Kadsila® (Kadcyla®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTrastuzumab emtanzineTrastuzumab emtanzine
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  • Kadsila®
    lyophilizate d / infusion 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbsp
    Liofilizate for the preparation of concentrate for the preparation of solution for infusion.
    Composition:

    1 bottle (100 mg) contains:

    active substance: trastuzumab emtanzine - 100 mg;

    Excipients: sucrose - 318.0 mg, succinic acid - 6.3 mg, sodium hydroxide -

    2.4 mg, polysorbate 20-1.1 mg.

    1 bottle (160 mg) contains:

    active substance: trastuzumab emtanzine - 160 mg;

    Excipients: sucrose - 514.0 mg, succinic acid - 10.1 mg, sodium hydroxide -

    3.9 mg, polysorbate 20 - 1.7 mg.

    1 ml The reconstituted solution contains 20 mg of trastuzumab emtanzine.

    Description:

    The porous mass, packed into a tablet, sometimes in the form of separate parts of the tablet, white or almost white.

    The reconstituted solution - Transparent or slightly opalescent, colorless or with a brownish hue solution.

    Pharmacotherapeutic group:Antineoplastic agent - monoclonal antibodies.
    ATX: & nbsp

    L.01.X.C.14   Trastuzumab emtanzine

    Pharmacodynamics:

    Methe action

    Trastuzumab emtansin is a conjugate of a humanized monoclonal antibody (IgG1) to the human epidermal growth factor receptor type 2 HER2 (trastuzumab) and inhibitor of polymerization of tubulin DM1 (a derivative of meitaisin) bound to each other via a stable thioether linker MCC (4-(N- maleniimidomethyl) cyclohexane-1-carboxylate). Emtansine is a complex DM1-MCC.

    Average number of molecules DM1, conjugated to each molecule of the trastuzum

    ba is 3.5.

    Trastuzumab emtansin selectively interacts with the human epic receptordermal growth factors of type 2 (HER2).

    After binding to HER2 trastuzumab emtansin enters the cell and undergoes proteolytic degradation in lysosomes, which leads to the release of DM1- containing cytotoxic catabolites (mainly, the complex of lysine-MCC-DM1). Thus, conjugation DM1 with trastuzumab causes selectivity cytotoxic drug against tumor cells with overexpression HER2 and facilitates delivery DM1 into the tumor cells. The mechanism of action of trastuzumab emtansin is a combination of the mechanisms of action of trastuzumab and DM1.

    Trastuzumab emtanzine, like trastuzumab, binds to the domain IV of the extracellular domain HER2, as well as with receptors Fcγ and complement protein Clq. Trastuzumab emtanzine, like trastuzumab, prevents the "sloughing" of the extracellular domain HER2 from the cell surface, inhibits the transfer of intracellular signal along the pathway of phosphatidylinositol-3-kinase (PI3-K), and also promotes the activation of antibody-dependent cell-

    mediated cytotoxicity (ADCC) in human breast cancer cells with overexpression HER2.

    DM1, cytotoxic component emtanzina Trastuzumab binds to tubulin and inhibits its polymerization. Due to the effect of the cytotoxic component of trastuzumab emtansin, as well as DM1, causes blockade of the cell cycle in phase G2/M, which ultimately leads to apoptosis. Results of the study of cytotoxicity DM1 in vitro demonstrated that activity DM1 in 20-200 times higher than the activity of taxa and alkaloids of the vinca.

    The structure of MCC linker allows to limit systemic release DM1 and promotes its directed delivery inside the cells, which is confirmed by the very low content of free DM1 in the blood plasma.

    Pre-clinical safety study data

    Mutagenicity

    Preclinical studies indicate the presence of at traetuzumaba emtanzina aneugennoy and / or clastogenic toxicity.

    Teratogenicity

    There are data on the embryotoxic effect of traetuzumab and on potential teratogenic and embryotoxic effects DM1.

    Impact on fertility

    The results of preclinical studies indicate a risk of impaired fertilitywith the use of traetuzumab emtanzine.

    Pharmacokinetics:

    Suction

    Trastuzumab emtansin is administered intravenously. Other ways of administering the drug are not studied

    .

    Distribution

    The pharmacokinetics of tratuzumab emtanzine with intravenous administration every 3 weeks at doses of 2.4-4.8 mg / kg is linear. In patients receiving doses of 1.2 mg / kg or less, a higher clearance of the drug was noted.

    The mean maximum concentration of traetuzumab emtansin in serum (CMax) is 83.4 (± 16.5) μg / ml with intravenous administration of the drug at a dose of 3.6 mg / kg every three weeks. After intravenous administration, the volume of distribution of trastuzumab emtanzine in the central chamber is 3.13 L and is approximately equal to the plasma volume.

