Composition, form of production and packaging
Lyophilizate for the preparation of a concentrate for the preparation of a solution for infusions in the form of a porous mass packed in a tablet, sometimes as separate parts of a tablet, white or almost white; reconstituted solution - transparent or slightly opalescent, colorless or with a brownish tinge solution.
1 f.
trastuzumab emtanzine 100 mg
Excipients: sucrose - 318 mg, succinic acid - 6.3 mg, sodium hydroxide - 2.4 mg, polysorbate 20 - 1.1 mg.
Vials of colorless glass (1) - packs cardboard.
Lyophilizate for the preparation of a concentrate for the preparation of a solution for infusions in the form of a porous mass packed in a tablet, sometimes as separate parts of a tablet, white or almost white; reconstituted solution - transparent or slightly opalescent, colorless or with a brownish tinge solution.
1 f.
trastuzumab emtanzine 160 mg
Excipients: sucrose - 514 mg, succinic acid - 10.1 mg, sodium hydroxide - 3.9 mg, polysorbate 20 - 1.7 mg.
Vials of colorless glass (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Antitumor drug.
Mechanism of action
Trastuzumab emtansin is a conjugate of a humanized monoclonal antibody (IgG1) to a human epidermal growth factor receptor 2 of the type HER2 (trastuzumab) and a tubulin polymerase inhibitor DM1 (a maytansine derivative) linked to each other via a stable thioester linker MCC (4- (N-maleniimidomethyl) cyclohexane-1-carboxylate). Emtansine is a complex of DM1-MCC.
The average number of DM1 molecules conjugated to each trastuzumab molecule is 3.5.
Trastuzumab emtansin selectively interacts with the human epidermal growth factor 2 receptor (HER2) receptor.
After binding to HER2 trastuzumab, emtansin enters the cell and undergoes proteolytic degradation in lysosomes, resulting in the release of DM1-containing cytotoxic catabolites (mainly lysine-MCC-DM1 complex). Thus, the conjugation of DM1 with trastuzumab causes the selectivity of the cytotoxic drug against tumor cells with overexpression of HER2 and facilitates the delivery of DM1 to the interior of the tumor cells.
The mechanism of trastuzumab emtansin is a combination of the mechanisms of action of trastuzumab and DM1.
Trastuzumab emtansin, like trastuzumab, binds to the domain IV of the extracellular domain of HER2, as well as to the Fc receptors. and the complement protein C1q. Trastuzumab emtansin, like trastuzumab, prevents the extracellular domain of HER2 from "squeezing" from the cell surface, inhibits intracellular signaling along the pathway of phosphatidylinositol-3-kinase (PI3-K), and also promotes the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) in breast cancer cells gland of a person with overexpression of HER2.
DM1, the cytotoxic component of trastuzumab emtansine, binds to tubulin and suppresses its polymerization. Due to the effect of the cytotoxic component of trastuzumab, emtansin, like DM1, causes blockade of the cell cycle in the G2 / M phase, which eventually leads to apoptosis. Results of the DM1 cytotoxicity study in vitro demonstrated that the activity of DM1 is 20-200 times higher than the activity of taxa and vinca alkaloids.
The structure of the MCC linker allows to limit the systemic release of DM1 and facilitates its directed delivery into the cells, which is confirmed by the very low content of free DM1 in the blood plasma.
Pre-clinical safety study data
Preclinical studies indicate that trastuzumab emtansin has an anaugenic and / or clastogenic toxicity.
There are data on the embryotoxic effect of trastuzumab and on the potential teratogenic and embryotoxic effects of DM1.
The results of preclinical studies indicate a risk of impaired fertility with the use of trastuzumab emtanzine.
PHARMACOKINETICS
Suction
Trastuzumab emtansin is administered iv. Other ways of drug administration have not been studied. The mean C max of trastuzumab emtanzine in serum is 83.4 (В± 16.5) mcg / mL with IV dose of the drug at a dose of 3.6 mg / kg every 3 weeks.
Distribution
The pharmacokinetics of trastuzumab emtanzine when administered iv every 3 weeks at doses of 2.4-4.8 mg / kg is linear. After intravenous administration of V d, trastuzumab emtanzine in the central chamber is 3.13 liters and is approximately equal to the plasma volume.
After repeated intravenous administration every 3 weeks, no cumulation of trastuzumab emtanzine was observed.
Metabolism
In studies on human liver microsomes in vitro, it has been shown that DM1, the low molecular weight component of trituzumab emtansine, is mainly metabolized by the CYP3A4 isoenzyme and, to a lesser extent, the CYP3A5 isoenzyme.
