Kadsila - Instructions For Use, Price, Reviews, Drug Analogues

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Kadsila

Kadsila: instructions for use and reviews

1. 1. Release form and composition
2. 2. Pharmacological properties
3. 3. Indications for use
4. 4. Contraindications
5. 5. Method of application and dosage
6. 6. Side effects
7. 7. Overdose
8. 8. Special instructions
9. 9. Application during pregnancy and lactation
10. 10. Use in childhood
11. 11. In case of impaired renal function
12. 12. For violations of liver function
13. 13. Use in the elderly
14. 14. Drug interactions
15. 15. Analogs
16. 16. Terms and conditions of storage
17. 17. Terms of dispensing from pharmacies
18. 18. Reviews
19. 19. Price in pharmacies

Latin name: Kadcyla

ATX code: L01XC14

Active ingredient: trastuzumab emtansine (Trastuzumab emtansine)

Manufacturer: F. Hoffmann-La Roche Ltd. (F. Hoffmann-La Roche, Ltd.) (Switzerland)

Description and photo update: 2019-09-07

Kadsila is an antineoplastic agent.

Release form and composition

Dosage form - lyophilisate for the preparation of a concentrate for the preparation of a solution for infusion: a porous mass of almost white or white compacted into a tablet or in the form of separate parts of a tablet (100 and 160 mg each in colorless glass bottles, 1 bottle in a cardboard box and instructions for use of Kadsila).

The solution recovered from the lyophilisate is transparent or slightly opalescent, colorless or with a brownish tint.

The composition of the lyophilisate in 1 bottle:

• active substance: trastuzumab emtansine - 100 or 160 mg;
• auxiliary components: sodium hydroxide, succinic acid, sucrose, polysorbate 20.

Pharmacological properties

Pharmacodynamics

Trastuzumab emtansine is a conjugate of a humanized monoclonal antibody (IgG1) to the human epidermal growth factor 2 receptor HER2 (trastuzumab) and tubulin polymerization inhibitor DM1 (a maytansine derivative), which are linked to each other via a stable thioether 4- (NCC malienimidomethyl) cyclohexane-1-carboxylate]. The drug selectively interacts with the HER2 receptor.

Emtansine is a DM1 – MCC complex. An average of 3.5 DM1 molecules are conjugated to each trastuzumab molecule.

Trastuzumab emtansine, binding to HER2, enters the cell and undergoes proteolytic degradation in lysosomes, resulting in the release of DM1-containing cytotoxic catabolites (mainly the lysine-MCC-DM1 complex). Conjugation of trastuzumab with DM1 facilitates the delivery of the latter into tumor cells, and also explains the selectivity of Kadsila against tumor cells that overexpress HER2.

Thus, the mechanism of action of Kadsila is a combination of the mechanisms of action of trastuzumab and DM1.

Like trastuzumab, trastuzumab emtansine binds to Fey receptors, complement protein C1q, and domain IV of the extracellular domain of HER2. The drug inhibits the transmission of intracellular signal along the pathway of phosphatidylinositol-3-kinase (PI3-K), prevents the desquamation of the extracellular domain of HER2 from the cell surface, and also activates antibody-dependent cell-mediated cytotoxicity (ADCC) in breast cells with overexpression of HER2, affected by cancer.

The cytotoxic component of the drug DM1 binds to tubulin and inhibits its polymerization. Like DM1, trastuzumab emtansine, due to the action of this component, promotes blockade of the cell cycle in the G2 / M phase, as a result of which apoptosis develops (a regulated process of programmed cell death).

In vitro studies of the cytotoxicity of DM1 found that the activity of DM1 exceeds that of the rose vinca alkaloids (vinblastine, vincristine) and yew alkaloids, the so-called. taxanes (paclitaxel, docetaxel), 20-200 times.

Plasma free DM1 is very low. This indicates a limited release of DM1 and its targeted delivery into cells (due to the structure of the MCC linker).

Preclinical safety data:

• teratogenicity: there is information confirming the embryotoxic effect of trastuzumab, the potential teratogenic and embryotoxic activity of DM1;
• mutagenicity: preclinical studies have shown that trastuzumab emtansine has clastogenic and / or aneogenic toxicity;
• effect on fertility: the risk of impaired fertility was identified during the use of Kadsila.

Pharmacokinetics

The pharmacokinetic parameters of trastuzumab emtansine have been studied only with intravenous (iv) administration.

The average maximum concentration (C _max) in the blood serum with the introduction of Kadsila every 3 weeks at 3.6 mg / kg is 83.4 (± 16.5) μg / ml.