    Metabolism

    In studies on microsomes of human liver in vitro shown, that DM1, The low molecular weight component of trastuzumab, emtanzine, is mainly metabolized by isoenzyme CYP3A4 and to a lesser extent isoenzyme CYP3A5. DM1 is not an inhibitor of the main isoenzymes of the cytochrome family CYP450 in vitro. Catabolites of trastuzumab emtanzine, Lys-MCC-DM1, MCC-DM1 and DM1 are found in human plasma in low concentrations. According to the research in vitro DM1 is a substrate of the glycoprotein R.

    Excretion

    After intravenous administration of trastuzumab emtanzine in patients with metastatic breast cancer with overexpression HER2 the clearance of trastuzumab emtanzine was 0.68 l / day, half-life (t1/2) - about 4 days. After repeated intravenous administration of trastuzumab, emtansin was not observed every 3 weeks.

    Macca body, the concentration of albumin in the blood serum, the sum of the largest diameter of the tumor sites according to the criterion RECIST (Criteria for evaluating the response in solid tumors

    Response Evaluation Criteria in Solid Tumors), the initial concentration of the "split"

    extracellular domain (ECD) HER2, initial trastuzumab concentration and baseline at.activity aspartate aminotransferase (ACT) in the serum are parameters, which have a statistically significant effect on the clearance of trastuzumab emtanzine. However, the clinically significant effect of these parameters, except for body weight, on the exposure of trastuzumab emtansin is unlikely.

    Catabolites of trastuzumab emtansine, in particular, DM1, Lys-MCC-DMl and MCC-DM1 mainly derived from bile and to a minimum extent with urine.

    Pharmacokinetics in specific patient groups

    Race and gender

    The race does not affect the pharmacokinetics of trastuzumab emtansine. Influence of sex on pharmacoksthe non-toxic of CadSil® has not been studied separately.

    Elderly and old age

    Age does not affect the pharmacokinetics of trastuzumab emtansine. There were no significant differences in the pharmacokinetics of trastuzumab emtanzine in patients <65 years of age, 65 to 75 years of age and older than 75 years.

    Impaired renal function

    According to the population pharmacokinetic analysis, the clearance of creatinine does not affect the pharmacokinetics of trastuzumab emtansine. The values ​​of pharmacokinetic parameters of trastuzumab emtansin in patients with mild (creatinine clearance 60-89 ml / min) and mean (KK 30-59 ml / min) degree of renal failure are similar to those in patients with normal renal function (QC >90 ml / min). Data on the pharmacokinetics in patients with severe and terminal renal insufficiency (CC <30 mL / min) are limited, so it is not possible to give special instructions for dosing.

    Dysfunction of the liver

    Special studies of pharmacokinetics in patients with impaired liver function were not performed.

    Indications:

    Metastatic breast cancer

    Kadsila® is used as a monotherapy after previous chemotherapy, which included trastuzumab and drugs from the taxane group (sequentially or in combination), or after the progression of the disease during or for 6 months after the completion of adyovant therapy that included trastuzumab and drugs from the taxane group (sequentially or in combination), in patients with inoperable locally advanced or metastatic HER2- positive breast cancer.

    Contraindications:
    Hypersensitivity to trastuzumab emtansin and to other components of the drug.
    Infusion reactions associated with the use of trastuzumab, leading to the abolition of therapy.
    Pregnancy and the period of breastfeeding.
    Age under 18 years (efficacy and safety of use in children not established).
    Diffuse interstitial lung disease, pneumonitis.
    Nodal regenerative hyperplasia of the liver.
    Symptomatic congestive heart failure.
    Renal failure of severe and terminal severity (creatinine clearance <30 ml / min), hepatic insufficiency, including increased hepatic aminotransferase activity> 3x of the upper limit of norm (VGN) at a concentration of total bilirubin> 2 VGN (efficacy and safety of application not established).
    The value of the left ventricular ejection fraction of the heart is <50% before the start of treatment; chronic heart failure in history; dyspnea at rest, caused by the progression of a malignant disease or concomitant pathology; serious heart rhythm disorders requiring drug therapy; myocardial infarction or unstable angina that developed within 6 months before the start of treatment; platelet count <100,000 / mm3 before treatment; peripheral neuropathy >3 degrees of severity before treatment (efficacy and safety of use not established).

