Perieta® (Perjeta®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substancePertuzumabPertuzumab
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  • Beyodeime®
    concentrate d / infusion 
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  • Perieta®
    concentrate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    1 bottle contains:

    active substance: 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 for injection up to 14 ml.

    The concentration of pertuzumab is 30 mg / ml.

    Description:Transparent or opalescent colorless or slightly brownish liquid.
    Pharmacotherapeutic group:Antitumor agent, antibodies monoclonal.
    ATX: & nbsp

    L.01.X.C.13   Pertuzumab

    Pharmacodynamics:

    Mechanism of action

    Pertuzumab is a recombinant humanized monoclonal antibody that selectively interacts with the extracellular subdomain II responsible for dimerization HER2 (human epidermal growth factor receptor of type 2). Binding of pertuzumab to subdomain II blocks the process of ligand-dependent heterodimerization HER2 with other proteins of the family HER, including EGFR (epidermal growth factor receptor), HER3 (human epidermal growth factor receptor of type 3) and HER4 (the receptor of epidermal growth factor of human type 4). In this way, 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. Besides, pertuzumab promotes activation of antibody-dependent cellular cytotoxicity (AZKTS).

    The molecular weight of pertuzumab is about 148 kDa, and it is expected that, like other monoclonal antibodies, pertuzumab practically does not pass through the blood-brain barrier.

    Pertuzumab in the form of a monoagent inhibits the proliferation of human tumor cells. An increase in the antitumor activity of pertuzumab on xenograft models with overexpression HER2 when used in combination with trastuzumab. Immunogenicity

    Approximately 6.2% of patients treated with trastuzumab in combination with docetaxel and 2.8% of patients who received trastuzumab in combination with docetaxel and pertuzumab, ATA were detected. 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.

    Pharmacokinetics:

    The pharmacokinetics of pertuzumab following intravenous administration (iv) in various doses (from 2 to 25 mg / kg) in patients with different types of tumor was studied.

    The clearance of pertuzumab was independent of the dose and indications.

    Pharmacokinetic parameters do not depend on age, gender and ethnicity (Japanese and other ethnic groups).

    The initial concentration of albumin and the "lean body weight" (a 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 concentration of albumin or body weight. Suction

    Pertuzumab is administered iv. Other ways of drug administration have not been studied.

    Distribution

    After IV introduction, the volume of distribution in the central chamber (Vc) is 3.07 liters and is approximately equal to the volume of the plasma. Values Vc and volume of distribution of pertuzumab at an equilibrium state (Vss) suggest that the distribution occurs only in plasma and extracellular fluid.

    Metabolism

    Metabolism of pertuzumab has not been studied. Like other antibodies, pertuzumab predominantly subjected to catabolism.

    Excretion

    The clearance of pertuzumab is approximately 0.239 l / day, half-life (T1/2) is approximately equal to 17.2 days.

    Pharmacokinetics in specific patient groups

    Patients of elderly and senile age

    Special studies of the pharmacokinetics of pertuzumab in elderly patients (> 65 years) and senile (> 75 years) were not conducted. According to the results of the population analysis, age does not affect the pharmacokinetic parameters of pertuzumab. Patients with impaired renal function

    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 is mild (creatinine clearance 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 to severe renal insufficiency are limited.

    Patients with impaired hepatic function

    The study of the pharmacokinetics of pertuzumab in patients with impaired liver function was not conducted.

    Indications:

    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.

    Contraindications:

    Hypersensitivity to pertuzumab and other components of the drug. Pregnancy and the period of breastfeeding.

    Children under 18 years of age (efficacy and safety of use not established). Values ​​of left ventricular ejection fraction (LVEF) before treatment <50%.

    Congestive heart failure in history.

    Uncontrolled hypertension.

    Recently suffered myocardial infarction.

    Serious heart rhythm disorders that require drug therapy at the time of prescription of Perieta®, 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 / m2.

    Dysfunction of the liver (efficacy and safety of use have not been studied).

    Carefully:

    Decrease in LVEF to <50% on the background of previous adjuvant therapy with trastuzumab. Prior 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:contraindicated
    Dosing and Administration:

    Before treatment with Perieta ® it is necessary to test for tumor expression HER2. An obligatory criterion is 3+ points according to the results of immunohistochemical analysis (IHC) and / or degree of amplification> 2.0 based on hybridization results in situ (ISH). Accurate and validated testing methods should be used.

    Preparation of Perieta ® inject only intravenously drip! Enter the drug intravenously struyno or bolusno not!

    Dosing regimen

    The duration of infusion with the administration of the first dose should be 60 minutes. If the first infusion is well tolerated, subsequent ones can be carried out for 30-60 minutes.

    Preparation of Perieta ®

    Loading dose preparation of Perieta ® is 840 mg as a 60-minute intravenous drip infusion. Further in 3 weeks and every 3 weeks is introduced maintenance dose 420 mg in the form of a 30-60 minute infusion.