With the introduction of Kadsila every 3 weeks at doses from 2.4 to 4.8 mg / kg, the pharmacokinetics is linear. The volume of distribution (Vd) in the central chamber is approximately equal to the volume of the plasma and is 3.13 liters. Cumulation of trastuzumab emtansine with long-term treatment is not observed.

In vitro studies on human liver microsomes have shown that the low molecular weight component of trastuzumab emtansine DM1 is metabolized mainly with the participation of the isoenzyme CYP3A4, to a lesser extent - CYP3A5. It is a substrate for glycoprotein R.

Under in vitro conditions, DM1 does not inhibit the main isozymes of cytochrome CYP450. Trastuzumab emtansine catabolites, such as DM1, Lys – MCC – DM1 and MCC – DM1, are found in human plasma at low concentrations.

In patients with metastatic breast cancer with HER2 overexpression after intravenous administration of Kadsila, the clearance of trastuzumab emtansine is 0.68 l / day, the half-life (T _1/2) is approximately 4 days. In patients receiving doses ≤ 1.2 mg / kg, drug clearance was higher.

The following patient parameters have a statistically significant effect on the clearance of trastuzumab emtansine: body weight, the sum of the largest diameters of tumor foci according to the RECIST criterion (Response Evaluation Criteria in Solid Tumors), the initial concentration of trastuzumab, the initial concentration of the cleaved extracellular domain (ECD) HER2, serum albumin concentration, baseline serum aspartate aminotransferase (AST) activity. However, the effect of these parameters (with the exception of body weight) on drug exposure is unlikely.

The catabolites DM1, MCC-DM1 and Lys-MCC-DM1 are excreted mainly in the bile, to a small extent in the urine.

Pharmacokinetics in special cases:

• race: changes in pharmacokinetics in representatives of different races have not been identified;
• gender: influence not studied;
• age: significant changes in the pharmacokinetic characteristics of Kadsila in patients younger and older than 65 have not been identified;
• renal function: data from a population pharmacokinetic analysis of creatinine clearance (CC) indicate that there is no effect of renal function on the pharmacokinetics of the drug. The main characteristics of renal failure of mild (CC 60–89 ml / min) and moderate (CC 30–59 ml / min) severity are similar to those in persons without functional impairment of renal function (CC ≥ 90 ml / min). Data on the parameters of the pharmacokinetics of trastuzumab emtansine in patients with severe renal failure, including in the terminal stage (CC <30 ml / min), are limited, so it is impossible to provide any guidance on the dosage regimen of Kadsila in this category of patients
• liver function: DM1 and catabolites containing DM1 are excreted primarily through the liver. The pharmacokinetic parameters of trastuzumab and DM1 (including in the composition of catabolites) were studied after the administration of Kadsila at a dose of 3.6 mg / kg to patients with metastatic HER2-positive breast cancer with normal hepatic function (n = 10), impaired mild [class A on the Child-Pugh scale with a concentration of total bilirubin 1.5 times the upper limit of normal (ULN) and / or ALT (alanine aminotransferase) and / or ACT (aspartate aminotransferase)> VGN, but VGN, but <20 VGN; n = 8) severity. Plasma concentrations of DM1 and catabolites containing it were low, the values were comparable to those in patients without liver dysfunction. In mild and moderate disorders, systemic exposures (AUC - area under the concentration-time pharmacokinetic curve) of trastuzumab emtansine in the first cycle were lower than in patients with normal liver function, by 38% and 67%, respectively. In the third cycle, the AUC of the drug after repeated administration to patients with mild to moderate impairment was approximately comparable to that in patients with normal liver function. The pharmacokinetics of Kadsila in patients with severely impaired liver function (class C on the Child-Pugh scale) has not been studied. In the third cycle, the AUC of the drug after repeated administration to patients with mild to moderate impairment was approximately comparable to that in patients with normal liver function. The pharmacokinetics of Kadsila in patients with severely impaired liver function (class C on the Child-Pugh scale) has not been studied. In the third cycle, the AUC of the drug after repeated administration to patients with mild to moderate impairment was approximately comparable to that in patients with normal liver function. The pharmacokinetics of Kadsila in patients with severely impaired liver function (class C on the Child-Pugh scale) has not been studied.