    Carefully:
    Activity of hepatic aminotransferases> 2.5xVGN or concentration of total bilirubin> 1.5xVGN before treatment.
    Dysfunction of the left ventricle (see section "Special instructions", subsection "Left ventricular dysfunction").
    Pregnancy and lactation:
    Women with reproductive potential, male patients, and
    Women of childbearing age who are the sexual partners of patients receiving
    Kadsila®, should use effective contraceptive methods during the treatment with Cadsil® and within 7 months after the last dose. In case of pregnancy, the patient should immediately consult a doctor. It is necessary to warn the woman about the possibility of harmful effects on the fetus. If the pregnant woman decides to continue therapy with Kadsila®, then she should be under the careful supervision of doctors.
    It is not known whether the trastuzumab emtanzine in breast milk. Breastfeeding is not recommended during treatment and at least 7 months after the end of therapy with Cadsil®
    Dosing and Administration:
    Before using the drug, it is necessary to check the label on the vial and make sure that the preparation used for preparation and administration is a preparation of Kadsila® (trastuzumab emtanzine), and not the drug Herceptin® (trastuzumab).
    The use of Kadsila® should only be carried out under the supervision of a doctor who has experience in the treatment of cancer.
    It is necessary to test for tumor expression of HER2 before starting treatment with Cadsil®. A mandatory criterion is 3+ points based on the results immunohistochemical analysis (1NS) and / or degree of amplification> 2.0 by hybridization results in situ (ISH). The test methods used must be validated.

    AT mThe patient's patient documentation should include the trade name of the prepapata (Cadsil®). The replacement of Kadsila® with another preparation of biological origin must be agreed with the attending physician.

    Dosing regimen

    The recommended dose of Cadsil® is 3.6 mg / kg body weight once every 3 weeks (21-day cycle) as an intravenous drip infusion. Therapy with Cadsil® should be continued until signs of progression appear

    disease or unacceptable toxicity. The first dose is recommended to be administered as a 90-minute intravenous drip infusion. It is necessary to monitor the patient during the first infusion and, at least 90 minutes after the end, for fever, chills, or other infusion reactions.Also, a thorough examination of the injection site for possible formation of subcutaneous infiltrates is necessary. If the previous infusion was well tolerated, the next infusion can be performed for 30 minutes, continuing to monitor the patient for at least 30 minutes after the end of the infusion. It is necessary to reduce the rate of infusion or temporarily stop the introduction of Cadsil® when the patient shows signs of an infusion reaction. In the event of a life-threatening infusion reaction, Kadsila® should be completely discontinued. Drugs for the treatment of possible infusion reactions of the allergic / anaphylactic type, as well as equipment for emergency care should be available for immediate use.

    Skipping in the planned introduction

    If you miss a planned introduction of KadSila®, you must enter the drug as soon as possible in the recommended dose, while the infusion rate may be the same, with which the previous infusion was well tolerated by the patient. Do not wait for the next scheduled cycle.The schedule of drug administration should be adjusted to maintain a 3-week interval between administrations.

    Correction of dose

    Possible measures to eliminate the symptoms of adverse reactions are dose reduction, a temporary interruption in treatment, or a complete cessation of therapy with Cadsil®. Relevant recommendations are given in Tables 1-5 below. If the dosage of the preparation Kadsila® had to be reduced, then with subsequent injections it can not be increased.

    Table 1. Scheme of dose reduction Kadsila®


    Rules for dose reduction (initial dose of 3.6 mg / kg)

    Recommended dose

    1st dose reduction

    3 mg / kg

    2nd dose reduction

    2.4 mg / kg

    Necessity of further dose reduction

    Completely stop therapy

    Table 2. Recommendations for correcting the dose of the preparation Kadsila® with an increase in the activity of hepatic aminotransferases (aspartate aminotransferase (ACT) / ala-ninaminotransferase (ALT)) in serum

    Degree 2 (from> 2.5 to <5хВГН *)

    Degree 3 (from> 5 to < 20хВНН)

    Degree 4 (> 20 × WGN)

    Correction of the dose of Kadsila® is not required.

    Discontinue therapy with Cadsil® until toxicity is reduced to <2 degrees, then reduce the dose (see Table 1).

    Completely discontinue therapy with Cadsil®.

    * VGN = upper limit of the norm

    Ta 3. Recommendations for dose adjustment of KadSil® with hyperbilirubinemia

    Degree 2 (from> 1.5 to <ЗхВГН)

    Degree 3 (from> 3 to<10хВГН)

    Degree 4 (> 10xVGN)

    Discontinue therapy with Cadsil® until the current decreases to <1 degree, then resume treatment at the same dose.

    Discontinue therapy with Cadsil® until toxicity is reduced to <1 degree, then lower the dose (see Table 1).

    Completely discontinue therapy with Cadsil®.

    Therapy with Cadsil® should be completely discontinued if the activity of hepatic aminotransferases in the serum is> 3 × VGN with a common bein> 2 × VHN, and also in the case of development of nodal regenerative hyperplasia.