DM1 is not an inhibitor of the basic isoenzymes of the cytochrome CYP450 family in vitro. Tratstuzumab emtanzine, Lys-MCC-DM1, MCC-DM1 and DM1 catabolites are found in human plasma in low concentrations. According to the in vitro study, DM1 is a substrate for the glycoprotein P.
Excretion
After intravenous administration of trastuzumab emtansin in patients with metastatic breast cancer with overexpression of HER2, the clearance of trastuzumab emtansin was 0.68 l / day, T 1/2 - about 4 days.
In patients receiving doses of 1.2 mg / kg or less, a higher clearance of the drug was noted.
Body weight, serum albumin concentration, the sum of the largest diameter of the tumor sites by the RECIST criterion (Response Evaluation Criteriain Solid Tumors), the initial concentration of the "cleaved" extracellular domain (ECD) of HER2, the baseline trastuzumab concentration and baseline activity ACT in the serum are parameters that 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 emtanzine, in particular DM1, Lys-MCC-DM1 and MCC-DM1, are mainly excreted in bile and, to a minimum, in urine.
Pharmacokinetics in specific patient groups
Race and sex. The race does not affect the pharmacokinetics of trastuzumab emtanzine. The effect of sex on the pharmacokinetics of KadSilВ® has not been studied separately.
Age does not affect the pharmacokinetics of trastuzumab emtanzine. There were no significant differences in the pharmacokinetics of trastuzumab emtansin 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, QA does not affect the pharmacokinetics of trastuzumab emtanzine. The values ​​of pharmacokinetic parameters of trastuzumab emtansin in patients with mild renal insufficiency (KC 60-89 ml / min) and mean (KK 30-59 ml / min) are similar to those in patients with normal renal function (KK-90 ml / min). Data on the pharmacokinetics in patients with severe renal insufficiency, including the terminal stage (CC <30 mL / min), are limited, so it is not possible to give special instructions for dosing.
Violation of the function of the liver. The liver is the main organ of excretion of DM1 and catabolites containing DM1. The pharmacokinetics of trastuzumab emtansin and catabolites containing DM1 were studied after administration of 3.6 mg / kg of the CadsilВ® preparation to patients with metastatic HER 2-positive breast cancer having normal liver function (n = 10), lung (class A on the Child-Pugh scale and concentration of total bilirubin> 1.5? VGN and / or ALT or ACT> VGN, but <20? VGN; n = 10) and moderate (B class on the Child-Pugh scale with ALT and / or ACT> VGN, but <20? VGN ; n = 8) a violation of the liver.
Plasma concentrations of DM1 and catabolites containing DM1 (Lys-MCC-DM1 and MCC-DM1) were low and comparable in patients with impaired and without disturbed liver function.
The systemic exposures (AUC) of tranzuzumab emtansine during cycle 1 in patients with mild to moderate liver impairment were approximately 38% and 67% below exposure in patients with normal liver function, respectively. During the 3rd cycle, the exposure of trastuzumab emtanzine (AUC) after repeated administration in patients with mild or moderate impairment of liver function was within the values ​​observed in patients with normal liver function.
Studies of the preparation Kadsila В® in patients with severe impaired liver function (class C on the scale Child-Pugh) were not conducted.
INDICATIONS
- metastatic breast cancer.
KadsilВ® is used as a monotherapy after previous chemotherapy, including trastuzumab and taxane drugs (sequentially or in combination), or after the progression of the disease during or for 6 months after completion of adjuvant therapy including trastuzumab and taxane drugs (sequentially or in combination) in patients with inoperable locally advanced or metastatic HER2-positive breast cancer.
DOSING MODE
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 CadsilВ® (trastuzumab emtansin), and not the drug HerceptinВ® (trastuzumab).
The use of Kadsil В® 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 CadsilВ®. An obligatory criterion is 3+ points based on the results of immunohistochemical analysis (IHC) and / or the degree of amplification of 2.0 2.0 by the results of in situ hybridization (ISH). The test methods used must be validated.
In the patient's medical records, the trade name of the drug (KadsilaВ®) should be indicated. The replacement of Kadsil В® with another preparation of biological origin must be agreed with the attending physician.
The recommended dose of CadsilВ® is 3.6 mg / kg body weight once every 3 weeks (21-day cycle) as an IV infusion.
Therapy with Cadsil В® should be continued until signs of disease progression or unacceptable toxicity.
