mg Day / l after 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 Cmax were 104 mg / L and 189 mg / L, and Cmin - 64.9 mg / L and 47.3 mg / L, respectively. When using a model-independent or non-chamber analysis method (non-compartmental analysis, NCA), the average Cmin in equilibrium by cycle 13 (week 37) was 63 mg / L in patients with early breast cancer who received trastuzumab at a loading dose of 8 mg / kg , then in the supporting 6 mg / kg, after 3 weeks, and was comparable to that in patients with breast cancer receiving trastuzumab weekly.
Clearance
The typical clearance of trastuzumab (for a patient weighing 68 kg) was 0.241 l / day.
Distribution volume
In all clinical trials, the distribution volume in the central chamber (Vc) was 3.02 L and in the peripheral (Vp) 2.68 L for a typical patient.
The circulating extracellular domain of the HER2 receptor (cell-desorbing antigen)
In the blood serum of some patients with breast cancer and HER2 hyperexpression, a circulating extracellular domain of the HER2 receptor (cell-descending antigen) was found. In 64% of the examined patients, the antigen peeling from the cell was detected in the initial serum samples at a concentration reaching 1880 ng / ml (median 11 ng / ml). Patients with a high concentration of antigen desquamation from the cell probably could have a lower Cmin. However, in most patients with an increased level of antigen desquamating from the cell with the introduction of the drug, the target serum trastuzumab concentration was reached by week 6. There was no significant relationship between the initial level of antigen peeling from the cell and the clinical response.
Common gastric cancer
Pharmacokinetics of trastuzumab against equilibrium To evaluate the pharmacokinetics of trastuzumab against equilibrium in patients with advanced gastric cancer after administration of trastuzumab at a loading dose of 8 mg / kg, followed by the administration of 6 mg / kg every 3 weeks, a non-linear two-dimensional pharmacokinetic method using data from a phase III study.
The observed serum trastuzumab concentration levels were lower, thus 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 in the same dose. The reason for this is unknown.
At high concentrations, the overall clearance is mostly linear, and T1 / 2 is about 26 days.
The median of the estimated AUC (in equilibrium over a 3 week period) is 1213 mg day / l, the median Cmax in equilibrium is 132 mg / l, and the median Cmin is 27.6 mg / l.
There are no data on the level of the circulating extracellular domain of the HER2 receptor (cell-disengaging antigen) in the serum of patients with gastric cancer.
Pharmacokinetics in special patient groups
No separate pharmacokinetic studies have been performed in elderly patients or patients with renal or hepatic impairment. Age does not affect the distribution of trastuzumab.
Indications
Breast cancer
Metastatic breast cancer with tumor overexpression HER2: as monotherapy, after one or more
chemotherapy regimens in combination with paclitaxel or docetaxel, in the absence of previous chemotherapy with first-line inhibitor aromatase with positive hormonal receptors (estrogen and / or progesterone) in postmenopausal women.
Early stages of breast cancer with tumor overexpression of HER2: as adjuvant therapy after surgery, completion of chemotherapy (neoadjuvant or adjuvant) and radiation therapy with
in combination with paclitaxel or docetaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide
in combination with adjuvant chemotherapy consisting of docetin adjuvant and carbohydrate adjuvant - a widespread (including inflammatory form) disease or in cases where the size of the tumor exceeds 2 cm in diameter.
Common gastric cancer
Common gastric adenocarcinoma or gastroesophageal junction with tumor overexpression of HER2: in combination with capecitabine or iv fluorouracil and platinum in the absence of previous antitumor therapy for metastatic disease.
Contraindications
Severe shortness of breath at rest caused by lung metastases, or requiring maintenance therapy with oxygen
children under 18 years of age (efficacy and safety of use in children have not been established)
pregnancy
breastfeeding or any other component drug, including to benzyl alcohol, contained as a preservative in bacteriostatic water for injection, attached to each 440 mg multi-dose vial.
Precautions: used for coronary heart disease, arterial hypertension, heart failure, concomitant lung diseases or lung metastases, prior therapy with cardiotoxic drugs, including anthracyclines / cyclophosphamide.