    Table 4. Recommendations for correcting the dosage of the preparation of Cadsil® with thrombocytopenia

    Degree 3

    Degree 4

    from 25,000 to <50000 / mm3

    <25000 / mm3

    Discontinue therapy with Cadsil® until toxicity is reduced to <1 degree (up to 75000 / mm)3) and resume treatment at the same dose

    Discontinue therapy with Cadsil® until toxicity is reduced to <1 degree (up to >75000 / mm3), then lower the dose (see Table 1).

    Table 5. Recommendations for correcting the dose of KadSil® with left ventricular dysfunction

    CImplamatory congestive heart failure

    LVEF * <40%

    LVEF 40% -45%

    decline >10% compared to the original value

    a decrease of <10% compared to the original value

    LVEF> 45%

    Completely discontinue therapy with Cadsil®.

    Interrupt drug therapy

    volume of Cadsil®.

    Conduct reassessment of LVEF after 3 weeks. When re-determining LVEF <40% completely discontinue therapy.

    Interrupt drug therapy

    volume of Cadsil®.

    Conduct reassessment of LVEF after 3 weeks.

    If LVEF did not recover to values ​​within 10% of the baseline should be completely discontinued with Cadsil®.

    Continue therapy with Kadsila®.

    Conduct reassessment of LVEF after 3 weeks.

    Continue therapy with Kadsila®.





    * LVEF - left ventricular ejection fraction

    Therapy with Cadsil® should be completely discontinued if the patient is diagnosed with interstitial lung disease or pneumonitis.

    With the development of peripheral neuropathy 3 and 4 degrees of severity, therapy with Kadsila® should be discontinued until the symptoms are resolved to a level <2 degrees.

    Special instructions for dosing

    Elderly and old age

    Correction of the initial dose of Cadsil® in patients aged >65 years is not required. Efficacy and safety of Kadsila® in patients aged >75 years have not been established due to insufficient data.

    Children

    The efficacy and safety of Cadsil® in children is not established.

    Impaired renal function

    Correction of the initial dose in patients with renal insufficiency is mild (KK 60-89 ml / min) and medium (KK 30-59 ml / min) severity is not required. The need for dose adjustment in patients with severe and terminal renal dysfunction (SC ml / min) is not established. NARhepatic function dysfunction

    The efficacy and safety of Cadsil® in patients with impaired liver function have not been studied.

    Preparation for introduction

    The drug Kadsila® is administered only by intravenous drip! Enter the drug intravenously struyno or bolusno not!

    Dissolution and dilution of Kadsila® should be carried out by highly qualified medical personnel.

    Preparation of the drug for administration should be carried out under aseptic conditions in compliance with the proper rules for the preparation of chemotherapeuticpreparations.

    Attention:

    Cadsil® is incompatible with a 5% dextrose solution because of the possibility of protein aggregation.

    Kadsila® should not be mixed or diluted with other medications.

    The solution of the preparation Kadsila® is compatible with infusion bags made of polyvinyl chloride (IIBX) or polyolefin (PVC-free or latex-free).

    When infusion is performed using 0.9% sodium chloride solution, it is mandatory to use an infusion system with a built-in polyethersulfone infusion filter (PES) with a pore diameter of 0.2-0.22 μm.

    In the case of using 0.45% sodium chloride solution, the use of a built-in infusion filter made of polyethersulfone with a pore diameter of 0.2-0.22 μm is not required. PaThe Kadsila® preparation contains no preservatives and is intended for single use.

    Yingstructure for the preparation of a concentrate (reconstituted solution) for the preparation of a solution for infusions

    1.Using a sterile syringe, slowly inject 5 ml of sterile water for injection into a vial containing 100 mg of trastuzumab emtanzine, or 8 ml of sterile water for injection into a vial containing 160 mg of trastuzumab emtanzine.The concentration of the resulting solution should be 20 mg / ml.

    2. Gently shake the bottle with rotational movements until the lyophilizate is completely dissolved. Do not shake!

    Before use, the concentrate obtained after dissolving the lyophilizate must be visually inspected for absence of foreign inclusions, discoloration and turbidity. Concentrate should be transparent or slightly opalescent, without visible particles, colorless or with brownish traces. Do not use concentrate if it contains visible particles, if it is clouded or discolored.

    Concentrate for the preparation of a solution for infusions should be used immediately after dissolving the lyophilizate. It is allowed to store the concentrate for 24 hours at a temperature of 2-8 ° C, provided that the dissolution takes place in controlled and validated optical conditions.

    Do not freeze!

    If after this period the concentrate is not used, it should be disposed of Instructions for the preparation of a solution for infusion

    1. Determine the required dose (mg / kg) of the Kadsila® preparation.

    2. Determine the amount of concentrate for the preparation of the infusion solution required to administer the desired dosage of the Kadsil® preparation using the following formula:

    body weight (kg) x dose (mg / kg)

    Volume (ml) = ............................................. .................................................. ..................