The first dose is recommended to be administered as a 90-minute IV 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 following infusions 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 В® when the patient has signs of an infusion reaction. In the case of a life-threatening infusion reaction, KadsilВ® 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 KadSilВ®, it is necessary to administer the drug as soon as possible in the recommended dose, while the infusion rate may be the same at 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 CadsilВ®. Relevant recommendations are given in Tables 1-5 below.
If the dose of the preparation Kadsila В® had to be reduced, then with subsequent injections it can not be increased.
Table 1. Scheme of dose reduction of KadSilВ®
Dose reduction rules (initial dose of 3.6 mg / kg) The recommended dose
1 dose reduction 3 mg / kg
2 dose reduction of 2.4 mg / kg
Necessity of further dose reduction Completely discontinue therapy
Table 2. Recommendations for correcting the dose of the preparation Kadsil В® with an increase in the activity of hepatic aminotransferases (ACT / ALT) in serum
Degree 2 (from> 2.5 to? 5? VGN) Degree 3 (from> 5 to? 20? VGN) Degree 4 (> 20? VGN)
Correction of the dosage of the preparation of Kadsil В® is not required. To discontinue therapy with Cadsil В® until the toxicity is reduced to? 2, then reduce the dose (see Table 1). Stop the therapy with Kadsil В®
Table 3. Recommendations for correcting the dose of the preparation Kadsila В® in the case of hyperbilirubinemia
Degree 2 (from> 1.5 to? 3? VGN) Degree 3 (from> 3 to? 10? VGN) Degree 4 (> 10? VGN)
Discontinue therapy with Cadsil® until the toxicity is reduced to ≥1 degree, then resume treatment at the same dose. Discontinue therapy with Cadsil® until the toxicity is reduced to ≥1 degree, then reduce the dose (see Table 1). Stop the therapy with Cadsil®
Therapy with Cadsil В® should be completely discontinued if the activity of hepatic aminotransferases in the serum is> 3? VGN with a total bilirubin> 2? VGN, and also in the case of development of nodal regenerative hyperplasia.
Table 4. Recommendations for correcting the dose of the preparation Kadsila В® in thrombocytopenia
Degree 3 Degree 4
from 25 000 to <50 000 / mm 3 <25 000 / mm 3
Discontinue therapy with Cadsil В® until the toxicity is reduced to? 1 degree (up to? 75 000 / mm 3 ) and resume treatment at the same dose Interrupt therapy with Cadsil В® until toxicity is reduced to? 1 degree (up to? 75 000 / mm 3 ), then lower the dose (see Table 1)
Table 5. Recommendations for correcting the dose of CadsilВ® in patients with left ventricular dysfunction
Symptomatic congestive heart failure LVEF * <40% LVEF 40% -45% LVEF> 45%
Decrease? 10% compared to the original value Decrease <10% compared to the original value
Completely discontinue therapy with Kadsil В® . Interrupt therapy with Cadsil В® . Interrupt therapy with Cadsil В® . Continue therapy with Cadsil В® . Continue therapy with Cadsil В® .
Conduct reassessment of LVEF after 3 weeks. When re-determining LVEF <40% completely discontinue therapy. Conduct reassessment of LVEF after 3 weeks. If LVEF is not restored to a value of 10% compared with the baseline, then completely discontinue treatment with the drug Kadsila В® . Conduct reassessment of LVEF after 3 weeks.
* LVEF - fraction of the ejection of the left ventricle.
Therapy with Cadsil В® should be completely discontinued if the patient is diagnosed with interstitial lung disease or pneumonitis.
With the development of peripheral neuropathy of 3 and 4 degrees of severity, therapy with KadsilВ® should be discontinued until symptoms are resolved to grade 2.
Special instructions for dosing
Correction of the initial dose of Cadsil ® in patients aged ≥65 years is not required. The efficacy and safety of the use of Cadsil ® in patients aged ≥75 years are not established due to insufficient data.
The efficacy and safety of Cadsil В® in children have not been established.
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 renal impairment, including the terminal stage of renal failure (QC <30 mL / min), has not been established.
Patients with mild or moderate impairment of liver function correction of the initial dose is not required (see subsection "Pharmacokinetics in special patient groups" in the section "Pharmacokinetics"). Studies of the preparation Kadsila В® in patients with severe impairment of liver function were not performed. When using Kadsila В® in patients with mild to moderate liver dysfunction, caution should be exercised in connection with known hepatotoxicity of the drug (see section "Special instructions").
