Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a transparent or opalescent colorless or slightly brownish liquid.
pertuzumab 420 mg
Excipients: L-histidine - 43.5 mg, glacial acetic acid - 9.2 mg, sucrose - 575.1 mg, polysorbate 20 - 2.8 mg, water d / and - up to 14 ml.
14 ml - bottles of colorless glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
Antitumor drug. Pertuzumab is a recombinant humanized monoclonal antibody that selectively interacts with the extracellular subdomain II HER2 (epidermal growth factor receptor of type 2 receptor) responsible for dimerization. Binding of pertuzumab to subdomain II blocks the process of ligand-dependent heterodimerization of HER2 with other proteins of the HER family, including EGFR (human epidermal growth factor receptor), HER3 (human type 3 epidermal growth factor receptor) and HER4 (human type E epidermal growth factor receptor). Thus, pertuzumab inhibits ligand-initiated transfer of intracellular signals along two main signaling pathways: the pathway of mitogen-activated protein kinase (MAP) and the pathway of phosphoinositide-3-kinase (PI3K). The inhibition of these signaling pathways can lead to the arrest of cell growth and apoptosis, respectively. In addition, pertuzumab promotes the activation of antibody-dependent cellular cytotoxicity (AZKTS).
Molecular weight of pertuzumab is about 148 kDa, and it is expected that, like other monoclonal antibodies, pertuzumab practically does not penetrate the BBB.
Pertuzumab in the form of a monoagent inhibits the proliferation of human tumor cells. Increased antitumor activity of pertuzumab on models of xenografts with overexpression of HER2 when used in combination with trastuzumab is shown.
Approximately 6.2% of patients treated with trastuzumab in combination with docetaxel and 2.8% of patients treated with trastuzumab in combination with docetaxel and pertuzumab had anti-monoclonal antibodies (ATA). A single link between the formation of antibodies to pertuzumab and the development of an anaphylactic reaction / hypersensitivity reaction has not been established in any of the patients.
The results of the immunogenicity assay largely depend on various factors, such as the sensitivity and specificity of the assay, the methodology of the assay, the manipulation of the samples taken, the sampling time, the concomitant medications and the nature of the underlying disease. Based on these considerations, a comparison of the frequency of detection of antibodies to pertuzumab and the frequency of detection of antibodies to other biological agents may not be informative.
The pharmacokinetics of pertuzumab was studied after intravenous administration in various doses (from 2 to 25 mg / kg) in patients with various types of tumors.
Pertuzumab is administered iv. Other ways of drug administration have not been studied.
After IV introduction, the volume of distribution in the central chamber (V c ) is 3.07 L and is approximately equal to the plasma volume. The values вЂ‹вЂ‹of V c and V d in the equilibrium state indicate that the distribution occurs only in plasma and extracellular fluid.
Metabolism of pertuzumab has not been studied. Like other antibodies, pertuzumab is mainly exposed to catabolism.
T 1/2 is approximately equal to 17.2 days. The clearance of pertuzumab is approximately 0.239 l / day and is independent of dose and indications.
Pharmacokinetics in special clinical cases
Pharmacokinetic parameters do not depend on age, gender and ethnicity (Japanese and other ethnic groups).
The initial concentration of albumin and the value of the true body weight (the value that characterizes the body weight minus the fat mass of the fat) have a negligible effect on the clearance of pertuzumab, and there is no need to adjust the dose of pertuzumab depending on the initial albumin concentration or body weight.
Special studies of the pharmacokinetics of pertuzumab in elderly (? 65 years) and senile (? 75 years) patients have not been conducted. According to the results of the population analysis, age does not affect the pharmacokinetic parameters of pertuzumab.
Special studies of the pharmacokinetics of pertuzumab in patients with renal insufficiency have not been carried out. According to the results of the population analysis, renal failure of mild (KK 60-90 ml / min), medium (KK 30-60 ml / min) and severe (QC <30 ml / min) does not affect the exposure of pertuzumab. However, data for patients with moderate and severe renal insufficiency are limited.
The study of the pharmacokinetics of pertuzumab in patients with impaired liver function was not performed.
Metastatic or locally recurrent, inoperable breast cancer with tumor overexpression HER2:
- in combination with trastuzumab and docetaxel in the absence of previous treatment or in the progression of the disease after adjuvant therapy.