    20 (mg / ml) (concentration of reconstituted solution)

    3. Select the required volume from the vial of concentrate and enter it into the infusion bag made of polyvinyl chloride (PVC) or polyolefin (not containing PVC or latex) with 250 ml of 0.45% or 0.9% sodium chloride solution.

    4. Carefully turn over the infusion bag to mix the solution. Do not shake!

    Solution for infusion should be used immediately after preparation. In exceptional cases infusion solution can be stored in the refrigerator at a temperature of 2-8 ° C not more than 24 hours before use, if the preparation of the solution was carried out in controlled and validated aseptic conditions. During storage solution for infusion, prepared using 0.9% sodium chloride solution, the formation of visible particles is allowed. He freeze!

    Side effects:

    The most frequent serious adverse reactions are fever, thrombocytopenia, vomiting, abdominal pain, nausea, constipation, diarrhea, dyspnea and pneumonitis.

    The most frequent (>25%), adverse reactions are bleeding (including nasal bleeding),increased activity of hepatic aminotransferases, increased fatigue, musculoskeletal pain, headache. Most observers

    The undesirable reactions were 1 or 2 degrees of severity.

    The most frequent (> 2%) adverse reactions are 3 and 4 degrees of severity, according to the National Cancer Institute (NCI CTC AE), version 3.0, are thrombocytopenia, increased fatigue, increased hepatic aminotransferase activity, anemia, hypokalemia, musculoskeletal pain and neutropenia.

    In this section, unwanted reactions are grouped according to the classes of systems of the medical dictionary authorities for regulatory activities MedDRA. To describe the frequency of undesired reactions, the following classification is used: very frequent (>1/10), frequent (>1/100 and <1/10), infrequent (>1/1000 and <1/100) are rare (>1/10000 and <1/1000) and very rare (<1/10000), including isolated cases. UnwillingnessThe reactions of each group are arranged in order of decreasing severity, determined according to the criteria for toxicity according to the National Cancer Institute (NCI CTC AE), version 3.0.

    Disturbances from the blood system and lymphatic system: very often thrombocytopenia, anemia; often - neutropenia, leukopenia.

    Immune system disorders: often - drug hypersensitivity.

    Metabolic and nutritional disorders: very often - hypokalemia. Disorders of the psyche: very often insomnia.

    Impaired nervous system: very often - peripheral neuropathy, headache, dizziness; often - a violation of taste sensations (dysgeusia), memory impairment.

    Disorders from the side of the organ of vision: often - dry eyes, conjunctivitis, blurred vision, increased tearing.

    Heart Disease: often - left ventricular dysfunction.

    Vascular disorders: very often bleeding; often, high blood pressure.

    Disturbances from the respiratory, thoracic and mediastinal organs: very often - nosebleeds, cough, shortness of breath; infrequently - pneumonitis.

    Disorders from the gastrointestinal tract: very often - stomatitis, diarrhea, vomiting, nausea, constipation, dry mouth, abdominal pain; often - dyspepsia, bleeding gums.

    Disorders from the liver and bile ducts: infrequently - the phenomenon of hepatotoxicity, hepatic insufficiency, nodal regenerative hyperplasia, portal hypertension.

    Hskin and subcutaneous tissue disorders: very often - a rash; often - itching, alopecia, a violation of the structure of the nails, palmar-plantar erythrodysesthesia, urticaria.

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

    Disorders from the kidneys and urinary tract: very often - urinary tract infections.

    General disorders and disorders at the site of administration: very often - increased fatigue, fever, asthenia, chills; often - peripheral edema; infrequently - extravasation at the site of infusion.

    Laboratory and instrumental data: very often - increased activity of hepatic aminotransferases; often - an increase in the activity of alkaline phosphatase in the blood.

    Trauma, intoxication and complications of manipulation: often - infusion reactions.

    Below information is provided on individual adverse reactions

    Increased activity of hepatic aminotransferases (AST / ALT) Observed with the use of the preparation Kadsila®an increase in the activity of aminotransferases 1-4 of the severity level and the accumulation of aminotransferases in the blood serum were in most cases reversible.

    Aminotransferase activity increased as much as possible on day 8 after infusion, and was usually restored to 1 degree or up to the norm by the time of the next infusion. This indicator in most cases was restored to 1 degree or up to the norm within 30 days after discontinuation of therapy.

    An increase in hepatic aminotransferase activity was observed in 28% of patients treated with Cadsil®.