Preparation for introduction
The preparation Kadsila В® is administered only in / in the drip! Enter the drug in / in a stream or bolusno it is impossible.
Dissolution and dilution of the preparation Kadsila В® 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 chemotherapeutic drugs.
CadsilВ® is incompatible with a 5% dextrose solution because of the possibility of protein aggregation.
The preparation of KadsilВ® should not be mixed or diluted together with other medicinal products.
The solution of the preparation Kadsila В® is compatible with infusion bags made of PVC (PVC) or polyolefin (PVC 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 polyester-sulfone (PES) infusion filter with a pore diameter of 0.2-0.22 Ојm.
In the case of using 0.45% sodium chloride solution embedded application infusion polyethersulfone filter with a pore diameter of 0.2-0.22 microns is required.
The solution preparation Quds В® contains no preservatives and is intended for single use.
Instructions for preparing the concentrate (reconstituted solution) for solution for infusion
1. The sterile syringe slowly introduce 5 ml of sterile water for injection into the vial containing 100 mg trastuzumab emtanzina or 8 ml sterile water for injection into the vial containing 160 mg trastuzumab emtanzina. The resulting concentration of the solution should be 20 mg / ml.
2. Gently shake the vial rotational movements until complete dissolution of the lyophilizate. Do not shake!
Before use the concentrate obtained after dissolving the lyophilisate, it is necessary to visually check for the absence of foreign bodies, discoloration or clouding. The concentrate must be transparent or slightly opalescent without visible particles colorless or brownish tint. It is impossible to use the concentrate, if it contains visible particles by its opacity or color change.
Concentrate for solution for infusion should be used immediately after dissolving the lyophilisate. Concentrate can be stored for 24 hours at a temperature of 2-8 В° C, provided that the dissolution took place in a controlled and validated aseptic conditions. Do not freeze!
If after this time the concentrate is not used, it should be disposed.
Instructions for preparing the solution for infusion
1. Determine the desired dose (mg / kg) drug Quds В® .
2. Determine the volume of the concentrate for solution for infusion required to administer the required dose of drug Quds В® , according to the following formula:
? Volume (ml) = body weight (kg) Dose (mg / kg) / 20 (mg / mL) (concentration reconstituted solution)
3. Select the required volume with the concentrate from the bottle and put it in an infusion bag made of polyvinylchloride (PVC) or polyolefin (containing no latex or PVC) with 250 ml of 0.45% or 0.9% sodium chloride solution.
4. Gently invert infusion bag mixing for the solution. Do not shake!
Infusion solutionshould be used immediately after preparation. In exceptional cases, the solution for infusion may be stored in a refrigerator at a temperature of from 2 В° to 8 В° C for up to 24 hours before use if preparation of the solution took place in a controlled and validated aseptic conditions. During storage, the solution for infusion prepared using 0.9% sodium chloride solution, allowed formation of visible particles. Do not freeze!
SIDE EFFECT
The most frequent serious adverse reactions are fever, thrombocytopenia, vomiting, abdominal pain, nausea, constipation, diarrhea, shortness of breath and pneumonia.
The most common (? 25%) adverse reactions were bleeding (including epistaxis), increase in liver transaminases, fatigue, musculoskeletal pain, headache. Most of the adverse reactions were observed by 1 or 2 degrees.
The most frequent (> 2%) adverse reactions 3 and 4 degrees of severity according to the criteria of toxicity scale of the National Cancer Institute (NCI CTC AE), Version 3.0, are thrombocytopenia, fatigue, elevated liver transaminases, anemia, hypokalemia, kostno muscle pain and neutropenia.
In this section, adverse reactions are grouped according to the classes of medical vocabulary organ systems for regulatory activities MedDRA. The following classification is used to describe the frequency of adverse reactions: very common (1/10?), Often, infrequently, rarely (1/10 (1/100 and <1/10?) (1/1000 and <1/100?)? 000 and <1/1000) and very rare (<1/10 000), including isolated cases. Adverse reactions of each group are arranged in decreasing order of severity, as determined in accordance with the scale toxicity criteria of the National Cancer Institute (NCI CTC AE), version 3.0.
From hemopoiesis system: very often - thrombocytopenia, anemia; often - neutropenia, leukopenia.
Immune system: often - drug hypersensitivity.
From a metabolism: often - hypokalemia.
Psychiatric disorders: very often - insomnia.
From the nervous system: very often - peripheral neuropathy, headache, dizziness; often - taste disturbance (dysgeusia), memory impairment.
From a sight organ: often - dry eyes, conjunctivitis, blurred vision, increased lacrimation.
