Кадсила®

General characteristics. Structure:

Active ingredient: 100,0 mg or 160,0 mg of a trastuzumab of an emtanzin.

Excipients: sucrose, succinic acid, sodium hydroxide, polysorbate 20.

The drug Kadsila® is used in the form of monotherapy after the previous chemotherapy including трастузумаб and drugs from group of taxons (it is consecutive or in a combination), or after progressing of a disease in time or within 6 months after completion of the adjuvant therapy including трастузумаб and drugs from group of taxons (it is consecutive or in a combination), at patients with an inoperable locally-spread or metastatic HER2 positive breast cancer.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Trastuzumab эмтанзин represents a conjugate of the humanized monoclone (IgG1) to a receptor of a human epidermal growth factor 2 HER2 types (трастузумаб) and inhibitor of polymerization of a tubulin of DM1 (derivative a meytanzina) connected with each other by means of a stable thioradio linker of MCC (4 (N-maliyenimidometil) cyclohexane - 1 - carboxylat). Emtanzin represents the DM1-MCC complex.

The average quantity of the molecules DM1 conjugated with each molecule of a trastuzumab makes 3.5.

Trastuzumab эмтанзин selectively interacts with a receptor of a human epidermal growth factor 2 types (HER2).

After linkng with HER2 трастузумаб эмтанзин gets in a cell and is exposed to proteolytic degradation in lysosomes that leads to release of the DM1 containing cytotoxic catabolits (mainly, a complex a lysine - MCC - DM1). Thus, conjugation of DM1 with trastuzumaby causes selectivity of cytotoxic drug concerning tumor cells with a hyper expression of HER2 and facilitates delivery of DM1 in tumor cells.

The mechanism of action of a trastuzumab of an emtanzin is a combination of mechanisms of action of a trastuzumab and DM1.

Trastuzumab эмтанзин, as well as трастузумаб, contacts the domain IV of the extracellular HER2 domain, and also receptors of Fcγ and protein of a complement of C1q. Trastuzumab эмтанзин, like a trastuzumab, prevents "exfoliating" of the extracellular HER2 domain from a cell surface, inhibits transfer of an intracellular signal on the way of a phosphatidylinositol-3-kinase (PI3-K), and also promotes activation of antitelozavisimy cell-mediated cytotoxicity (ADCC) in cells of a breast cancer of the person with HER2 hyper expression.

DM1, cytotoxic component of a trastuzumab of an emtanzin, communicates with tubuliny and suppresses its polymerization. Thanks to action of a cytotoxic component трастузумаб эмтанзин, as well as DM1, causes blockade of a cellular cycle in the phase G2/M that as a result leads to apoptosis. Results of a research of cytotoxicity of DM1 in vitro showed that activity of DM1 by 20-200 times exceeds activity of taxons and alkaloids of a periwinkle.

The structure of a linker of MCC allows to limit system release of DM1 and promotes its directed delivery in cells that is confirmed by very low maintenance of free DM1 in a blood plasma.

The safety given preclinical studying. Mutagenicity. Preclinical trials demonstrate existence at a trastuzumab of an emtanzin of aneugenny and/or clastogene toxicity.

Teratogenecity. There are data on embriotoksichesky action of a trastuzumab and on potential teratogenic and embriotoksichesky action of DM1.

Influence on fertility. Results of preclinical trials demonstrate risk of disturbances of fertility at use of a trastuzumab of an emtanzin.

Pharmacokinetics. Absorption. Trastuzumab эмтанзин is entered intravenously. Other ways of administration of drug were not studied.

Distribution. The pharmacokinetics of a trastuzumab of an emtanzin at intravenous administration in doses of 2.4-4.8 mg/kg has each 3 weeks linear character. At the patients receiving the doses equal to 1.2 mg/kg or less higher clearance of drug was noted.

Average maximum concentration of a trastuzumab of an emtanzin in blood serum (Смакс) makes 83.4 (±16.5) mkg/ml at intravenous administration of drug in a dose of 3.6 mg/kg each three weeks. After intravenous administration the volume of distribution of a trastuzumab of an emtanzin in the central camera makes 3.13 l and is approximately equal to plasma volume.

Metabolism. In researches on microsomes of a liver of the person of in vitro it is shown that DM1, the low-molecular component of a trastuzumab of an emtanzin, is mainly metabolized by an isoenzyme of CYP3A4 and to a lesser extent CYP3A5 isoenzyme.

DM1 is not inhibitor of the main isoenzymes of family of CYP450 in vitro cytochrome. Catabolits of a trastuzumab of an emtanzin, Lys-MCC-DM1, MCC-DM1 and DM1 are found in plasma of the person in low concentration. According to the research in vitro DM1 is P glycoprotein substrate.