    Trastuzumab

    When used in combination with a preparation of Perieta ® the following dosing regimen is recommended:

    loading dose - 8 mg / kg of body weight as a 90-minute intravenous drip infusion;

    maintenance dose - 6 mg / kg body weight every 3 weeks as an intravenous drip infusion for 30-90 minutes.

    The maintenance dose is given 3 weeks after loading.

    Docetaxel

    When used in combination with a preparation of Perieta ® the recommended initial dose of docetaxel is 75 mg / m as an intravenous 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 in subsequent cycles.

    Duration of treatment

    If signs of disease progression or unacceptable toxicity appear, treatment with Perieta ® should be discontinued.

    Skipping in the planned introduction

    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 the interruption in the administration of pertuzumab is 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.

    Correction of dose

    Reduction of the dose of Perieta ® Not recommended.

    Preparation of Perieta ® should be discontinued in the event that treatment with trastuzumab is reversed. With the cancellation of docetaxel, treatment with Perieta ® and trastuzumab can continue until the disease progresses or the development of unacceptable toxicity. Reducing the dose of trastuzumab is not recommended.

    For instructions on modifying the dose of docetaxel, see the instructions for the medical use of docetaxel.

    Violation of the function of the left ventricle

    Introduction of the drug Perieta ® and trastuzumab should be suspended for at least 3 weeks in the following cases:

    - decreased LVEF to below 40%;

    - Values ​​of LVEF 40-45% with a decrease in LVEF by> 10% relative to the values ​​observed before treatment.

    Resume treatment with Perieta ® and trastuzumab is possible if LVEF is restored to> 45% or 40-45% with a decrease of <10% with respect to the values ​​observed before treatment.

    If, according to the reassessment data after 3 weeks, LVEF does not increase or further decline occurs, treatment with Perieta ™ and trastuzumab should be discontinued, unless the benefits of using them in each specific case exceed the risk.

    Infusion reactions

    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

    Patients of elderly and senile age

    Correction of dose in elderly patients and in senile patients is not required. Patients with impaired renal function

    Efficacy and safety of Perieta ® in patients with impaired renal function were not studied.

    Patients with impaired hepatic function

    Efficacy and safety of Perieta ® in patients with impaired liver function were not studied.

    Patients of childhood

    Efficacy and safety of Perieta ® in children and adolescents under the age of 18 years are not established.

    Preparation of a solution for infusions

    Attention! Preparation of Perieta ® not compatible with 5% dextrose solution. Dilution in such a solution leads to chemical and physical instability of the drug Perieta ®. Preparation of Perieta ® should be diluted only in 0.9% solution of sodium chloride. Perieta ™ should not be mixed or diluted with other medications.

    Solution of the drug Perieta ® compatible with infusion bags made of polyvinyl chloride, polyethylene and polyolefin.

    Preparation of the preparation for administration should be carried out under aseptic conditions. Preparation of Perieta ® 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 ° 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.

    Side effects:

    The most frequent adverse reactions (observed in more than 50% of patients) associated with the use of Perieta ® in combination with trastuzumab and docetaxel, were diarrhea, alopecia and neutropenia.

    The most frequently observed (> 10%) undesired reactions of the 3rd-4th degree of severity according to the classification of the National Cancer Institute National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE), version 3, there were neutropenia, febrile neutropenia, and leukopenia.

    The most severe and clinically significant adverse reaction, observed with a frequency of less than 10%, was left ventricular dysfunction, including symptomatic left ventricular systolic dysfunction (congestive heart failure).

    Below are the undesirable reactions reported in the study of Perieta ® in combination with trastuzumab and docetaxel. Since the preparation of Perieta ® was used in combination with trastuzumab and docetaxel, it is problematic to establish the causal relationship between the undesirable phenomenon and the specific drug. To describe the frequency of unwanted reactions, the following classification is used: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100), rarely (> 1/10000 and <1/1000) and very rarely (<1/10000), including isolated cases.

    Violations from the blood and lymphatic system: very often - neutropenia, anemia, leukopenia, febrile neutropenia (including fatal). Immune system disorders: often - hypersensitivity.

    Disorders from the metabolism and nutrition: very often - a decrease in appetite. Disorders of the psyche: very often - insomnia.

    Disturbances from the nervous system: very often - peripheral neuropathy, headache, perversion of taste, dizziness.

    Disorders from the side of the organ of vision: very often - increased tearing. Heart Disease: often - a violation of the function of the left ventricle, including congestive heart failure.

    Disturbances from the respiratory system, chest and mediastinal organs: very often - shortness of breath; often - pleural effusion.

    Disorders from the gastrointestinal tract: very often - diarrhea, nausea, vomiting, constipation, stomatitis.

    Disturbances from the skin and subcutaneous tissues: very often - alopecia, rash, pathology of the nails, itching, dry skin; often paronychia.