Indications for use

Kadsila is indicated for the treatment of metastatic breast cancer. It is used as a monopreparation in the following cases:

• after previous therapy, which included trastuzumab and drugs from the taxane group (sequentially or in combination);
• after disease progression during or within 6 months after the end of adjuvant (auxiliary) therapy, which included trastuzumab and drugs from the taxane group (sequentially or in combination);
• inoperable locally advanced or metastatic HER2-positive breast cancer.

Contraindications

Absolute (the appointment of Kadsila is strictly contraindicated):

• a history of chronic heart failure;
• symptomatic congestive heart failure;
• left ventricular ejection fraction (LVEF) value <50% before starting treatment;
• serious heart rhythm disturbances requiring drug therapy;
• unstable angina pectoris or myocardial infarction, developing in the 6 months preceding the start of treatment;
• peripheral neuropathy grade 3 and higher, before treatment;
• dyspnea at rest, caused by concomitant pathology or progression of cancer;
• diffuse interstitial lung disease, pneumonitis;
• nodular regenerative hyperplasia of the liver;
• severe functional disorders of the liver (class C on the Child-Pugh scale), increased activity of hepatic aminotransferases> 3 VGN with a total bilirubin concentration> 2 VGN;
• severe renal failure, severe, including in the terminal stage (CC <30 ml / min);
• platelet count <100,000 / mm ³ before treatment;
• age up to 18 years;
• period of pregnancy and lactation;
• infusion reactions with a history of trastuzumab, leading to the cancellation of therapy;
• hypersensitivity to any component of the drug.

Relative (the use of Kadsila requires special care): left ventricular dysfunction, liver dysfunction of mild to moderate severity.

Kadsila, instructions for use: method and dosage

Treatment with Kadsila should only be carried out by a physician with relevant experience in the treatment of cancer.

Before the start of the course, testing for tumor expression of HER2 is performed. A mandatory criterion is the presence of 3+ points according to the results of immunohistochemical analysis (IHC) and / or the degree of amplification ≥ 2.0 according to the results of in situ hybridization (ISH). The test methods used must be validated.

Kadsilu is administered at 3.6 mg / kg of body weight every 3 weeks (21-day treatment cycle) as an intravenous drip infusion. The introduction of the drug is carried out in an office equipped with specialized equipment and drugs for the provision of emergency care in the event of the development of infusion reactions of an allergic / anaphylactic type.

The trade name of the drug and its batch number are indicated in the patient's medical record. In the case of replacing Kadsila with a similar drug of biological origin, agreement with a doctor is required.

It is recommended that the first dose be administered within 90 minutes. During the infusion and for at least 90 minutes after its completion, the patient should be under close medical supervision in order to identify possible infusion reactions (including fever or chills) in time. In the event of such reactions, the rate of administration of the drug should be reduced or the infusion should be temporarily suspended. Life-threatening reactions are a contraindication to the further use of Kadsila.

Also, after the introduction of Kadsila, it is required to carefully examine the injection site for the formation of subcutaneous infiltrates.

If the first infusion is well tolerated, subsequent infusions can be carried out within 30 minutes with a further 30-minute observation of the patient.

Treatment with the drug is continued until signs of disease progression are detected or symptoms of unacceptable toxicity develop.

Preparation, dilution and recovery of the drug

Only intravenous drip of Kadsila is allowed. It is prohibited to administer the drug in a stream or bolus.

Dissolution and dilution of the drug is carried out only by qualified medical personnel in aseptic conditions in compliance with the rules for the preparation of chemotherapeutic agents.

Kadsila is diluted with sterile water for injection and sodium chloride solution of 0.9% or 0.45%. It can be administered using infusion bags made of polyolefin (PVC or latex free) or polyvinyl chloride (PVC).

When using 0.9% sodium chloride solution as a solvent, it is mandatory to use an infusion system with a built-in polyethersulfone (PES) infusion filter with a pore diameter of 0.2-0.22 μm (in the case of using a 0.45% sodium chloride solution, this is not required).

Due to incompatibility, Kadsilu should not be mixed with 5% dextrose solution (protein aggregation is possible). It must not be mixed / diluted with other medicinal products.

The preparation contains no preservatives, therefore 1 bottle is designed for single use.

Instructions for preparing the concentrate (reconstituted solution):

1. Draw 5 or 8 ml of sterile water for injection into a sterile syringe (for a dose of trastuzumab emtansine 100 mg or 160 mg, respectively) and enter it into a vial with a lyophilisate. The concentration of the solution will be 20 mg / ml.
2. Gently shake the bottle with rotary movements until the lyophilisate is completely dissolved. Do not shake or turn the bottle over.
3. Visually inspect the concentrate for discoloration, turbidity or foreign matter. The solution should be clear or slightly opalescent, colorless or brownish, without visible inclusions. If changes are detected, the concentrate must not be used.