    Increased activity ACT and ALT of 3 and 4 severity were observed in 4.1% and 2.8% of patients, respectively, and, as a rule, occurred at the beginning of therapy (on the 1-6 cycle). TO

    As a rule, liver dysfunction >3 degrees of severity were not associated with an unfavorable outcome, and liver function indicators at follow-up indicated a gradual improvement in the patient's condition to a level that allowed

    continue therapy with Kadsila® in the recommended or reduced dose.

    The regular dependence of the increase in aminotransferase activity in the blood serum from exposure (AUC, area under the curve "concentration-time"), the total exposure

    the maximum concentration (CMax) trastuzumab emtansin in serum or from CMax DM1 was not observed.

    Violation of the function of the left ventricle of the heart

    The incidence of left ventricular dysfunction in patients with Kadsila®put 2%. In most cases, there was an asymptomatic decrease in the left ventricular ejection fraction of 1 or 2 degrees. Cases of left ventricular dysfunction of 3 or 4 severity were observed with a frequency of 0.3%, usually at the beginning of treatment (on the 1-2 cycle).

    Additional monitoring of the left ventricular ejection fraction is recommended in patients with LVEF <45%.

    Infusion reactions

    Infusion reactions (release of cytokines) are characterized by one oozeand several of the following symptoms: "hot flashes", chills, fever, shortness of breath, arterial hypotension, wheezing, bronchospasm and tachycardia. The incidence of infusion reactions with the use of the preparation Kadsila® was 4.5%. Infusion reactions of the 3rd degree of severity were observed very rarely, no cases of the 4th degree of severity were noted.

    The time for resolving the symptoms of the infusion reactions was usually from a few hours to 1 day after the end of the infusion.

    There was no dependence of the frequency of development of infusion reactions on the dose.

    Hypersensitivity / Anaphylaxis Reactions

    The frequency of hypersensitivity reactions was 2.6%, with no hypersensitivity reactions of 3 and 4 severity levels recorded. In most cases, hypersensitivity reactions were mild and moderate, and resolved after appropriate treatment.

    Thrombocytopenia

    The incidence of thrombocytopenia (decrease in the number of platelets) during therapy with Kadsila® was 31.4%.

    Most of the cases of thrombocytopenia were 1 or 2 degrees of severity (number platelets >50000 / mm), with the lowest content of platelets was observed on the 8th day after the administration of the drug. In the following days, this indicator increased and reached 0 or 1 degree of severity (>75000 / mm3) to the moment the next introduction of the preparation Kadsila®. There was a higher incidence and severity of thrombocytopenia in patients from Asian countries. Regardless the frequency of thrombocytopenia cases of grade 3 and 4 (<50000 / mm3) on the background of therapy with Kadsila® was 11.3%.

    Frequency of severe bleeding (>3 degrees of severity) was 1.7%. In patients from Asia, this indicator was 1%.

    Immunogenicity

    Perhaps the development of an immune response to trastuzumab emtanzine. With the use of the preparation Kadsila ® in 5.3% of patients showed antibodies to trastuzumab emtansin in one or more temporary points after the administration of the drug. The clinical significance of the formation of antibodies to trastuzumab emtansin is not established.

    Extravasion

    When using the drug Kadsila®, reactions associated with the ingestion of the drug under the skin were observed and manifested as erythema, soreness, skin irritation, pain or swelling at the site of administration.

    These phenomena most often occurred within the first 24 hours after the infusion and were usually of mild severity.

    When infusion of the Kadsila® drug should be monitored, the possible formation of subcutaneous infiltrates at the site of administration. Specific treatment of symptoms of extravasation of the preparation Kadsila® is absent.

    Changes in laboratory performance

    Table 6. Certain violations of laboratory indicators observed with the use of the preparation Kadsila®

    All degrees

    severity%

    Power

    gravity 3%

    Power

    gravity 4%

    Indicators of liver function

    Increased bilirubin concentration

    20

    <1

    0

    Increased activity ACT

    98

    7

    <1

    Increased ALT activity

    82

    5

    <1

    Hematologic indices

    Decreased platelet count

    84

    14

    3

    Reduction of hemoglobin concentration

    62

    4

    1

    Decreased number of neutrophils

    39

    4

    <1

    Electrolytes

    Decreased potassium concentration

    34

    3

    <1

    Overdose:
    The antidote for the treatment of an overdose with Cadsil® is unknown. If the recommended dose of Cadsil® is exceeded, careful monitoring of the patient for signs or symptoms of adverse reactions associated with the pharmacological action of the drug and the appropriate symptomatic treatment is necessary.
    Cases of excess of the dose of Cadsil® were reported, most of which were accompanied by thrombocytopenia.
    Interaction:
    There have been no separate studies of interactions with other drugs.
    It should avoid the simultaneous use of potent inhibitors of the isoenzyme CYP3A4 (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,telithromycin and voriconazole) and Cadsil® because of a possible increase in exposure and toxic manifestation of DM1 (a component of trastuzumab emtanzine).
    Consider an alternative drug whose inhibitory effect on the CYP3A4 isoenzyme is minimal or absent.
    If the use of potent inhibitors of the CYP3A4 isoenzyme is necessary, consideration should be given to postpone therapy with the Cadsil® preparation before removing the CYP3A4 isozyme inhibitor preparation from the bloodstream (approximately 3 CYP3A4 isoenzyme inhibitor half-life).
    If therapy with Cadsil® can not be delayed, the patient should be carefully monitored for the development of adverse reactions while being used with a potent CYP3A4 isoenzyme inhibitor.