Use during pregnancy and lactation
Women of childbearing age during treatment with HerceptinВ® and at least 6 months after the end of treatment must use reliable methods of contraception.
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 HerceptinВ®, then she should be under close supervision of doctors of various specialties. It is not known whether HerceptinВ® affects fertility in women. The results of animal experiments did not reveal 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 treatment with HerceptinВ®.
Benzyl alcohol, contained as a preservative in bacteriostatic water for injection, supplied with each 440 mg multi-dose vial, has a toxic effect in infants and children up to 3 years old.
Composition
1 vial contains:
Active substances: trastuzumab 150 mg.
Excipients: L-histidine hydrochloride - 3.36 mg, L-histidine - 2.16 mg,?,? - trehalose dihydrate - 136.2 mg, polysorbate 20 - 0.6 mg.
Dosage and Administration
Testing for tumor expression of HER2 prior to 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 drugs.
Herceptin® solution is compatible with infusion bags made of polyvinyl chloride, polyethylene and polypropylene.
Preparation of
solution Preparation of the drug for administration should be carried out under aseptic conditions.
Instruction for the preparation of
concentrate The contents of the Herceptin® vial are diluted in 20 ml of bacteriostatic water for injection, which is supplied with the preparation, containing 1.1% benzyl alcohol as an antimicrobial preservative. The result is a solution concentrate suitable for repeated use, containing 21 mg of trastuzumab in 1 ml and having a pH = 6.0.
During dissolution, the preparation should be carefully handled. When dissolving, excessive foaming should be avoided, the latter can make it difficult to set the right dose of the drug from the bottle.
Using a sterile syringe, slowly inject 20 ml of bacteriostatic water for injection into a 440 mg vial of Herceptin®, directing a stream of liquid directly to the lyophilisate.
To dissolve, gently shake the vial with rotational movements. Do not shake!
When a drug is dissolved, a small amount of foam is often formed. To avoid this, let the solution stand for about 5 minutes. The prepared concentrate should be transparent 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 РC. 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 for Herceptin® 440 mg, sterile water for injection (without preservative) is allowed. 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 РC and should be discarded after this time. Do not freeze!
Instructions for preparing an infusion solution
Determine the volume of solution: required to administer a loading dose of trastuzumab equal to 4 mg / kg 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)
necessary to administer a loading dose of trastuzumab equal to 8 mg / kg body weight, or a maintenance dose equal to 6 mg / kg every 3 weeks, determined by the following formulas :
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 vial with the prepared concentrate, dial the appropriate volume and enter it into the infusion bag with 250 ml of 0.9% sodium chloride solution. Then the infusion bag should be carefully turned over to mix the solution, avoiding foaming. Before administration, the solution should be checked (visually) for any mechanical impurities and discoloration. The solution for infusion is administered immediately after its preparation.
In exceptional cases, the prepared infusion solution can be stored for no more than 24 hours at a temperature of 2-8 РC, if the concentrate was dissolved and the infusion solution was prepared under controlled and validated aseptic conditions. In this case, the storage conditions (storage rules and duration) are the responsibility of the specialist who prepared the solution.
Instructions for disposing of an unused or expired product
The release of a drug into the environment should be minimized. Do not dispose of the product with wastewater or with household waste. If possible, use special systems for the disposal of drugs.
Standard dosing regimen
During each administration of trastuzumab, the patient should be closely 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 done by a medical professional experienced in the treatment of anaphylaxis.
In case of infusion reactions, the infusion is interrupted. After the disappearance of symptoms of infusion reactions of mild to moderate severity according to NCI-CTC (general criteria for toxicity of the National Cancer Institute in the USA), the resumption of infusion is possible. In case of development of severe life-threatening infusion reactions, consideration should be given to discontinuing further therapy with Herceptin®.
Metastatic breast cancer
Weekly administration of
Loading dose: 4 mg / kg body weight as a 90-minute iv drip infusion.
Maintenance dose: 2 mg / kg body weight 1 time per week. A maintenance dose is administered 1 week after exercise. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.
Alternative administration - after 3 weeks
Loading dose: 8 mg / kg body weight as a 90-minute intravenous drip infusion.