It is recommended to use the concentrate immediately to prepare the solution. However, if dissolution was carried out under controlled and validated aseptic conditions, it can be stored, but not more than 24 hours at a temperature of 2–8 ° C (without freezing). If the concentrate has not been used within 24 hours, it should be disposed of.

Instructions for preparing solution for infusion:

1. Determine the volume of concentrate required to prepare the required dose of Kadsely using the following formula: volume (ml) = body weight (kg) × dose (mg / kg) / 20 (mg / ml).
2. Take the required volume from the vial with the concentrate and introduce it into an infusion bag made of PVC or polyolefin that does not contain PVC or latex with 250 ml of sodium chloride solution 0.45% or 0.9%.
3. Turn the bag over gently to mix the solution. Do not shake.

It is recommended to prepare the infusion solution immediately before administration. However, if it is prepared under controlled and validated aseptic conditions, it can be stored for 24 hours at 2-8 ° C (no freezing). It should be borne in mind that when storing a solution for the preparation of which a 0.9% sodium chloride solution was used, the formation of visible particles is possible.

Skip in planned introduction

There is no need to wait for the next scheduled injection, the infusion of Kadsila must be carried out as soon as possible after the pass. The dosage is not changed. The infusion rate is maintained at the same rate as in the previous administration if it is well tolerated by the patient.

The further schedule of injections is adjusted so that there are intervals of 3 weeks between injections.

Dose adjustment

With the development of undesirable symptoms, it is possible to reduce the dose of trastuzumab emtansine, temporarily discontinue Kadsila or completely stop treatment.

If the dose is reduced with further injections, it cannot be increased. If a decision is made to reduce the dose (initial - 3.6 mg / kg), the next time the dose is administered, the recommended dose is 3 mg / kg. For patients who are poorly tolerated this dose is reduced to 2.4 mg / kg. Further dose reduction in case of poor tolerance of the drug is impractical, Kadsila is canceled.

Recommendations for dose adjustment with an increase in ACT and / or ALT in serum:

• grade 2 (> 2.5 to ≤ 5 VHN): no correction required;
• Grade 3 (> 5 to ≤ 20 ULN): Treatment is temporarily interrupted until toxicity has subsided to ≤ grade 2. The therapy is resumed at a reduced dose;
• degree 4 (> 20 VGN): Kadsela is canceled.

Recommendations for dose adjustment in the development of hyperbilirubinemia:

• Grade 2 (> 1.5 to ≤ 3 ULN): Treatment is temporarily interrupted until toxicity has subsided to ≤ Grade 1. The therapy is resumed at a reduced dose;
• Grade 3 (> 3 to ≤ 10 ULN): Treatment is interrupted until toxicity has subsided to grade 1. The therapy is resumed at a reduced dose;
• degree 4 (> 10 VGN): Kadsela is canceled.

In case of development of nodular regenerative hyperplasia, an increase in the activity of hepatic aminotransferases in the blood serum> 3 VHN with total bilirubin> 2 VHN, therapy with Kadsila is stopped completely.

Recommendations for dose adjustment in the development of thrombocytopenia:

• grade 3 (25,000 to <50,000 / mm ³): Treatment is temporarily interrupted until toxicity has subsided to ≤ grade 1 (≥ 75,000 / mm ³). The therapy is resumed at the same dose;
• Grade 4 (<25,000 / mm ³): Treatment is interrupted until toxicity has subsided to ≤ Grade 1 (≥ 75,000 / mm ³). The therapy is resumed at a reduced dose.

Recommendations for dose adjustment for left ventricular dysfunction depending on LVEF:

• LVEF <40%: Kadsilu is temporarily canceled. After 3 weeks, LVEF is reassessed. If this indicator remains <40%, the drug is canceled completely;
• LVEF 40–45%: if the decrease is <10% compared to the initial value, drug therapy is continued, after 3 weeks, a re-assessment of LVEF is performed; if the decrease is ≥ 10% compared to the initial value, the therapy is interrupted, after 3 weeks the LVEF is re-assessed, in the absence of an increase in the indicator to values within 10% compared to the initial value, the drug is completely canceled;
• LVEF> 45%: treatment with Kadsila continues.

Treatment is stopped completely if symptomatic congestive heart failure develops, as well as interstitial lung disease or pneumonitis.

If grade 3 and 4 peripheral neuropathy develops, treatment is temporarily interrupted until symptoms resolve to ≤ grade 2.