Before starting treatment with Perieta в„ў, it is necessary to test for tumor expression of HER2. An obligatory criterion is 3+ points according to the results of immunohistochemical analysis and / or the degree of amplification of? 2.0 by the results of in situ hybridization (ISH). Accurate and validated testing methods should be used.
The preparation of Perieta в„ў is administered only in / in the drip. You can not inject the drug intravenously in a bolus or bolus.
The duration of infusion with the administration of the first dose is 60 minutes. If the first infusion is well tolerated, subsequent ones can be carried out for 30-60 minutes.
Perieta в„ў: loading dose - 840 mg in the form of intravenous drip infusion for 60 min. After 3 weeks and every 3 weeks, the drug is administered in a maintenance dose of 420 mg in the form of IV infusion for 30-60 minutes.
Trastuzumab: when used in combination with the preparation of Perieta в„ў, the loading dose of trastuzumab - 8 mg / kg body weight as an IV infusion for 90 minutes;maintenance dose - 6 mg / kg body weight every 3 weeks as an IV infusion for 30-90 minutes. The maintenance dose is given 3 weeks after the loading.
Docetaxel: when used in combination with Perieta в„ў, the recommended initial dose of docetaxel is 75 mg / m 2 as an IV infusion, after which the drug should be given at the same dose every 3 weeks. With good tolerability in the first cycle, the dose of docetaxel can be increased to 100 mg / m 2 in subsequent cycles.
If signs of disease progression or unacceptable toxicity appear, treatment with Perieta в„ў should be discontinued.
If the pass in the planned administration of pertuzumab was less than 6 weeks, the drug should be administered as soon as possible in a dose of 420 mg in the form of a 30-60 minute intravenous drip infusion, without waiting for the next scheduled administration.
If a break in the introduction of pertuzumab was 6 weeks or more, the drug should be administered at an initial dose of 840 mg in the form of a 60-minute intravenous drip infusion. Then continue the administration of the drug at a dose of 420 mg every 3 weeks as a 30-60 minute intravenous infusion.
Reducing the dose of Perieta в„ў is not recommended.
The drug Perieta в„ў should be discontinued if treatment with trastuzumab is reversed. With the cancellation of docetaxel, treatment with Perieta в„ў and trastuzumab can continue until the disease progresses or unacceptable toxicity develops. Reducing the dose of trastuzumab is not recommended.
Instructions for modifying the dose of docetaxel are provided in the instructions for the medical use of docetaxel.
Violation of the function of the left ventricle
The administration of Periet в„ў and trastuzumab should be suspended for at least 3 weeks in the following cases:
- reduction of LVEF to a level below 40%;
- LVEF values вЂ‹вЂ‹of 40-45% with a decrease in LVEF by> 10% with respect to the values вЂ‹вЂ‹observed before treatment.
Renewal treatment with Perieta and trastuzumab is possible if LVEF is restored to> 45% or 40-45% with a decrease of <10% relative to the values вЂ‹вЂ‹observed before treatment.
If, according to the reassessment data after 3 weeks, LVEF does not increase or further decline occurs, treatment with Perieta в„ў and trastuzumab should be discontinued, unless the benefits of using them in each specific case exceed the risk.
It is necessary to reduce the rate of infusion or temporarily stop the drug when the infusion reaction develops. Infusion should be discontinued immediately when a serious hypersensitivity reaction develops.
Special instructions for dosing
Correction of dose in patients of elderly and senile age is not required.
The efficacy and safety of Perieta в„ў in patients with impaired renal function have not been studied.
The efficacy and safety of Perieta в„ў in patients with impaired liver function have not been studied.
The effectiveness and safety of Perieta в„ў in children and adolescents under the age of 18 years have not been established.
Preparation of a solution for infusions
The preparation of Perieta в„ў is incompatible with a 5% solution of dextrose. Dilution in such a solution leads to chemical and physical instability of the Perieta в„ў preparation. Preparation Perieta в„ў should be diluted only in 0.9% sodium chloride solution. Perieta в„ў should not be mixed or diluted with other medications.
The Perieta solution is compatible with infusion bags made of polyvinyl chloride, polyethylene and polyolefin.
Preparation of the drug for administration should be carried out under aseptic conditions. Perieta в„ў does not contain antimicrobial preservatives. In this regard, it is necessary to take precautions to maintain the sterility of the prepared solution for infusion.