Removal. After intravenous administration of a trastuzumab of an emtanzin at patients with a metastatic breast cancer with HER2 hyper expression the clearance of a trastuzumab of an emtanzin made 0.68 l/day, an elimination half-life (t1/2) – about 4 days. After repeated intravenous administration each 3 weeks of accumulation of a trastuzumab of an emtanzin it was not observed.

The body weight, concentration of albumine in blood serum, the sum of the largest diameters of the centers of a tumor by criterion of RECIST (Criteria for evaluation of the answer at solid tumors – Response Evaluation Criteria in Solid Tumors), initial concentration of the "chipped-off" extracellular domain (ECD) HER2, initial concentration of a trastuzumab and initial activity of aspartate aminotransferase (nuclear heating plant) in blood serum are the parameters exerting statistically significant impact on clearance of a trastuzumab of an emtanzin. However clinically significant influence of these parameters, except for body weight, on exposure of a trastuzumab of an emtanzin is improbable. 

Catabolits of a trastuzumab of an emtanzin, in particular, DM1, by Lys-MCC-DM1 and MCC-DM1 are generally removed with bile and in the minimum degree with urine. 

Pharmacokinetics at special groups of patients. Race and floor. Race does not influence pharmacokinetics of a trastuzumab of an emtanzin. Influence of a floor on drug Kadsila® pharmacokinetics separately was not studied.

Advanced and senile age. The age does not exert impact on pharmacokinetics of a trastuzumab of an emtanzin. Significant differences in pharmacokinetics of a trastuzumab of an emtanzin at patients aged were not noted <65 years, from 65 to 75 years and 75 years are more senior.

Renal failure. According to the population pharmacokinetic analysis the clearance of creatinine does not influence pharmacokinetics of a trastuzumab of an emtanzin. Values of pharmacokinetic parameters of a trastuzumab of an emtanzin at patients with easy (the clearance of creatinine (CC) of 60-89 ml/min.) and average (KK of 30-59 ml/min.) degree of a renal failure are similar to those at patients with normal function of kidneys (KK of ≥90 ml/min.). Data on pharmacokinetics at patients with a heavy and terminal renal failure (KK <30 ml/min.) are limited therefore it is not possible to give special instructions on dosing.

Abnormal liver functions. Special researches of pharmacokinetics at patients with abnormal liver functions were not conducted.

Indications to use:

Metastatic breast cancer. The drug Kadsila® is used in the form of monotherapy after the previous chemotherapy including трастузумаб and drugs from group of taxons (it is consecutive or in a combination), or after progressing of a disease in time or within 6 months after completion of the adjuvant therapy including трастузумаб and drugs from group of taxons (it is consecutive or in a combination), at patients with an inoperable locally-spread or metastatic HER2 positive breast cancer.

Route of administration and doses:

Before use of medicine it is necessary to check the label on a bottle and to be convinced that the drug used for preparation and introduction represents the drug Kadsila® (трастузумаб эмтанзин), but not the drug Gertseptin® (трастузумаб).

Use of the drug Kadsila® has to be carried out only under observation of the doctor having experience of treatment of oncological diseases.

It is necessary to hold testing for a tumoral expression of HER2 before an initiation of treatment the drug Kadsila®. Obligatory criterion are 3+ points by results of the immunohistochemical analysis (IHC) and/or extent of amplification ≥2.0 by results of hybridization of in situ (ISH). The used methods of testing have to be validirovana.

It is necessary to specify the trade name of drug (Кадсила®) in medical documentation of the patient. Replacement of the drug Kadsila® by other drug of a biological origin has to be coordinated with the attending physician.

Dosing mode. The recommended dose of the drug Kadsila® makes 3.6 mg/kg of body weight of 1 times in 3 weeks (a 21-day cycle) in the form of intravenous drop infusion.

Therapy by the drug Kadsila® should be continued before emergence of signs of progressing of a disease or unacceptable toxicity.

The first dose is recommended to be entered in the form of 90-minute intravenous drop infusion.

Observation of the patient is necessary during the first infusion and, at least, within 90 minutes after its termination regarding emergence of fever, a fever or other infusional reactions. Careful survey of an injection site of drug regarding possible formation of hypodermic infiltrates is also necessary.

If the previous infusion was transferred well, then the following infusions can be carried out within 30 minutes, continuing observation of the patient within at least 30 minutes after the end of infusion. 

It is necessary to reduce the speed of infusion or for a while to stop administration of the drug Kadsila® at emergence in the patient of signs of infusional reaction.

In case of life-threatening infusional reaction therapy by the drug Kadsila® should be stopped completely.

Medicines for therapy of possible infusional reactions of allergic/anaphylactic type, and also the equipment for rendering acute management have to be available to immediate use.

The admission in planned introduction. At the admission in planned administration of the drug Kadsila® it is necessary to administer the drug in the recommended dose as soon as possible, at the same time the speed of infusion can be the same at which the previous infusion well was transferred by the patient. It is not necessary to wait for the following planned cycle. The schedule of administrations of drug has to be corrected for the purpose of maintenance of a 3 weeks interval between introductions.