    Special instructions:

    The preparation Kadsila® should be appointed only in the presence of tumor overexpression of the protein HER2, determined by the method of immunohistochemical reaction (IHC), or amplification of the gene HER2, determined by the hybridization method in situ (FISH or SISH).

    Disorders from the side of the lungs

    With the use of the Kadsila® preparation, cases of diffuse interstitial lung disease (IBL), in particular pneumonitis, have been reported.Some of them led to the development of an acute respiratory distress syndrome or to a lethal outcome. Symptoms of IBL include shortness of breath, cough, increased fatigue and lung infiltrates. Therapy Cadsil® should be completely discontinued if diffuse interstitial lung disease or pneumonitis is diagnosed.

    In patients with dyspnea at rest, caused by the progression of a malignant disease or concomitant pathology, the risk of developing pulmonary disorders is increased.

    Hepatotoxicity

    Hepatotoxicity of the preparation Kadsila® was mainly manifested in the asymptomatic increase in the activity of aminotransferases of 1-4 degrees, for which the accumulation effect is characteristic.

    There have also been cases of serious hepatobiliary disorders, in particular, nodal regenerative liver hyperplasia, as well as fatal drug-induced liver damage. Concomitant diseases, as well as simultaneous use of drugs with established risk of toxic effects on the liver are possible additional risk factors. The liver function should be evaluated before the start of therapy, and also before each subsequent administration of the Cadsil® preparation. In patients with increased activity ALT before the beginning of treatment (for example, in the presence of metastases in the liver), the risk of developing hepatotoxicity 3-5 degrees of severity or an increase in liver function parameters is increased. Recommendations for reducing the dose or temporary discontinuation of therapy due to increased activity of hepatic aminotransferases and the content of total bilirubin are given in the section "Method of administration and dose".

    The efficacy and safety of Kadsila® has not been studied in patients with aminotransferase activity> 2.5xVGN or with a total bilirubin concentration> 1.5xVGN before treatment.

    Therapy with the drug Kadsila® should be completely discontinued in the event of an increase in the activity of aminotransferases in the serum> 3xVGN with a total bilirubin> 2 × VGN. Nodular regenerative liver hyperplasia (URH) is a rare liver disease in which as a result of benign parenchyma transformation in the liver, multiple small regenerative nodes are formed. WRG may be the cause of portal hypertension of non-cirrhotic origin. The diagnosis of URG should be confirmed by the results of histological analysis.

    Diagnostic UGG should be performed in all patients with clinical symptoms of portal hypertension and / or computerized tomography of the liver, indicating the development of cirrhosis, with normal activity of aminotransferases and the absence of other manifestations of cirrhosis. Therapy with Cadsil® should be completely discontinued if the patient is diagnosed with URH.

    Left ventricular dysfunction

    On the background of therapy with Kadsila®, the risk of developing left ventricular dysfunction increases. The cases of LVEF <40% were registered, which indicates a possible risk

    development of symptomatic congestive heart failure. Risk factors for the development of cardiological adverse events identified in clinical studies of trastuzumab in adjuvant therapy were: age> 50 years, low LVEF before treatment (<55%), low LVEF value before or after adjuvant treatment with paclitaxel, previous or simultaneous use of antihypertensive drugs, prior anthracycline therapy and high body mass index (> 25 kg / m2).

    Before the appointment of the drug Kadsila®, as well as during therapy with the recommended

    my frequency of 1 every 3 months should be a standard cardiac examination, including echocardiography or radioisotope ventriculography.

    The efficacy and safety of Cadsil® treatment in patients with LVEF <50% before prescribing therapy, with chronic heart failure in the anamnesis were not studied; dyspnea at rest, caused by the progression of a malignant disease andjland concomitant pathology; with serious heart rhythm disorders requiring drug therapy; with myocardial infarction or unstable angina that developed within 6 months before the start of treatment.

    In the case of developing left ventricular dysfunction, the administration of the KadSil® drug should be postponed or the therapy should be completely canceled. Recommendations for dose reduction

    or temporary discontinuation of therapy with Cadsil® is given in the section "Method of administration and dose".