    Disturbances from the musculoskeletal and connective tissue: very often - myalgia, arthralgia.

    General disorders and disorders at the site of administration: very often - increased 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 only Perieta ® 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 the drug Perieta ® , trastuzumab and docetaxel, starting with the second cycle of therapy, 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 Perieta ®, trastuzumab and docetaxel; of these phenomena, 2.5% and 2% were characterized by the 3rd and 4th degree of severity according to the classification NCI-CTCAE, version 3, respectively. A total of 2 patients after simultaneous administration of trastuzumab and docetaxel and in 4 patients after simultaneous administration of Perieta ®, trastuzumab and docetaxel, anaphylaxis developed.

    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.

    Deviations from the norm of laboratory indicators

    The frequency of cases of a decrease in the number of neutrophils of the 3rd-4th degree of severity by classification NCI-CTCAE, version 3, was approximately the same with a combination of trastuzumab and docetaxel concurrently with Perieta ® and without it.

    Overdose:

    The maximum tolerated dose of Perieta ® not installed. Single doses exceeding 25 mg / kg (1,727 mg) have not been studied.

    In case of overdose, patients should be closely monitored in order to detect signs or symptoms of adverse reactions and to prescribe appropriate symptomatic treatment.

    Interaction:

    Signs of pharmacokinetic interaction between the preparation of Perieta ® and trastuzumab, docetaxel, gemcitabine, erlotinib, capecitabine was not found. Compatibility

    Preparation of Perieta ® not compatible with 5% dextrose solution. Dilution in such a solution leads to chemical and physical instability of the drug Perieta ® . Preparation of Perieta ® Do not mix or dilute with other medicines.

    Solution of the drug Perieta ® compatible with infusion bags made of polyvinyl chloride, polyethylene and polyolefin.

    Special instructions:

    Treatment with Perieta ® should be carried out only under the supervision of an oncologist.

    Against the background of the use of drugs that block activity HER2, including the preparation of Perieta ® , it was observed decreased LVEF. Application of the drug Perieta ® in combination with trastuzumab and docetaxel was not accompanied by an increase in the frequency of symptomatic systolic dysfunction of the left ventricle or a decrease in LVEF, compared with the use of only trastuzumab and docetaxel. However, in patients who have previously received anthracyclines or radiotherapy for the thoracic region, the risk of reducing LVEF may be higher.

    LVEF should be evaluated before applying Perieta ® and regularly (for example, every 3 months) to determine against the background of treatment in order to make sure that LVEF is within the normal values ​​established in this institution. If LVEF is less than 40% or 40-45% with a decrease of> 10% of baseline before treatment, the use of Perate ™ and trastuzumab should be stopped. If, after a reassessment carried out in the period of approximately 3 weeks, LVEF does not improve or further decline occurs, consideration should be given to the abolition of Periet's drug ® and trastuzumab unless it is decided that the benefits of their use for a particular patient outweigh the risk.

    When using Perieta ® possible development infusion reactions and hypersensitivity reactions. With the introduction of Perieta ® carefully monitor the patient during the first infusion and within 60 minutes after the end, as well as during subsequent infusions and within 30 minutes after their termination. If a clinically significant reaction to infusion develops, slow the infusion rate or interrupt it and take appropriate therapeutic measures. Careful observation of the patient and evaluation of his condition are recommended until the symptoms are completely resolved. In patients with severe infusion reactions, the need for complete discontinuation of the drug should be assessed, taking into account the severity of the observed response and the nature of the response to treatment prescribed in connection with the adverse reaction. Women with reproductive potential and women of childbearing age who are the sexual partners of patients receiving the drug on the background of Perieta ™ and within 6 months after the last dose should use effective methods of contraception.

    Destruction of an unused preparation or product with an expired shelf life should be carried out in accordance with the requirements of the medical institution.

    Effect on the ability to drive transp.cf. and fur:The effect of the drug on the ability to drive and work with machinery has not been studied. With the development of some undesirable reactions, in particular, dizziness, one should refrain from managing vehicles and mechanisms.
    Form release / dosage:Concentrate for the preparation of a solution for infusions 420 mg / 14 ml 420 mg / 14 ml of the drug in a bottle of colorless glass (hydrolytic class 1 EF), sealed with a plug of butyl rubber laminated with fluoropolymer, crimped with an aluminum cap and closed with a plastic lid. 1 bottle with the drug, along with instructions for use, is placed in a cardboard box.
    Packaging:vials - cardboard boxes
    vials - polypropylene boxes
    vials (1) - packs cardboard
    bottles (1) - pallets cardboard-packs cardboard
    bottles (1) - plastic pallets, cardboard
    Storage conditions:

    Store at 2-8 ° C in a dark place.

    Keep out of the reach of children.

    Shelf life:Do not use after the expiration date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-002034
    Date of registration:22.03.2013
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp30.08.2015
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