Dose adjustment. Possible measures for elimination of symptoms of undesirable reactions are the dose decline, a temporary break in treatment or complete cessation of therapy by the drug Kadsila®. The corresponding recommendations are given below in Tables 1-5. If the dose of the drug Kadsila® had to be lowered, then at the subsequent introductions it is impossible to increase it.

 Table 1. Scheme of a dose decline of the drug Kadsila®

Rules of a dose decline (initial dose of 3.6 mg/kg)	The recommended dose
1st dose decline	3 mg/kg
2nd dose decline	2.4 mg/kg
Need of a further dose decline	To completely stop therapy

 

Table 2. Recommendations about dose adjustment ^{of the drug Kadsila®} at increase in activity of hepatic aminotransferases (aspartate aminotransferase (nuclear heating plant) / alaninaminotranspherase (ALT)) in blood serum

Degree 2 (from> 2.5 to ≤5 x VGN *)	Degree 3 (from> 5 to ≤20 x VGN)	Degree 4 (> 20 x VGN)
Dose adjustment of the drug Kadsila® is not required.	To interrupt therapy with the drug Kadsila® before decrease in toxicity to the ≤2nd degree, then to lower a dose (see table 1).	To completely stop therapy by the drug Kadsila®.

* VGN = upper bound of norm

Table 3. Recommendations about dose adjustment ^{of the drug Kadsila®} at a hyperbilirubinemia

Degree 2 (from> 1.5 to ≤3 x VGN)	Degree 3 (from> 3 to ≤10 x VGN)	Degree 4 (> 10 x VGN)
To interrupt therapy with the drug Kadsila® before decrease in toxicity to ≤1 degree, then to resume treatment in the same dose.	To interrupt therapy with the drug Kadsila® before decrease in toxicity to ≤1 degree, then to lower a dose (see table 1).	To completely stop therapy by the drug Kadsila®.

Therapy ^{by the drug Kadsila®} should be stopped completely if activity of hepatic aminotransferases in blood serum makes> 3 x VGN at the general bilirubin> 2 x VGN, and also in case of development of a nodal regenerative hyperplasia.

Table 4. Recommendations about dose adjustment ^{of the drug Kadsila®} at thrombocytopenia

Degree 3	Degree 4
from 25000 to <50000/mm3	<25000/mm3
To interrupt therapy with the drug Kadsila® before decrease in toxicity to £1 of degree (to 75000/mm3) and to resume treatment in the same dose.	To interrupt therapy with the drug Kadsila® before decrease in toxicity to £1 of degree (to 75000/mm3), then to lower a dose (see table 1).

Table 5. Recommendations about dose adjustment ^{of the drug Kadsila®} at dysfunction of a left ventricle

Symptomatic congestive heart failure	FVLZH * <40%	FVLZH OF 40%-45%		FVLZH> 45%
		decrease in ≥10% in comparison with a reference value	decrease <10% in comparison with a reference value
To completely stop therapy by the drug Kadsila®.	To interrupt therapy with the drug Kadsila®.	To interrupt therapy with the drug Kadsila®.	To continue therapy by the drug Kadsila®.	To continue therapy by the drug Kadsila®.
	To carry out repeated assessment of FVLZh in 3 weeks. At repeated definition of FVLZh <40% completely to stop therapy.	To carry out repeated assessment of FVLZh in 3 weeks. If FVLZh was not recovered to values within 10% in comparison with a reference value, it is necessary to stop completely treatment by the drug Kadsila®.	To carry out repeated assessment of FVLZh in 3 weeks.

* FVLZh - fraction of emission of a left ventricle

Therapy ^{by the drug Kadsila®} should be stopped completely if the intersticial pulmonary disease or a pneumonitis is diagnosed for the patient.

At development of peripheral neuropathy 3 and 4 severity therapy ^{by the drug Kadsila®} should be interrupted to permission of symptoms to level ≤2 degrees.

Correction of an initial dose ^{of the drug Kadsila®} at the age of ≥65 years is not required from patients. Efficiency and safety of use ^{of the drug Kadsila®} for patients at the age of ≥75 years are not established in view of the insufficient number of data.

Children. Efficiency and safety ^{of the drug Kadsila®} at children are not established.

Renal failure. Correction of an initial dose with a renal failure easy (KK of 60-89 ml/min.) and average (KK of 30-59 ml/min.) is not required to severity from patients. Need of dose adjustment at patients with a heavy and terminal renal failure (KK <30 ml/min.) is not established. 

Abnormal liver function. Efficiency and safety ^{of the drug Kadsila®} at patients with an abnormal liver function were not studied.

Preparation for introduction. ^{The drug Kadsila®} is administered only intravenously kapelno! To administer the drug intravenously struyno or it is bolyusno impossible!

Dissolution and cultivation ^{of the drug Kadsila®} has to be carried out by highly skilled medical personnel.