Side effects

The most common serious side effects were: fever, nausea, vomiting, constipation, diarrhea, abdominal pain, thrombocytopenia, shortness of breath, pneumonitis.

Adverse reactions of the 1st and 2nd severity, developing with a frequency of ≥ 25%: increased fatigue, headache, musculoskeletal pain, increased activity of hepatic aminotransferases, bleeding (including nosebleeds).

Undesirable effects of the 3rd and 4th degree of severity (according to the toxicity criteria determined by the National Cancer Institute scale, version 3.0), occurring with a frequency of> 2%: musculoskeletal pain, hypokalemia, anemia, neutropenia, thrombocytopenia, increased liver activity aminotransferases, increased fatigue.

The following side effects are classified by frequency of development as follows: very often - ≥ 1/10, often - from ≥ 1/100 to <1/10, infrequently - from ≥ 1/1000 to <1/100, rarely - from ≥ 1 / 10,000 to <1/1000, very rarely - <1/10,000, including isolated cases:

• from the side of metabolism: very often - hypokalemia;
• from the hematopoietic system: very often - anemia, thrombocytopenia ¹; often - leukopenia, neutropenia;
• from the respiratory system: very often - epistaxis, shortness of breath, cough; infrequently - pneumonitis;
• from the digestive system: very often - dry mouth, stomatitis, constipation, diarrhea, abdominal pain, nausea, vomiting; often - bleeding gums, dyspepsia;
• from the immune system: often - hypersensitivity reactions ², immunogenicity ³;
• on the part of the cardiovascular system: very often - bleeding; often - increased blood pressure, left ventricular dysfunction ⁴;
• from the urinary system: very often - urinary tract infections;
• from the musculoskeletal system: very often - myalgia, arthralgia, musculoskeletal pain;
• from the liver and biliary tract: infrequently - phenomena of hepatotoxicity, portal hypertension, nodular regenerative hyperplasia, hepatic failure;
• from the nervous system and psyche: very often - insomnia, dizziness, headache, peripheral neuropathy; often - dysgeusia (violation of taste), memory impairment;
• from the skin and subcutaneous tissues: very often - a rash; often - urticaria, itching, palmar-plantar erythrodysesthesia, violation of the structure of the nails, alopecia;
• on the part of the organ of vision: often - increased lacrimation, dry eyes, blurred vision, conjunctivitis;
• on the part of laboratory and instrumental data ⁵: very often - an increase in the activity of hepatic aminotransferases and bilirubin, a decrease in the concentration of hemoglobin and potassium, the number of neutrophils and the number of platelets; often - increased activity of alkaline phosphatase in the blood;
• general disorders and reactions at the injection site: very often - chills, fever, fatigue, asthenia; often - infusion reactions ⁶, peripheral edema; infrequently - extravasation at the infusion site ⁷.

Explanation of notes:

¹ According to research results, thrombocytopenia occurred with a frequency of 31.4%. In most cases, the disorder was of the 1st or 2nd degree of severity (platelet count ≥ 50,000 / mm ³), with the greatest decrease in platelet count observed on the 8th day after administration of Kadsila. The Asian race had a higher incidence and severity of thrombocytopenia. Regardless of race, the incidence of grade 3 and 4 impairment (<50,000 / mm ³) was 11.3%. The frequency of severe (≥ grade 3) bleeding was 1.7%, in representatives of Asian countries - 1%.

² Hypersensitivity reactions developed with a frequency of 2.6%, were predominantly mild to moderate and resolved after appropriate treatment. Violations of the 3rd and 4th severity were not registered.

³ In 5.3% of patients treated with Kadsila, antibodies to trastuzumab emtansine were detected at one or more time points after administration of the solution. The clinical significance of this phenomenon has not been established.

⁴ Left ventricular dysfunction during drug therapy was observed in 2% of patients. In most cases, an asymptomatic decrease in LVEF of grade 1 or 2 was observed. The incidence of grade 3 and 4 dysfunction was 0.3%; the disorder usually developed at the beginning of treatment (in cycles 1–2). In patients with LVEF ≤ 45%, careful monitoring of left ventricular ejection fraction is recommended.

^{5 The} increase in the activity of aminotransferases of the 1-4th degree of severity and the effect of the accumulation of aminotransferases in the blood serum, observed with the use of Kadsila, were usually reversible. The maximum increase in the activity of aminotransferases was noted on the 8th day after drug administration. As a rule, this indicator was restored to grade 1 or to normal by the time of the next infusion, or within 30 days after discontinuation of therapy.