Maintenance dose: 6 mg / kg body weight every 3 weeks. A maintenance dose is administered 3 weeks after exercise. 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 was administered the day after the administration of Herceptin® (for dosage recommendations, see the corresponding instructions for medical use) or immediately after the subsequent administration of Herceptin®, if with the previous administration of Herceptin® tolerated well.
Use in combination with the arrdase inhibitor
Herceptin® and anastrozole were administered on day 1. There were no time limits for the administration of the drug Herceptin® and anastrozole (for dosage recommendations, see the medical instructions for use of anastrozole or other aromatase inhibitors).
Early stages of breast cancer
Weekly administration of
With weekly administration, Herceptin® is administered at a loading dose of 4 mg / kg body weight, followed by a maintenance dose of 2 mg / kg body weight 1 time per week.
Maintenance dose is administered 1 week after exercise. The loading dose is administered as a 90-minute intravenous drip infusion. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.
Introduction after 3 weeks
When administered after 3 weeks, loading dose: 8 mg / kg body weight (as a 90-minute iv drip infusion). Maintenance dose: 6 mg / kg body weight every 3 weeks.
Maintenance dose is administered 3 weeks after exercise. 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 schemes described below.
Use in combination with paclitaxel or docetaxel after chemotherapy with doxorubicin and cyclophosphamide
Paclitaxel: 80 mg / m2 as a continuous IV infusion, weekly for 12 weeks or
175 mg / m2 as a continuous IV infusion, every 3 weeks for 4 cycles (on day 1 of each cycle).
Docetaxel: 100 mg / m2 as an iv infusion for 1 hour, every 3 weeks, for 4 cycles (starting on day 2 in cycle 5, then on day 1 in each subsequent cycle).
Herceptin®: starting with the first dose of paclitaxel or docetaxel, Herceptin® was administered according to the weekly schedule during chemotherapy (loading dose of 4 mg / kg, then at a maintenance dose of 2 mg / kg every week).
Subsequently, Herceptin® monotherapy continued according to the weekly schedule after administration in combination with paclitaxel or according to the administration 3 weeks after administration in combination with docetaxel. The total duration of Herceptin® therapy from the moment of the first injection 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, then 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 at a dose of 75 mg / m2 in the form of iv infusion for 1 h, followed by carboplatin in a dose to achieve the target AUC - 6 mg / ml / min, in the form of an intravenous infusion, for 30-60 minutes.
Herceptin®: Herceptin® together with chemotherapy was administered according to a weekly schedule (loading dose of 4 mg / kg, then in a maintenance dose of 2 mg / kg every week). After chemotherapy, Herceptin® monotherapy continued according to the administration after 3 weeks. The total duration of Herceptin® therapy from the moment of the first injection 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, then docetaxel was the first to be administered, 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
further - paclitaxel 150 mg m2, every 3 weeks, for 4
cycles, followed by cyclophosphamide, methotrexate and fluorouracil on days 1 and 8, every 4 weeks, for 3 cycles.
After surgery, adjuvant monotherapy with Herceptin® continued according to the regimen every 3 weeks. The total duration of Herceptin® therapy was 1 year.
Common gastric cancer
Introduction after 3 weeks
Loading dose: 8 mg / kg body weight as a 90-minute iv drip infusion.
Maintenance dose: 6 mg / kg body weight every 3 weeks. A maintenance dose is administered 3 weeks after exercise. If the previous loading dose was well tolerated, the drug can be administered as a 30-minute drip infusion.
Metastatic and early stages of breast cancer and advanced gastric cancer
Duration of therapy
Treatment with Herceptin® in patients with metastatic breast cancer or advanced gastric cancer is carried out before the disease progresses. Patients with early breast cancer should receive Herceptin® therapy for 1 year or until the disease recurs (whichever is faster).
Skip in planned administration
If the skip in scheduled administration of trastuzumab was 7 days or less, the drug should be administered as soon as possible in 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 introduction. Next, administer the drug in a maintenance dose (weekly regimen: 2 mg / kg body weight regimen every 3 weeks: 6 mg / kg body weight) in accordance with the previously established schedule.