Preparation of drug for introduction has to be carried out in aseptic conditions with observance of appropriate rules of preparation of chemotherapeutic drugs.

Attention! ^{The drug Kadsila®} is incompatible from 5% dextrose solution because of a possibility of aggregation of protein.

^{The drug Kadsila®} cannot be mixed or dissolved together with other medicines.

Solution ^{of the drug Kadsila®} is compatible to the infusional packages made of the polyvinylchloride (PVC) or polyolefin (which is not containing PVC or latex).

When performing infusion with use of 0.9% of solution of sodium of chloride  use of infusional system with the built-in infusional filter from polyethersulphone (PES) with a diameter of time of 0.22 microns is obligatory.

In case of use of 0.45% of solution of sodium of chloride use of the built-in infusional filter from polyethersulphone with a diameter of time of 0.22 microns is not required.

Solution ^{of the drug Kadsila®} does not contain preservatives and is intended for disposable.

The instruction for preparation of a concentrate (the recovered solution) for preparation of solution for infusions

1.     The sterile syringe slowly to enter 5 ml of sterile water for injections into the bottle containing 100 mg of a trastuzumab of an emtanzin, or 8 ml of sterile water for injections in the bottle containing 160 mg of a trastuzumab of an emtanzin. Concentration of the turned-out solution has to make 20 mg/ml.

2.     To accurately shake a bottle rotary motions before full dissolution of lyophilisate. Not to stir up!

Before use the concentrate received after lyophilisate dissolution needs to be checked visually regarding lack of foreign particulates, discoloration or opacification. The concentrate has to be transparent or slightly opalescent, without visible particles, colourless or with a brownish shade. It is impossible to use a concentrate if it contains visible particles, at its opacification or change of coloring.      

The concentrate for preparation of solution for infusions should be used right after lyophilisate dissolution. Storage of a concentrate during 24 h at a temperature of 2-8 °C is allowed provided that dissolution took place in controlled and validirovanny aseptic conditions.

Not to freeze! If after this term the concentrate is not used, it should be utilized.

Instructions for preparation of solution for infusion:

1.     To define a required dose (mg/kg) ^{of the drug Kadsila®}.

2.     To determine concentrate volume for preparation of solution for infusions, necessary for introduction of a required dose ^{of the drug Kadsila®}, by the following formula:

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

The volume (ml) =----------------------------------------------------------------------

          20 (mg/ml) (concentration of the recovered solution)

3.     To select necessary volume from a bottle with a concentrate and to enter it into an infusional package from the polyvinylchloride (PVC) or polyolefin (which is not containing PVC or latex) from 250 ml of 0.45% or 0.9% of solution of sodium of chloride.

4.     To carefully turn an infusional package for solution hashing. Not to stir up!

Solution for infusion should be used right after preparation. In exceptional cases solution for infusion can be stored in the refrigerator at a temperature of 2-8 °C no more than 24 watch before use if preparation of solution took place in controlled and validirovanny aseptic conditions. In storage time of the solution for infusion prepared with use of 0.9% of solution of sodium of chloride formation of visible particles is allowed. Not to freeze!

Features of use:

The drug Kadsila® has to be appointed only in the presence of the tumoral hyper expression of protein HER2 determined by method of immunohistochemical reaction (IGH), or gene amplification of HER2 determined by method of hybridization of in situ (FISH or SISH).

Disturbances from lungs. At use of the drug Kadsila® cases of the diffusion intersticial pulmonary disease (IPD), in particular, of a pneumonitis are registered. Some of them led to development acute respiratory a distress syndrome or by a lethal outcome. Symptoms of IBL include short wind, cough, increased fatigue and infiltrates in lungs. Therapy by the drug Kadsila® should be stopped completely if the diffusion intersticial pulmonary disease or a pneumonitis is diagnosed.
At patients with the asthma at rest caused by progressing of a malignant disease or the accompanying pathology, the risk of development of disturbances from lungs is increased.

Hepatotoxic. A hepatotoxic of the drug Kadsila® was generally shown in asymptomatic increase in activity of aminotransferases 1-4 degrees of which the effect of accumulation is characteristic.

Also cases of serious gepatobiliarny violations, in particular, of a nodal regenerative hyperplasia of a liver, and also the fatal medicinal induced damage of a liver are noted. Associated diseases, and also simultaneous use of drugs with the established risk of toxic impact on a liver are possible accessory factors of risk. It is necessary to estimate function of a liver before therapy, and also before each subsequent administration of the drug Kadsila®.

At patients with the increased activity of ALT before an initiation of treatment (for example, in the presence of metastasises in a liver), the risk of development of a hepatotoxic 3-5 severity or increases in indicators of function of a liver is increased. Recommendations concerning a dose decline or the temporary termination of therapy owing to increase in activity hepatic аминотраснфераз and contents of the general bilirubin are provided in the section "Route of Administration and Doses".