The incidence of increased hepatic aminotransferase activity in patients treated with Cadcilu was 28%. An increase in the activity of ALT and / or ACT grade 3 and 4 was observed in 4.1% and 2.8% of patients, respectively, and usually occurred at the beginning of therapy (on cycles 1–6). In most cases, these disorders were not associated with an unfavorable outcome, and the functional parameters of the liver during follow-up gradually improved to the level that allowed continuing the use of Kadsila (in the usual or reduced dose). There was no regular dependence of the increase in serum ALT and / or ACT activity on AUC, C _max and the total exposure of trastuzumab emtansine or on C _{max of} DM1.

Frequency of violations of other laboratory parameters:

• increased concentration of bilirubin: all severity - 21%, 3rd degree - <1%, 4th degree - 0%;
• increased ACT activity: all severity - 98%, 3rd degree - 8%, 4th degree - <1%;
• increased ALT activity: all severity - 82%, 3rd degree - 5%, 4th degree - <1%;
• decrease in the number of platelets: all severity - 85%, 3rd degree - 14%, 4th degree - 3%;
• decrease in hemoglobin concentration: all severity - 63%, 3rd degree - 5%, 4th degree - 1%;
• decrease in the number of neutrophils: all severity - 41%, 3rd degree - 4%, 4th degree - <1%;
• decrease in potassium concentration: all severity - 35%, 3rd degree - 3%, 4th degree - <1%.

⁶ Infusion reactions can manifest the following symptoms: fever, chills, hot flashes, arterial hypotension, tachycardia, wheezing, shortness of breath, bronchospasm. The frequency of such reactions was 4.5%. Reactions of the 3rd degree of severity were noted very rarely, violations of the 4th degree of severity were not observed. Typically, symptoms resolved within the first 24 hours after the end of the infusion. The incidence of infusion reactions did not depend on the dose.

⁷ After the infusion of Kadsila, some patients experienced reactions due to the ingestion of the drug under the skin: skin irritation, soreness, erythema, edema at the injection site. Most often, these reactions occurred within 24 hours after infusion, and were usually mild. After administration of the drug, it is recommended to observe the patient for the appearance of subcutaneous infiltrates. There is no specific treatment for manifestations of extravasation.

Overdose

In most of the known cases of exceeding the recommended dose of Kadsila, thrombocytopenia developed. Death was reported approximately 3 weeks after the patient was mistakenly given 6 mg / kg, but the cause of death and its association with trastuzumab emtansine have not been established.

The antidote is unknown. If the recommended dose has been exceeded, the patient's condition should be carefully monitored for signs of adverse reactions, and symptomatic treatment should be prescribed if necessary.

special instructions

Kadsila can only be prescribed for patients with tumor overexpression of the HER2 protein, as determined by the IHC method, or amplification of the HER2 gene, as determined by the ISH method. The test methods used must be validated.

Clinical experience with the use of Kadsila in patients with ECOGPS ≥ 2 (the scale of the Eastern Cooperative Oncology Group for assessing the general condition) is insufficient, the safety and efficacy of the drug have not been established.

Women of reproductive age, as well as male patients, should use reliable contraception during treatment and for 7 months after the last dose.

Hypersensitivity reactions

During the period of therapy, it is necessary to carefully monitor the patient's condition for the development of allergic reactions, the manifestations of which may be similar to the symptoms caused by the administration of the solution (infusion reactions).

Cases of severe anaphylactic reactions are known.

In the room in which the introduction of Kadsila is carried out, the necessary medicines and equipment should be provided to provide emergency care in the event of hypersensitivity reactions.

If there was a true hypersensitivity reaction (characterized by an increase in severity with each subsequent infusion) Kadsela is completely canceled.

The safety of further use of Kadsila has not been established in patients who, with the previous administration of trastuzumab, developed hypersensitivity reactions that required discontinuation of therapy. The doctor decides on the possibility of continuing treatment with the drug.

Infusion reactions

With the introduction of Kadsila, especially during the first infusion, it is necessary to carefully monitor the patient's condition for the development of infusion reactions. They can be manifested by one or more symptoms, such as fever, chills, hot flashes, arterial hypotension, tachycardia, wheezing, bronchospasm.

In most cases, the observed reactions were mild or moderate and were resolved within the first days after the end of the drug administration. If there is a clinically significant reaction, the infusion is discontinued until symptoms resolve.

If therapy is resumed, the patient should be closely monitored. If the reactions were life-threatening, Kadsela is completely canceled.