    Infusion reactions

    In patients whose previous therapy with trastuzumab had to be completely discontinued due to the development of infusion reactions, the safety and efficacy of the Kadsila® preparation were not established.

    During treatment with Cadsil®, especially during the first infusion, the patient should be closely monitored for the development of infusion reactions. Infusion reactions were manifested by one or more symptoms: "hot flashes", chills, fever, shortness of breath, arterial hypotension, wheezing,

    bronchospasm and tachycardia. On average, the observed infusion reactions were not severe and in most cases the symptoms were resolved within a few hours

    or 1 day after the end of the infusion. With the development of a clinically significant reaction to infusion, therapy with Cadsil® should be discontinued until the symptoms are completely resolved.

    When reopening of the drug should be carefully monitored by the patient. The decision to resume therapy in patients with severe infusion reactions should be made taking into account the clinical evaluation of the degree of severity of the observed reaction. If a life-threatening infusion reaction occurs, treatment with Cadsil® should be discontinued.

    Reactions hypersensitivity

    In patients in whom previous therapy with trastuzumab had to be completely discontinued due to the development of reactionshypersensitivity, safety and efficacy of Cadsil® are not established.

    During treatment with Cadsil®, patients should be closely monitored for the development of hypersensitivity reactions / allergic reactions, the clinical manifestations of which may be similar to the clinical manifestations of infusion reactions.

    Serious anaphylactic reactions have been reported. Drugs to treat the symptoms of these reactions, as well as equipment for emergency care should be available for immediate use. The decision to continue therapy should be taken in consideration of the clinical evaluation of the observed reaction: in the case of a true hypersensitivity reaction (characterized by an increase in severity with subsequent infusions), therapy with Kadsila® should be completely abolished.

    Thrombocytopenin

    There have been reports of frequent cases of a decrease in the number of platelets in the use of prthe product Cadsil®. Thrombocytopenia was the most common cause of discontinuation of therapy.

    Cases of bleeding with a lethal outcome on the background of therapy with Kadsila®, as well as severe cases of bleeding, in particular, intracranial hemorrhage, have been reported; the frequency of cases does not depend on ethnicity.Part of patients who had severe cases of bleeding received concomitant therapy with anticoagulants.

    During treatment, patients with platelet counts <100,000 / mm should be carefully monitored3, as well as for patients receiving anticoagulant treatment (for example, warfarin, heparin, including low molecular weight heparins

    us). It is recommended to evaluate the number of platelets before each administration of Cadsil®. Effectiveness and safety of therapy with Cadsil® in patients with platelet count <100,000 / mm3 before the appointment of therapy is not established. In the case of development of thrombocytopenia 3 and more severity (<50000 / mm3) therapy Kadsila® should be discontinued until the symptoms are resolved and the condition is reached, corresponding to the 1-st degree of severity (>75000 / mm3).

    Neurotoxicity

    Cases of peripheral neuropathy have been reported, most of which had a 1 st degree of severity.

    In most cases, peripheral sensory neuropathy was observed. The efficacy and safety of Cadsil® has not been studied in patients with peripheral neuropathy >3 degrees of severity at the time of prescribing. Treatment with drug

    Cadsil® should be discontinued if peripheral neuropathy of grade 3 or 4 is developed

    severity to complete resolution of symptoms and achievement of a condition corresponding to severity. It is necessary to conduct regular medical examination for the development of signs or symptoms of neurotoxicity.

    The general state index (PS) on the scale of the Eastern Cooperative Oncology groups (ECOG) >2

    The efficacy and safety of the use of Cadsil® in patients with ECOG PS > 2 Because of insufficient data.

    Instructions for the disposal of an unused product or expired.

    The entry of the medicinal product of KadSil® into the environment must be

    is reduced to a minimum. Do not dispose of the product with sewage or with household waste. Destruction of an unused preparation or product with 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 trastuzumab emtanzine on the ability to drive and work with machinery has not been studied.With the development of some unwanted reactions, in particular, dizziness, insomnia, increased fatigue and blurred vision, as well as infusion reactions, one should refrain from managing vehicles and mechanisms.
    Form release / dosage:Liofilizate for the preparation of concentrate for the preparation of a solution for infusions of 100 mg and 160 mg.
    Packaging:For 100 mg or 160 mg trastuzumab emtanzine in a bottle of colorless glass (hydrolytic class 1 EF), sealed with a stopper 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.
    Storage conditions:Store at 2-8 ° C. Keep out of the reach of children.
    Shelf life:
    3 years. Do not use after the expiry date stated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002692
    Date of registration:31.10.2014
    Date of cancellation:2019-10-31
    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: & nbsp01.10.2015
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