Cardio-vascular system: very often - bleeding; often - left ventricular dysfunction, increased blood pressure.
The respiratory system: very often - nosebleeds, cough, shortness of breath; infrequently - pneumonitis.
From the digestive system:very often - stomatitis, diarrhea, vomiting, nausea, constipation, dry mouth, abdominal pain; often - indigestion, bleeding gums.
Of the liver and biliary tract: infrequently - phenomenon hepatotoxicity, liver failure, nodular regenerative hyperplasia, portal hypertension.
Skin and subcutaneous tissue disorders: very often - rash; often - itching, alopecia, impaired nail structure, palmar-plantar eritrodizesteziya, urticaria.
On the part of the musculoskeletal system: very often - musculoskeletal pain, arthralgia, myalgia.
From the urinary system: very often - urinary tract infection.
From the laboratory and instrumental data:very often - increase in liver transaminases; often - increasing the activity of alkaline phosphatase in the blood.
General disorders and reactions at the injection site: very often - fatigue, fever, fatigue, chills; often - peripheral edema, infusion reactions; infrequently - extravasation at the infusion site.
Below is the information on selected adverse reactions.
Elevated liver transaminases (AST / ALT)
is observed against the drug Quds В® increased activity of aminotransferases 1-4 severity and accumulation effect aminotransferase in serum, in most cases were reversible.
Aminotransferase activity increased maximum on day 8 after infusion, and tend restored to 1 degree or to normal by the time the next infusion. This indicator in most cases restored to 1 degree or to normal within 30 days after discontinuation of therapy.
Elevated liver transaminases observed in 28% of patients receiving drug therapy Quds В® .
Increased ALT activity and ACT 3 and 4 severity was observed in 4.1% and 2.8% of patients, respectively, and are usually occurred at the beginning of therapy (1-6 cycles). Typically, the human liver? 3 severity were not associated with adverse outcome, and liver function tests at follow-up showed a gradual improvement in the patient to a level allowing to continue therapy with Quds В® at the recommended dose or reduced. Depending legitimate increase in serum transaminase activity from the exposure (AUC), total exposure, C MAX trastuzumab serum emtanzina or C MAX DM1 was not observed.
Impaired function of the left ventricle of the heart
The incidence of left ventricular dysfunction on background therapy with Quds В® was 2%. In most cases, there was an asymptomatic decline in left ventricular ejection fraction 1 or 2 degrees. Cases left ventricle 3 or 4 severity dysfunction were observed with a frequency of 0.3%, usually at the beginning of treatment (cycle 1-2).
Additional monitoring of LVEF is recommended in patients with LVEF? 45%.
Infusion reactions
Infusion reactions (cytokine release), characterized by one or more of the following symptoms: "flushes", chills, fever, dyspnea, hypotension, wheezing, bronchoconstriction, and tachycardia.
The frequency of infusion reactions when using the drug Quds В®It was 4.5%. Infusion reaction severity was observed 3 is very rare, cases of grade 4 severity were observed.
Time resolution of symptoms infusion reactions is generally from several hours to one day after the end of infusion.
It was observed depending on the incidence of infusion reactions on the dose.
Hypersensitivity reactions / anaphylaxis
incidence of hypersensitivity reactions was 2.6%, with hypersensitivity reactions 3 and 4 severity registered. In most cases, hypersensitivity reactions were mild to moderate and resolved after appropriate treatment.
Thrombocytopenia
The incidence of thrombocytopenia (platelet count decrease) in the treatment of drug Quds В®It amounted to 31.4%.
Most cases of thrombocytopenia was 1 or 2 severity (number of platelets? 50,000 / mm 3 ), with the most low platelet count was observed at day 8 after injection. In the following days, the figure increases and reaches 0 or 1 severity (? 75,000 / mm 3 ) the time following drug administration Quds В® . There was a higher incidence and severity of cases of thrombocytopenia in patients - Asians. Regardless of race incidence of thrombocytopenia grade 3 and 4 (<50,000 / mm 3 ) due to drug therapy Quds В® was 11.3%.
The frequency of major bleeding (? Grade 3) was 1.7%. Patients - immigrants from Asia the figure was 1%.
Immunogenicity
may develop an immune response to trastuzumab emtanzin.
In applying the drug Quds В® in 5.3% of patients were found to antibody trastuzumab emtanzinu in one or more time points after drug administration. The clinical significance of antibody to trastuzumab emtanzinu not installed.