From the vial (flasks), you should take all the liquid concentrate and enter it into the infusion bag with 250 ml of 0.9% sodium chloride solution. The concentration of the final solution is approximately 3.36 mg / ml (840 mg / 250 ml) for loading and 1.68 mg / ml (420 mg / 250 ml) for the maintenance dose.
Then the infusion bag must be turned gently to mix the solution, avoiding foaming. Before administration, the drug should be checked (visually) for lack of mechanical impurities and discoloration. Solution for infusion is administered immediately after its preparation.
In exceptional cases, the prepared solution can be stored for no more than 24 hours at a temperature of 2-8 В° C if the preparation of the infusion solution occurred in controlled and validated aseptic conditions. At the same time for the storage conditions (storage rules and duration) is the specialist who prepared the solution.
When applying Perate в„ў in combination with trastuzumab and docetaxel, most often (> 50%): diarrhea, alopecia and neutropenia.
Adverse reactions of the 3rd-4th degree of severity, according to the classification of the National Cancer Institute of the National Cancer Institute CommonTerminology Criteria of Adverse Events (NCI-CTCAE) (version 3), which were observed most often (> 10%): neutropenia, febrile neutropenia, leukopenia.
The most severe and clinically significant adverse reaction, observed with a frequency of <10% , was a disturbance of left ventricular function, incl. symptomatic systolic dysfunction of the left ventricle (congestive heart failure).
The following are side effects reported in the study of the use of Perieta в„ў in combination with trastuzumab and docetaxel. Because the Perieta в„ў preparation was used in combination with trastuzumab and docetaxel, an exact causal relationship between adverse reactions and a specific drug has not been established.Determination of the frequency of adverse reactions: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1000 and <1/100), rarely (? 1/10 000 and <1 / 1000) and very rarely (<1/10 000), including isolated cases.
From the hemopoietic system: very often - neutropenia, anemia, leukopenia, febrile neutropenia (including fatal).
From the immune system: often - hypersensitivity.
From the side of metabolism and nutrition: very often - a decrease in appetite.
Disorders of the psyche: very often - insomnia.
From the side of the nervous system: very often - peripheral neuropathy, headache, perversion of taste, dizziness.
From the side of the organ of vision: very often - increased tearing.
From the cardiovascular system: often - a violation of the function of the left ventricle, incl. congestive heart failure.
From the respiratory system: very often - shortness of breath; often - pleural effusion.
From the digestive system: very often - diarrhea, nausea, vomiting, constipation, stomatitis.
From the skin and subcutaneous tissues: very often - alopecia, rash, pathology of the nails, itching, dry skin; often paronychia.
From the musculoskeletal system: very often - myalgia, arthralgia.
General reactions: very often - fatigue, asthenia, peripheral edema, inflammation of the mucous membranes of various locations, increased body temperature, attachment of secondary infections (upper respiratory tract infection, nasopharyngitis).
After docetaxel withdrawal, all adverse reactions were observed with a lower incidence (<10%, except for diarrhea, upper respiratory tract infections, rash, headache and fatigue (> 10%)).
Infusion reactions, hypersensitivity reactions / anaphylaxis
Any adverse reactions that occurred during the infusion or infusion day were attributed to infusion reactions. After the introduction of Perate в„ў alone, most infusion reactions were mild or moderate and were observed in approximately 20% of patients. The most frequent infusion reactions (> 1.5%) were nausea, fever, diarrhea, chills, fatigue and headache.
After simultaneous administration of Periet, Trastuzumab and Docetaxel, the most frequent (> 1.5%) infusion reactions were alopecia, nausea, decreased appetite, fatigue, constipation, diarrhea, stomatitis and drug hypersensitivity.
The overall incidence of hypersensitivity / anaphylaxis was 9.1% after simultaneous administration of trastuzumab and docetaxel and 10.8% after simultaneous administration of Periet в„ў, trastuzumab and docetaxel; of these phenomena, 2.5% and 2% were characterized by the 3rd and 4th degree of severity according to the NCI-CTCAE classification, version 3, respectively. In total, anaphylaxis developed in 2 patients after simultaneous administration of trastuzumab and docetaxel and in 4 patients after simultaneous administration of Perieta в„ў, trastuzumab and docetaxel.
Most of the hypersensitivity reactions were of mild or moderate severity and were resolved after appropriate treatment. Based on the results of the analysis of hypersensitivity reactions with changing dosage regimens, it was found that hypersensitivity phenomena were associated with docetaxel infusions.