If the break in the administration of the drug was more than 7 days, it is necessary to re-enter the loading dose of trastuzumab (weekly regimen: 4 mg / kg body weight regimen every 3 weeks: 8 mg / kg body mass), as a 90-minute intravenous drip infusion . Then continue the administration of the drug in a maintenance dose (weekly regimen: 2 mg / kg body weight regimen every 3 weeks: 6 mg / kg body mass).
dose adjustment During the period of occurrence of reversible myelosuppression caused by chemotherapy, Herceptin® therapy can be continued after the chemotherapy dose is reduced or temporarily withdrawn (according to the relevant recommendations in the instructions for use of paclitaxel, docetaxel or aromatase inhibitor), provided that complications are carefully monitored , due to neutropenia
Special instructions for dosing
Elderly patients
Reducing the dose of the drug Herceptin® in elderly patients is not required.
Side effects of
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 often ( 1/10)
often ( 1/100, but <1/10)
infrequently ( 1/1000, but <1/100)
rarely ( 1/10 000, but <1/1000)
very rarely (<1/10 000), unknown (cannot be calculated based on available data).
Within each group, adverse reactions are presented in accordance with a decrease in severity.
The following are the adverse reactions that have been reported with Herceptin®, both in monotherapy and in combination with chemotherapy in basic clinical trials and in post-marketing use. The frequency is indicated in accordance with the maximum found in basic clinical studies.
Infectious and parasitic diseases: often - pneumonia1 (< 1%), neutropenic sepsis, cystitis, Herpes zoster, infections, flu, nasopharyngitis, sinusitis, skin infections, rhinitis, upper respiratory tract infections, urinary tract infections, erysipelas, phlegmon infrequently - sepsis.
Benign, malignant and unspecified neoplasms (including cysts and polyps): unknown - progression of a malignant neoplasm, progression of a neoplasm.
From the blood and lymphatic system: very often - febrile neutropenia often - anemia, neutropenia, thrombocytopenia, leukopenia is unknown - hypoprothrombinemia.
On the part of the immune system: often - hypersensitivity reactions unknown - anaphylactic reactions1, anaphylactic shock1.
From the side of metabolism: often - weight loss, anorexia is unknown - hyperkalemia.
From the psyche: often - anxiety, depression, insomnia, impaired thinking.
From the side of the nervous system: very often - tremor2, dizziness, headaches often - peripheral neuropathy, paresthesia, muscle hypertonicity, drowsiness, dysgeusia (distortion of taste perception), ataxia rarely - paresis is unknown - cerebral edema.
From the side of the organ of vision: very often - conjunctivitis, increased lacrimation often - dry eyes are unknown - swelling of the optic disc, retinal hemorrhage.
On the part of the organ of hearing and labyrinth disorders: infrequently - deafness.
From the side of the cardiovascular system: very often - a decrease and increase in blood pressure, heart rhythm disturbance2, palpitations2, atrial or ventricular flutter2, a decrease in the ejection fraction of the left ventricle3, hot flashes often - heart failure (congestive) 1 (2%), supraventricular tachyarrhythmia 1.2, cardiomyopathy, arterial hypotension 1.2, vasodilation infrequently - pericardial effusion is unknown - cardiogenic shock, pericarditis, bradycardia, gallop rhythm.
From the respiratory system, chest and mediastinal organs: very often - wheezing1,2, shortness of breath1 (14%), cough, nosebleeds, rhinorrhea often - bronchial asthma, impaired lung function, pharyngitis infrequently - pleural effusion1 rarely - pneumonitis is unknown - pulmonary fibrosis1, respiratory failure1, lung infiltration1, acute pulmonary edema1, acute respiratory distress syndrome1, bronchospasm1, hypoxia1, decreased oxygen saturation of hemoglobin1, laryngeal edema, orthopnea, pulmonary edema.
From the gastrointestinal tract: very often - diarrhea, vomiting, nausea, swelling of the lips2, abdominal pain often - pancreatitis, dyspepsia, hemorrhoids, constipation, dry mouth.
From the side of the liver and biliary tract: often - hepatitis, pain in the liver, hepatocellular damage rarely - jaundice is unknown - liver failure.
On the part of the skin and subcutaneous tissues: very often - erythema, rash, facial edema2 often - acne, alopecia, dry skin, ecchymosis, hyperhidrosis, maculopapular rash, impaired nail structure, itching unknown - angioedema, dermatitis, urticaria.