The safety of further use of the drug has not been established in patients who, with the previous administration of trastuzumab, developed infusion reactions that required discontinuation of therapy. After severe infusion reactions, the doctor decides whether to continue treatment.

Neurotoxicity

Cases of development of peripheral neuropathy (mainly sensory), mainly of the 1st severity, have been reported.

The efficacy and safety of Kadsila has not been established for patients who, at the time of appointment, have grade 3-4 peripheral neuropathy.

In severe disorders, treatment is interrupted until the symptoms are completely resolved and a state of 1–2 severity is achieved. The patient should be monitored for signs of neurotoxicity.

Hepatotoxicity

The hepatotoxicity of Kadsila was manifested mainly by an increase in the activity of grade 1–4 aminotransferases with an accumulation effect. There were no clinical symptoms.

Cases of the development of serious hepatobiliary disorders such as nodular regenerative hyperplasia of the liver and fatal drug-induced liver damage are known. Additional risk factors may be concomitant diseases and co-administration of drugs with a potential hepatotoxic effect.

Before prescribing Kadsila and before each subsequent administration of the solution, it is necessary to assess the patient's liver function.

In patients with elevated ALT activity before treatment (for example, in the presence of liver metastases), the risk of increased liver function parameters and the development of hepatotoxicity of 3-5 degrees of severity increases. In this case, recommendations for dose reduction or temporary cancellation of Kadsila should be followed, depending on the level of increased activity of hepatic aminotransferases and the content of total bilirubin.

In patients who have an aminotransferase activity of> 2.5 ULN or a total bilirubin concentration> 1.5 ULN before treatment, the efficacy and safety of trastuzumab emtansine have not been studied.

In case of an increase in the activity of aminotransferases in the serum of more than 3 VGN with a total bilirubin of more than 2 VGN, treatment with the drug should be completely stopped.

Due to portal hypertension of non-cirrhotic genesis, it is possible to develop nodular regenerative hyperplasia of the liver (URH), a rare disease in which, as a result of benign transformation of the parenchyma, multiple small regenerative nodes are formed in the liver.

All patients with clinical manifestations of portal hypertension and / or cirrhosis detected by computed tomography of the liver (in the absence of symptoms, including increased activity of aminotransferases) should be diagnosed with urinary tract imaging. If the diagnosis is confirmed, Kadsela is completely canceled.

Thrombocytopenia

A decrease in the number of platelets against the background of anticancer therapy is often noted. The development of thrombocytopenia is the most common reason for the complete cancellation of Kadsila.

Cases of fatal bleeding are known. Severe bleeding has been reported, in particular intracranial hemorrhage. The frequency of violations does not depend on race. Some patients with severe bleeding received concomitant anticoagulant therapy.

Careful observation during the period of drug treatment is required for patients with a platelet count of less than 100,000 / mm ³, as well as taking anticoagulants (for example, heparin or warfarin).

In patients whose platelet count was <100,000 / mm ³ prior to treatment initiation, the safety and efficacy of trastuzumab emtansine have not been established.

It is recommended that the platelet count be determined before each infusion of Kadsila.

With the development of thrombocytopenia ≥ grade 3 (<50,000 / mm ³), Kadsela is discontinued until symptoms resolve and a grade 1 condition is achieved (≥ 75,000 / mm ³).

Left ventricular dysfunction

Kadsila increases the risk of developing left ventricular dysfunction. There are known cases of LVEF <40%, which is accompanied by the likelihood of symptomatic congestive heart failure.

In clinical trials of adjuvant trastuzumab revealed the following risk factors of adverse cardiac events: age over 50, high body mass index (> 25 kg / m ²), initially low value of left ventricular ejection fraction (<55%), low value of LVEF before or after adjuvant paclitaxel therapy, prior anthracyclines therapy, prior or concurrent use of antihypertensive drugs.

Before the appointment of Kadsila and during the entire period of its use, at least once every 3 months, a standard cardiac examination of the patient should be performed, including radioisotope ventriculography or echocardiography.

In case of development of left ventricular dysfunction, the dose of Kadsila is reduced, the administration is temporarily suspended or the therapy is completely stopped (the corresponding recommendations are indicated in the section "Method of administration and dosage").

Safety and efficacy of Kadsila have not been studied in the following cases: LVEF <50% before treatment; a history of chronic heart failure; dyspnea at rest, caused by concomitant pathology or the progression of a malignant disease; serious heart rhythm disturbances requiring drug therapy; unstable angina pectoris or myocardial infarction that occurred within 6 months before the start of the therapeutic course.