Efficiency and safety of the drug Kadsila® are not studied at patients with activity аминотраснфераз> 2.5×ВГН or concentration of the general bilirubin> 1.5×ВГН before an initiation of treatment.

Therapy by the drug Kadsila® should be stopped completely in case of increase in activity of aminotransferases in blood serum> 3×ВГН at the general bilirubin> 2×ВГН.

Nodal regenerative hyperplasia of a liver (URG) – a rare disease of a liver at which as a result of high-quality transformation of a parenchyma in a liver multiple small regenerator nodes are formed. URG can be the cause of portal hypertensia of not cirrhotic genesis. The diagnosis of URG has to be confirmed with results of the histologic analysis.
Diagnosis of URG has to be carried out at all patients with clinical symptoms of portal hypertensia and/or given to a computer tomography of a liver, testimonial of development of cirrhosis, at normal activity of aminotransferases and lack of other displays of cirrhosis. Therapy by the drug Kadsila® should be stopped completely if URG is diagnosed for the patient.

Cardiotoxicity. Against the background of therapy by the drug Kadsila® the risk of development of dysfunction of a left ventricle increases. FVLZh cases were registered <40% that demonstrates possible risk of development of symptomatic congestive heart failure.

Risk factors of development of the cardiological undesirable phenomena are age> 50 years, the FVLZh low value before an initiation of treatment (<55%), the FVLZh low value to or after adjuvant therapy paklitaksely, the previous or simultaneous use of hypotensive drugs, the previous therapy anthracyclines and a high index of body weight (> 25 kg/sq.m).

Before purpose of the drug Kadsila®, and also throughout therapy with the recommended frequency of 1 time of 3 months it is necessary to conduct standard cardiological examination, including an echocardiography or a radio isotope ventrikulografiya.

Efficiency and safety of treatment by the drug Kadsila® at patients with FVLZh <50% before purpose of therapy, with chronic heart failure in the anamnesis were not studied; the asthma at rest caused by progressing of a malignant disease or the accompanying pathology; at the serious violations of a cordial rhythm demanding medicinal therapy; with a myocardial infarction or unstable stenocardia which developed within 6 months prior to treatment.

In case of development of dysfunction of a left ventricle it is necessary to postpone administration of the drug Kadsila® or to completely cancel therapy. Recommendations concerning a dose decline or the temporary termination of therapy by the drug Kadsila® are provided in the section "Route of Administration and Doses".

Infusional reactions. At patients at whom the previous therapy trastuzumaby had to be stopped completely because of development of infusional reactions safety and efficiency of the drug Kadsila® are not established.

During treatment by the drug Kadsila®, in particular during the first infusion, it is necessary to watch carefully the patient regarding development of infusional reactions.

Infusional reactions were shown by one or several symptoms: "inflows", fever, fervescence, short wind, arterial hypotension, rattles, bronchospasm and tachycardia. On average the observed infusional reactions were not heavy and in most cases symptoms were resolved within several hours or the 1st day after the end of infusion. At development of clinically significant reaction to infusion therapy by the drug Kadsila® should be interrupted to full permission of symptoms.

When resuming administration of drug it is necessary to watch the patient attentively. The decision on resuming of therapy at patients with heavy infusional reactions should be made taking into account clinical assessment of severity of the observed reaction. At emergence of infusional reaction, life-threatening, treatment by the drug Kadsila® should be cancelled completely.

Hypersensitivity reactions. At patients at whom the previous therapy trastuzumaby had to be stopped completely because of development of reactions of hypersensitivity safety and efficiency of the drug Kadsila® are not established.

During treatment by the drug Kadsila® it is necessary to watch carefully the patient regarding development of reactions of hypersensitivity / allergic reactions which clinical manifestations can be similar to clinical manifestations of infusional reactions.

It was reported about serious anaphylactic reactions. Drugs for treatment of symptoms of these reactions, and also the equipment for rendering acute management have to be available to immediate use. The decision on continuation of therapy should be made taking into account clinical assessment of the observed reaction: in case of true reaction of hypersensitivity (increase in severity at the subsequent infusions is characteristic) therapy by the drug Kadsila® should be cancelled completely.

Thrombocytopenia. It was reported about frequent cases of decrease in quantity of thrombocytes at drug Kadsila® use. Thrombocytopenia was the most frequent reason of the termination of therapy.

Cases of bleedings with a lethal outcome against the background of therapy by the drug Kadsila®, and also hard cases of bleedings, in particular, intracraneal hemorrhage are registered; frequency of cases does not depend on an ethnic origin. A part of patients at whom hard cases of bleedings were registered received the accompanying therapy by anticoagulants. 