From the musculoskeletal system and connective tissue: very often - arthralgia, muscle stiffness2, myalgia often - arthritis, back pain, ossalgia, muscle cramps, neck pain.
From the side of the kidneys and urinary tract: often - kidney disease is unknown - membranous glomerulonephritis, glomerulonephropathy, renal failure.
Effect on pregnancy, postpartum and perinatal conditions: unknown - oligohydramnios, fatal hypoplasia of the lungs 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, pains, fever, often peripheral edema, malaise, mucositis, edema.
Injuries, intoxications and complications of manipulations: often - a bruise.
1 - unwanted reactions that have been associated with death in messages.
2 - adverse reactions, which were mainly reported in association with infusion reactions. The exact percentage has not been established.
3 - adverse reactions were observed with combination therapy after anthracyclines and in combination with taxanes.
The exact percentage of the frequency for those terms that were reported along with a fatal outcome with frequency often or very often is given in parentheses. Percentage refers to the total number of these phenomena with and without a fatal outcome.
The following adverse reactions have been reported in baseline clinical studies with a frequency of 1/10 in any of the treatment groups, without a significant difference between the treatment group containing Herceptin® and the comparison therapy group: lethargy, hypesthesia, pain in the extremities, pain in the mouth and throat, lymphedema, weight gain, onychoclasia, musculoskeletal pain, pharyngitis, bronchitis, chest discomfort, epigastric pain, gastritis, stomatitis, vertigo, arterial hypertension, hiccups, palmar-plantar syndrome, pain in the mammary gland, onychorexis, dyspnea during physical exertion and dysuria.
Information on selected adverse reactions is given below
Infusion and hypersensitivity reactions
It is estimated that about 40% of patients receiving Herceptin® experience some form of infusion. However, most infusion reactions are mild and moderate in severity (according to NCI-CTC) and tend to occur at the beginning of treatment, i.e. during the 1st, 2nd and 3rd infusions, with subsequent injections occur less frequently. Reactions include (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, most likely to occur during the first or second infusion of the drug Herceptin®, such reactions were associated with a fatal outcome.
Cardiotoxicity
Cardiotoxicity (heart failure) NYHA Functional Class II-IV is a common adverse reaction with Herceptin® and has been associated with a fatal outcome. In 3 basic clinical trials of the use of trastuzumab in combination with adjuvant chemotherapy, the frequency of cardiac dysfunction of 3/4 degree (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 greatest in patients receiving Herceptin® together with taxanes (2%).
The safety of continuing or resuming therapy with Herceptin® in patients experiencing cardiotoxicity has not been studied prospectively. However, the status of most patients who experienced heart failure in baseline studies improved with standard therapy, which included diuretics, cardiac glycosides, beta-blockers, and / or ACE inhibitors.
Most 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.
Hematologic toxicity
Very often febrile neutropenia occurred. Adverse reactions that frequently occur 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
Herceptin® is associated with severe adverse events in the lungs (including fatal outcomes). These reactions include (but are not limited to): lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, acute pulmonary edema, and respiratory failure.
Drug Interaction
No specific human drug interaction studies have been conducted with Herceptin® in humans.
In clinical studies, no clinically relevant interaction with concomitantly administered drugs (including doxorubicin, paclitaxel, docetaxel, capecitabine or cisplatin) was noted.
Herceptin® is not compatible with 5% dextrose solution due to the possibility of protein aggregation.
Herceptin® cannot be mixed or dissolved with other medicines.
No incompatibilities were observed between the solution of Herceptin® and infusion bags made of polyvinyl chloride, polyethylene or polypropylene.
overdose
No clinical overdose of drug was observed. The administration of the drug Herceptin® in single doses greater than 10 mg / kg has not been studied. Herceptin® at doses of 10 mg / kg was well tolerated.
Storage conditions
Keep out of the reach of children at temperatures from 2 ° to 8 РC.
Expiration
4 years.
Deystvuyuschee substances
Trastuzumab
dosage form
dosage form
solution infusion
F. Hoffmann-La Roche Ltd, Switzerland p19hoff77
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