Extravasation
In applying the drug Quds В® observed responses associated with hit drug under the skin and were manifested in the form of erythema, pain, skin irritation, pain or swelling at the injection site.
These phenomena are most often occurred during the first 24 hours post infusion and were generally mild.
When conducting infusions Quds В® should track the possible formation of subcutaneous infiltration at the injection site. Specific treatment of symptoms extravasation preparation Quds В® absent.
Changes in laboratory parameters
Table 6. Certain disorders laboratory parameters were observed when using the drug Quds В®
All severity (%) Severity 3 (%) Severity 4 (%)
Liver function tests
Increased bilirubin concentration 21 <1 0
Increased activity ACT 98 8 <1
Increased ALT 82 5 <1
Hematological parameters
Reduction in platelet count 85 March 14
Reduced hemoglobin concentration 1 63 5
decrease in the number of neutrophils 41 4 <1
Electrolytes
Reduction of potassium concentration of 35 3 <1
CONTRAINDICATIONS
- increased sensitivity to trastuzumab emtanzinu and to other components of the formulation;
- infuzionnnye reactions associated with the use of trastuzumab, which led to the cancellation of therapy;
- severe renal failure, including end-stage (QC <30 mL / min);
? - hepatic insufficiency, including enhancement of hepatic transaminases> 3 ULN at a concentration of total bilirubin> 2 ULN (efficacy and safety have not been established);
- regenerative nodular hyperplasia of the liver;
- symptomatic congestive heart failure;
- the value of ejection fraction of the left ventricle <50% before treatment;
- serious cardiac arrhythmia requiring drug therapy;
- myocardial infarction or unstable angina who developed within 6 months prior to treatment;
- chronic heart failure history;
- diffuse interstitial lung disease, pneumonitis;
- dyspnea at rest caused by progression of the malignant disease or a comorbidity;
- platelet count <100,000 / mm 3 before treatment;
- peripheral neuropathy of grade 3 severity before treatment (efficacy and safety have not been established);?
- Pregnancy;
- the period of lactation (breastfeeding);
- the age of 18 years (effectiveness and safety of use in children has not been established);
Precautions: dysfunction of mild or moderate liver (see section "Disturbances of liver function" in "Pharmacokinetics" sections "Dosage" and "Cautions".).
Left ventricular dysfunction (see. Section "Special instructions", subsection "left ventricular dysfunction").
PREGNANCY AND LACTATION
In case of pregnancy the patient should consult a doctor immediately. It is necessary to warn the woman of the possibility of adverse effects on the fetus. If a pregnant woman decides to continue therapy with Quds В® , it should be under close medical supervision.
Women with reproductive potential and male patients, as well as women of childbearing age who are sexual partners of patients receiving the drug Quds В® , must use effective contraception during treatment with Quds В® and for 7 months after the last dose.
It is not known whether trastuzumab emtanzin excreted in breast milk. Breast-feeding is not recommended during treatment and for at least 7 months after therapy with Quds В® .
APPLICATION FOR FUNCTIONS OF THE LIVER
Use of the drug in patients with severe renal insufficiency, including terminal phase (creatinine clearance <30 mL / min) is contraindicated.
Correcting the initial dose in patients with mild renal insufficiency (CC 60-89 ml / min) and average (CC 30-59 ml / min) the severity required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Precautions should primenenyat drug in patients with active liver transaminases> 2.5? ULN or total bilirubin concentration of> 1.5 Г— ULN at baseline.
Use of the drug is contraindicated in hepatic impairment, including increase in liver transaminases> 3 ULN during the concentration of total bilirubin> 2? ULN (efficacy and safety have not been established).
APPLICATION FOR CHILDREN
Do not use this medication in children and adolescents under 18 years of age (efficacy and safety in children has not been established).
APPLICATION IN ELDERLY PATIENTS
Correction of the initial dose of the drug Quds ® in patients aged ≥65 years of age is not required. Efficacy and safety of the drug Quds ® in patients aged? 75 years have not been established because of insufficient data.
SPECIAL INSTRUCTIONS
Preparation Quds В® should be administered only in the presence of a tumor overexpressing HER2 protein as determined by immuno-histochemical reaction (IHC), or HER2 gene amplification, by specific hybridization in situ (FISH or SISH).
Violations of the lung
Using the drug Quds В® are registered cases of diffuse interstitial lung disease (ILD), inter alia, pneumonitis. Some of them have led to the development of acute respiratory distress syndrome, or death. ILD symptoms include shortness of breath, cough, fatigue and pulmonary infiltrates. T