During treatment it is necessary to watch carefully patients at whom the quantity of thrombocytes makes <100000/mm3, and also for the patients receiving treatment by anticoagulants (for example, warfarin, heparin, including low-molecular heparins). It is recommended to estimate quantity of thrombocytes before each administration of the drug Kadsila®. Efficiency and safety of therapy by the drug Kadsila® at patients with quantity of thrombocytes <100000/mm3 before purpose of therapy are not established. In case of development of thrombocytopenia 3 and more severity (<50000/mm3) therapy by the drug Kadsila® should be interrupted to permission of symptoms and achievement of the state corresponding to the 1st severity (75000/mm3).

Neurotoxicity. Cases of peripheral neuropathy, the majority of which had the 1st severity, are registered.

Peripheral touch neuropathy was in most cases observed. Efficiency and safety of the drug Kadsila® are not studied at patients with peripheral neuropathy ≥3 severity at the time of purpose of drug. Treatment by the drug Kadsila® should be interrupted in case of development of peripheral neuropathy 3 or 4 severity to full permission of symptoms and achievement of a state corresponding ≤2 severity. It is necessary to perform regular medical examination regarding development of signs or symptoms of a neurotoxicity.

Indicator of the general state (PS) on a scale of East cooperative oncological group (ECOG) ≥2. Efficiency and safety of use of the drug Kadsila® for patients with ECOG PS ≥2 are not established in view of the insufficient number of data.

Instructions for destruction of unused drug or expired.

Hit of Kadsila® medicine to the environment has to be minimized. It is not necessary to utilize drug by means of sewage or together with household waste. Destruction of unused drug or drug expired has to be carried out according to requirements of medical institution.

Influence on ability to manage vehicles and mechanisms. Influence of a trastuzumab of an emtanzin on ability to drive the car and to work with mechanisms was not studied. At development of some undesirable reactions, in particular, of dizziness, sleeplessnesses, increased fatigue and misting of sight, and also infusional reactions, it is necessary to refrain from control of vehicles and mechanisms.

The women having breeding potential, male patients and also women of childbearing age who are sexual partners of the patients receiving the drug Kadsila® have to use effective methods of contraception during treatment by the drug Kadsila® and within 6 months after introduction of the last dose.

In case of pregnancy approach the patient has to see a doctor immediately. It is necessary to warn the woman about a possibility of harmful effects on a fruit. If the pregnant woman decides to continue therapy by the drug Kadsila®, then it has to be under careful observation of doctors.

It is unknown whether gets трастузумаб эмтанзин into breast milk. Breastfeeding is not recommended during treatment and at least within 6 months after the end of therapy by the drug Kadsila®.

Side effects:

The most frequent serious undesirable reactions are fervescence, thrombocytopenia, vomiting, abdominal pains, nausea, a lock, diarrhea, short wind and a pneumonitis.

The most frequent (≥25%) undesirable reactions are bleedings (including nasal bleeding), increase in activity of hepatic aminotransferases, increased fatigue, musculoskeletal pain, a headache. The majority of the observed undesirable reactions were 1 or 2 severity.

The most frequent (> 2%) undesirable reactions 3 and 4 severity according to criteria of toxicity on a scale of National institute of cancer (NCI CTC AE), version 3.0, are thrombocytopenia, increased fatigue, increase in activity of hepatic aminotransferases, anemia, a hypopotassemia, musculoskeletal pains and a neutropenia.

In this section undesirable reactions are grouped according to classes of systems of bodies of the medical dictionary for normative and legal activity of MedDRA.

For the description of frequency of undesirable reactions the following classification is used: very frequent (≥1/10), frequent (≥1/100 and <1/10), infrequent (≥1/1000 and <1/100) rare (≥1/10000 and <1/1000) and very rare (<1/10000), including isolated cases. Undesirable reactions of each group are located as reduction of the severity determined according to criteria of toxicity by a scale of National institute of cancer (NCI CTC AE), version 3.0.

Disturbances from system of blood and lymphatic system: very often – thrombocytopenia, anemia; often – a neutropenia, a leukopenia.

Disturbances from immune system: often – medicinal hypersensitivity.

Disbolism and food: very often – a hypopotassemia.

Disturbances of mentality: very often – sleeplessness.

Disturbances from a nervous system: very often – peripheral neuropathy, a headache, dizziness; often – disturbance of flavoring feelings (dysgeusia), memory disturbances.

Disturbances from an organ of sight: often – a xerophthalmus, conjunctivitis, sight misting, the raised slezootdeleniye.

Disturbances from heart: often – dysfunction of a left ventricle.

Disturbances from vessels: very often – bleedings; often – increase in arterial pressure.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often – nasal bleeding, cough, an asthma; infrequently – a pneumonitis.

Disturbances from digestive tract: very often – stomatitis, diarrhea, vomiting, nausea, a lock, dryness in a mouth, an abdominal pain; often – dyspepsia, bleeding of gums.

Disturbances from a liver and biliary tract: infrequently – the hepatotoxic phenomena, a liver failure, a nodal regenerative hyperplasia, portal hypertensia.