Lung disorders

It was reported about the development of diffuse interstitial lung disease (IBD), in particular, pneumonitis during treatment with the drug. In some cases, the disease has led to the development of acute respiratory distress syndrome and death. IBD can be manifested by the following symptoms: shortness of breath, cough, fatigue, infiltrates in the lungs. If the diagnosis is confirmed, Kadsela is completely canceled.

The risk of pulmonary disorders is increased in patients with resting dyspnea due to comorbidity or progression of malignant disease.

Disposal instructions

Unused or expired product should not be allowed to enter the environment. It should not be disposed of with household waste or sewage.

Destruction of the drug must be carried out in accordance with the requirements of the medical institution.

Influence on the ability to drive vehicles and complex mechanisms

The effect of Kadsila on reaction rate and ability to concentrate has not been studied. However, it is known about the occurrence of some negative effects, such as dizziness, blurred vision, increased fatigue, infusion reactions. With their development, patients are advised to refrain from driving vehicles and performing potentially hazardous work.

Application during pregnancy and lactation

Kadsila is contraindicated during pregnancy and lactation.

If pregnancy occurs during the period of anticancer therapy, the patient should immediately inform her doctor about it. She should be informed about the likelihood of a negative impact on the development of the fetus. In the case of continuing therapy with the drug, careful medical supervision is required.

Pediatric use

Kadsila is contraindicated in childhood and adolescence (up to 18 years), since its effectiveness and safety in pediatric patients has not been established.

With impaired renal function

With mild (CC 60–89 ml / min) and moderate (CC 30–59 ml / min) degree of renal failure, it is not necessary to adjust the treatment regimen.

There is no information on the use of Kadsila in patients with severe renal failure, including in the terminal stage (CC <30 ml / min).

For violations of liver function

In case of mild and moderate functional impairments of hepatic function, the initial dose of Kadsila is not adjusted, however, the treatment is carried out under close medical supervision, since the antineoplastic agent has a known hepatotoxicity.

There is no information on the use of Kadsila in patients with severe hepatic impairment.

Use in the elderly

There is no need to adjust the initial dose of Kadsila for patients aged 65–75 years. The safety and effectiveness of therapy in patients over 75 years of age are unknown, since the clinical experience of treating people of this age group is very limited.

Drug interactions

Special studies on the interaction of trastuzumab emtansine with other drugs have not been conducted.

It is necessary to avoid the co-administration of potent inhibitors of the CYP3A4 isoenzyme (such as nelfinavir, telithromycin, saquinavir, ritonavir, nefazodone, atazanavir, clarithromycin, ketoconazole, indinavir, voriconazole, itraconazole), since this combination may increase the exposure of DM1 and trastanzuramine toxin … It is recommended to select an alternative drug with no or minimal inhibitory effect on the CYP3A4 isoenzyme.

If it is not possible to avoid the use of potent inhibitors of the isoenzyme CYP3A4, the doctor should consider the possibility of postponing the infusion of Kadsila until the inhibitor of the isoenzyme CYP3A4 is cleared from the bloodstream (approximately 3 of its half-life). If it is impossible to transfer therapy with trastuzumab emtansine, the patient should be carefully monitored for the development of possible side effects.

Analogs

Kadsila's analogs are Avastin, Arserra, Bevacizumab, Blintsito, Vektibiks, Gertikad, Kitruda, Mabtera, Opdivo, Perieta, Removab, Tecentrik, Tsiramza, Erbitux, etc.

Terms and conditions of storage

Keep out of the reach of children at a temperature of 2-8 ° C (in the refrigerator, without freezing).

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Kadsil

There are few reports of the drug, since it began to be used relatively recently. However, many are already calling Kadsilu, which is a combination of humanized monoclonal antibodies (trastuzumab) and a tubulin polymerization inhibitor DM1, a real breakthrough in breast cancer treatment.

On specialized forums and sites, reviews of Kadsil from patients are also positive. They note the great antitumor efficacy of the drug and quite acceptable tolerance. Side effects include chills, fever, and pain in the spine and bones, but these reactions usually resolved within a few days after the infusion. The cost of the drug is estimated as very high.

Price for Kadsila in pharmacies

Depending on the region of sale and the pharmacy network, the price of Kadsela for 1 bottle may be: dosage of 100 mg - 63,500–96,200 rubles, dosage of 160 mg - 105,300–158,000 rubles.

Maria Kulkes Medical journalist About the author

Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!