Changes in laboratory indicators
The incidence of a reduction in the number of neutrophils of grade 3-4 of the NCI-CTCAE classification, version 3, was approximately the same with the combination of trastuzumab and docetaxel concurrently with and without Perieta.
- hypersensitivity to pertuzumab and other components of the drug;
- Values вЂ‹вЂ‹of left ventricular ejection fraction of heart (LVEF) before treatment? 50%;
- congestive heart failure in history;
uncontrolled arterial hypertension;
- recently transferred myocardial infarction;
- Serious cardiac arrhythmias requiring drug therapy at the time of the appointment of Perieta в„ў , with the exception of atrial fibrillation and paroxysmal supraventricular tachycardia;
- Prior treatment with anthracyclines with a cumulative dose of doxorubicin or an equivalent preparation> 360 mg / m 2 ;
- impaired liver function (efficacy and safety of use not studied);
- the period of breastfeeding;
- children and adolescents under 18 years of age (efficacy and safety of use not established).
With caution: reduced LVEF to <50% with previous adjuvant therapy with trastuzumab; previous treatment with anthracyclines or previous radiation therapy on the thoracic region; conditions that can disrupt the function of the left ventricle; with violations of kidney function.
PREGNANCY AND LACTATION
The use of the drug during pregnancy and lactation (breastfeeding) is contraindicated.
Women with reproductive potential and women of childbearing age who are the sexual partners of patients receiving the drug, when using Perieta в„ў and within 6 months after the last dose, should use effective methods of contraception.
Treatment with Perieta в„ў should only be performed under the supervision of an oncologist. Against the background of the use of drugs blocking the activity of HER2, including the preparation of Perieta в„ў, a decrease in LVEF was observed . Use of the drug Pereta в„ў in combination with docetaxel and trastuzumab was not accompanied by an increase in the frequency of symptomatic left ventricular systolic dysfunction or decline LVEF, compared with only docetaxel and trastuzumab. However, in patients previously treated with anthracyclines or radiotherapy to the chest area, reducing the risk of left ventricular ejection fraction may be higher.
LVEF should be evaluated to determine during treatment prior to use of the drug Pereta в„ў and regularly (eg every 3 months) to make sure that the LVEF is within the normal values established in the facility. If left ventricular ejection fraction less than 40% or 40-45% with a decrease of? 10% from baseline to the treatment, the use Pereta в„ў drug should suspend and trastuzumab. If after re-evaluation carried out in a period of approximately 3 weeks, LVEF did not improve or will reduce it further, you should consider the abolition of the drug Pereta в„ў and trastuzumab, unless it is decided that the benefits of their use for a particular patient outweigh the risk.
In applying the drug Pereta в„ў may develop infusion reactions and hypersensitivity reactions.With the introduction of Pereta в„ў drug should carefully monitor the patient during the first infusion and for 60 minutes after its termination, as well as for the next infusion and for 30 minutes after their completion. With the development of clinically relevant reactions to the infusion rate should be slow infusion or interrupt it, and conduct appropriate therapeutic measures. Careful observation of the patient and an assessment of its condition are recommended to complete resolution of symptoms. Patients with serious infusion reactions should assess the need for full withdrawal of the drug, with the severity and nature of the observed response of response, assigned to an unwanted reaction.
Destruction of unused preparation or expired conducted in accordance with the requirements of the facility.
Impact on the ability to drive vehicles and manage mechanisms
Effect on the ability to road management and operation mechanisms have not been studied. With the development of some adverse reactions, such as dizziness, should refrain from driving vehicles and mechanisms.
The maximum tolerated dose of the drug Pereta в„ў is not installed. Single doses exceeding 25 mg / kg (1727 mg), were not studied.
Treatment: in case of overdose must carefully monitor patients for signs or symptoms of adverse reactions and the corresponding destination symptomatic treatment.
Symptoms of a pharmacokinetic interaction between the drug and Pereta в„ў trastuzumab, docetaxel, gemcitabine, erlotinib, capecitabine was found.
drug Pereta в„ў incompatible with 5% dextrose solution. Dilution in such a solution leads to chemical and physical instability Pereta в„ў drug.
The drug Pereta в„ў should not be mixed or diluted with other drugs.
A solution Pereta в„ў drug compatible with infusion bags made of polyvinyl chloride, polyethylene and polyolefin.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children, protected from light at a temperature of 2 В° to 8 В° C. Shelf life - 2 years. Do not use beyond the expiration date printed on the package.