Disturbances from skin and hypodermic fabrics: very often – rash; often – an itch, an alopecia, disturbance of structure of nails, a palmar and bottom eritrodizesteziya, a small tortoiseshell.

Disturbances from skeletal and muscular and connecting fabric: very often – musculoskeletal pain, an arthralgia, a mialgiya.

Disturbances from kidneys and urinary tract: very often – infections of urinary tract.

The general frustration and disturbances in an injection site: very often – increased fatigue, fervescence, an adynamy, a fever; often – peripheral hypostases; infrequently – an ekstravazation in the place of infusion.

Laboratory and tool data: very often – increase in activity of hepatic aminotransferases; often – Yopovysheny activities of an alkaline phosphatase in blood.

Injuries, intoxications and complications of manipulations: often – infusional reactions.

Below information on separate undesirable reactions is provided. Increase in activity of hepatic aminotransferases (AST/ALT). The activities of aminotransferases observed against the background of drug Kadsila® use increase 1-4 severity and effect of accumulation of aminotransferases in blood serum in most cases were reversible.
Activity of aminotransferases as much as possible increased for the 8th day after infusion, and was, as a rule, recovered to 1 degree or to norm by the time of the following infusion. This indicator was in most cases recovered to 1 degree or to norm within 30 days after the therapy termination. 

Increase in activity of hepatic aminotransferases was observed at 28% of the patients receiving therapy by the drug Kadsila®.

Increase in activity of nuclear heating plant and ALT 3 and 4 of severity was observed at 4.1% and 2.8% of patients respectively and, as a rule, there were therapies in the beginning (on 1-6 cycle).

As a rule, abnormal liver functions ≥3 severity were not associated with a failure, and indicators of function of a liver at the subsequent observation demonstrated gradual improvement of a condition of the patient to the level allowing to continue therapy by the drug Kadsila® in the recommended or reduced dose.

Natural dependence of increase in activity of aminotransferases in blood serum from exposure (AUC, the area under a curve "concentration time"), total exposure, the maximum concentration (Smaks) of a trastuzumab of an emtanzin in blood serum or from Smaks DM1 was not observed.

Dysfunction of a left ventricle of heart. Frequency of cases of dysfunction of a left ventricle against the background of therapy by the drug Kadsila® made 2%. Asymptomatic decrease in fraction of emission of a left ventricle 1 or 2 degrees was in most cases observed. Cases of dysfunction of a left ventricle 3 or 4 severity were observed with a frequency of 0.3%, as a rule, in an initiation of treatment (on 1-2 cycle).

Additional monitoring of fraction of emission of a left ventricle is recommended at patients with FVLZh of ≤45%.

Infusional reactions. Infusional reactions (release of cytokines) are characterized by one or several of the following symptoms: "inflows", fever, fervescence, short wind, arterial hypotension, rattles, bronchospasm and tachycardia.

Frequency of infusional reactions at use of the drug Kadsila® made 4.5%. Infusional reactions 3 severity were observed very seldom, cases 4 severity are noted.

Time of permission of symptoms of infusional reactions made, as a rule, from several hours to 1 day after the end of infusion.

Dependence of frequency of development of infusional reactions on a dose was not observed.

Reactions of a hypersensitivity/anaphylaxis. Frequency of reactions of hypersensitivity made 2.6%, at the same time hypersensitivity reactions 3 and 4 severity is not registered. In most cases reactions of hypersensitivity were easy and moderate severity and were allowed after the corresponding treatment.

Thrombocytopenia. Frequency of cases of thrombocytopenia (decrease in quantity of thrombocytes) at therapy by the drug Kadsila® made 31.4%.

The most part of cases of thrombocytopenia was 1 or 2 severity (number of thrombocytes 50000/mm3), at the same time the lowest maintenance of thrombocytes was observed for the 8th day after administration of drug. In the next days this indicator increased and reached 0 or 1 severity (75000/mm3) by the time of the following administration of the drug Kadsila®. Higher frequency and severity of cases of thrombocytopenia at patients – natives of the countries of Asia was noted. Irrespective of race the frequency of cases of thrombocytopenia 3 and 4 degrees (<50000/mm3) against the background of therapy by the drug Kadsila® made 11.3%.

Frequency of heavy bleedings (≥3 severity) made 1.7%. At patients – natives of the countries of Asia this indicator made 1%.

Immunogenicity. Development of an immune response on трастузумаб эмтанзин is possible.

At use of the drug Kadsila® for 5.3% of patients antibodies to a trustuzumab to an emtanzin in one and more temporary points after administration of drug were found. The clinical importance of antibody formation to a trastuzumab is not established to an emtanzin.

Ekstravazation. At use of the drug Kadsila® the reactions connected with hit of drug under skin were observed and morbidities, irritations of skin, pain or hypostasis in an injection site were shown in the form of an erythema.

These phenomena most often arose within the first 24 hours after infusion and usually were easy severity.

When performing infusion of the drug Kadsila® it is necessary to monitor possible formation of hypodermic infiltrates in an injection site. Specific treatment of symptoms of an ekstravazation of the drug Kadsila® is absent.

Changes in laboratory indicators. Table 6. The separate disturbances of laboratory indicators observed at ^{drug Kadsila®} use

	All severity %	Severity 3  %	Severity 4 %
Indicators of function of a liver
Increase in concentration of bilirubin	20	<1	0
Increase in activity of nuclear heating plant	98	7	<1
Increase in activity of ALT	82	5	<1
Hematologic indicators
Decrease in quantity of thrombocytes	84	14	3
Decrease in concentration of hemoglobin	62	4	1
Decrease in number of neutrophils	39	4	<1
Electrolytes
Decrease in potassium concentration	34	3	<1

Interaction with other medicines:

Separate researches of interaction with other medicines were not conducted.

It is necessary to avoid simultaneous use of powerful inhibitors of an isoenzyme of CYP3A4 (for example, a ketokonazola, an itrakonazola, a klaritromitsina, an atazanavira, an indinavira, a nefazodona, a nelfinavira, a ritonavira, a sakvinavira, a telitromitsina and a vorikonazola) and the drug Kadsila® because of possible increase in exposure and toxic manifestations of DM1 (a component of a trastuzumab of an emtanzin).

It is necessary to consider alternative medicine which inhibiting influence on CYP3A4 isoenzyme minimum or is absent.

If use of powerful inhibitors of an isoenzyme of CYP3A4 is necessary, it is necessary to consider the possibility to postpone therapy by the drug Kadsila® until CYP3A4 isoenzyme drug-inhibitor removal from a blood-groove (about 3 elimination half-lives of drug-inhibitor of an isoenzyme of CYP3A4).

If therapy by the drug Kadsila® cannot be postponed, it is necessary to watch carefully the patient regarding development of side reactions at simultaneous use with powerful inhibitor of an isoenzyme CYP3A4.

Contraindications:

Hypersensitivity to a trastuzumab to an emtanzin and to other components of drug.

The infusional reactions connected using a trastuzumab, which led to therapy cancellation.

Pregnancy and period of breastfeeding.

Age up to 18 years (efficiency and safety of use for children are not established).

Diffusion intersticial pulmonary disease, pneumonitis.

Increase in activity hepatic аминторансфераз> 3 x upper bound of norm (UBN) or concentration of the general bilirubin> 2 x VGN.

Nodal regenerative hyperplasia of a liver.

Symptomatic congestive heart failure.

Renal failure of heavy and terminal degree (clearance of creatinine <30 ml/min.), a liver failure (efficiency and safety of use are not established).

Value of fraction of emission of a left ventricle of heart <50% before an initiation of treatment; chronic heart failure in the anamnesis; the asthma at rest caused by progressing of a malignant disease or the accompanying pathology; the serious violations of a cordial rhythm demanding medicinal therapy; a myocardial infarction or unstable stenocardia which developed within 6 months before an initiation of treatment; quantity of thrombocytes <100 000/mm3 before an initiation of treatment; peripheral neuropathy ≥3 severity before an initiation of treatment (efficiency and safety of use are not established).

With care: - activity of hepatic aminotransferases> 2.5×ВГН or concentration of the general bilirubin> 1.5×ВГН before an initiation of treatment;
- FVLZh <55% before an initiation of treatment, to or after adjuvant therapy paklitaksely;
- the previous or simultaneous use of hypotensive drugs;
- the previous therapy by anthracyclines;
- at patients aged> 50 years;
- patients with an index have body weights> 25 kg/sq.m.

Overdose:

The antidote for overdose treatment by the drug Kadsila® is unknown. In case of exceeding of the recommended dose of the drug Kadsila® careful observation of the patient regarding emergence of signs or symptoms of the undesirable reactions connected with pharmacological effect of drug and purpose of the corresponding symptomatic treatment is necessary.

It was reported about cases of exceeding of a dose of the drug Kadsila®, the majority of which were followed by thrombocytopenia.

The case of a lethal outcome which came about 3 weeks later after wrong introduction to the patient of a trastuzumab of an emtanzin in a dose of 6 mg/kg is known, however the cause of death, and also communication with the drug Kadsila® are not established.

Storage conditions:

Period of validity 3 years. Not to use after the period of validity specified on packaging.

To store at a temperature of 2-8 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of a concentrate for preparation of solution for infusions of 100 mg and 160 mg. On 100 mg or 160 mg of a trastuzumab of an emtanzin in the bottle of colourless glass (a hydrolytic class 1 EF) corked by a stopper from the butyl rubber laminated by a ftorpolimer, which is pressed out by an aluminum cap and closed by a plastic cover.

1 bottle with drug together with the application instruction is placed in a cardboard pack.