Cabazred® (Kabazred®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceCabazitaxelCabazitaxel
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  • Jevtana®
    concentrate d / infusion 
    Sanofi-Aventis France     France
  • Cabazred®
    concentrate d / infusion 
    Dr. Reddy's Laboratories Ltd.     India
    • Dosage form: & nbspconcentrate for solution for infusion
    Composition:

    In 1 bottle with the drug contains:

    active substance: cabazitaxel acetone solvate (in terms of cabazitaxel) - 60.00 mg;

    Excipients: polysorbate 80, citric acid anhydrous.

    In 1 ml of the concentrate contains 40 mg of cabazitaxel acetone solvate (in terms of cabazitaxel).

    In 1 bottle with a solvent contains: Ethyl alcohol (ethanol 96%), water for injection.

    Notes

    1. An excess of the preparation is used to compensate losses during the preparation of the premix (concentrate-solvent mixture) and extract the dose from the premix. The target filling volume is 1.83 ml, which corresponds to a target weight of 1.976 g and the target content of cabazitaxel acetone solvate (in terms of cabazitaxel) 73.2 mg.

    2. The solvent is packaged in excess (a target volume of 5.7 ml) so that after addition to the Kabazred® concentrate, an accurate dose of the premix 10 mg / ml is recovered.

    Description:

    Concentrate for solution for infusion: transparent oily liquid from yellow to brownish-yellow color.

    Solvent: clear, colorless liquid.

    Pharmacotherapeutic group:Antitumor agent - alkaloid
    ATX: & nbsp

    L.01.C.D.04   Cabazitaxel

    Pharmacodynamics:

    Cabazitaxel is an antitumor agent that acts by destroying the microtubular cell network. Cabazitaxel binds to tubulin and promotes the assembly of tubulin in microtubules and at the same time inhibits their disassembly. This leads to the stabilization of microtubules, which eventually inhibits the mitotic and interphase activity of the cell.

    Kabasitaxel demonstrated a wide range of antitumor activity against late stages of human tumors, xenotransplanted to mice. Cabazitaxel is active against docetaxel-sensitive tumors. Besides cabazitaxel showed activity against tumor models that are insensitive to chemotherapy, including docetaxel.

    Pharmacokinetics:

    Population analysis of pharmacokinetic parameters was performed in patients, including patients with locally advanced solid tumors, metastatic breast cancer and metastatic prostate cancer. These patients received doses of cabazitaxel in the range of 10-30 mg / m2 body surface area weekly or every 3 weeks.

    Absorption

    After a one-hour intravenous infusion of cabazitaxel at a dose of 25 mg / m2 body surface area in patients with metastatic prostate cancer, the maximum concentration of cabazitaxel in blood plasma (FROMmax) was achieved by the end of a one-hour infusion (TmOh), the average value of Cmax was 226 ng / ml. The average area under the pharmacokinetic curve "concentration-time" (AUC) was 991 ng * h / ml.

    Patients with locally advanced solid tumors showed no large deviations in the dose-proportionality of concentrations of cabazitaxel in blood plasma in the dose range of 10-30 mg / m2 body surface area.

    Distribution

    The volume of the distribution in the equilibrium state (Vss) was 4870 liters (2640 l / m2 for patients with a median body surface area of ​​1.84 m2).

    In vitro The relationship between cabazitaxel and human serum proteins was 89-92% and was unsaturated to a concentration of 50,000 ng / ml. which exceeds FROMmOh, observed during clinical use of the drug. Cabazitaxel mainly communicates withSerum albumin (82.0%) and lipoproteins (87.9% for high-density lipoproteins, 69.8% for low-density lipoproteins, and 55.8% for very low-density lipoproteins). In vitro in human blood, the ratio of blood concentration and plasma concentration is in the range 0.90 - 0.99, indicating an equal distribution of cabazitaxel in blood and blood plasma. Studies conducted on animals have shown that cabazitaxel and its metabolites are excreted into breast milk, and cabazitaxel still penetrates and through the placental barrier.

    Metabolism

    Cabazitaxel is extensively metabolized in the liver (≥95%), mainly by isozymes of the subfamily CYP3A (80-90%). Cabazitaxel is the main compound circulating in the blood plasma. In addition to him, 7 metabolites (including 3 active metabolites formed as a result of O-demethylation) were identified in the blood plasma. The concentration in the blood plasma of the main of them is 5% of the concentration in the blood plasma of unchanged cabazitaxel. About 20 metabolites of cabazitaxel are excreted in urine and feces.

    According to research in vitro the potential risk of inhibition of cabazitaxel in clinically significant concentrations of hepatic metabolism is possible with regard to preparations that are mainly substrates of the isozymes of the subfamily CYP3A. However, there is no potential risk of inhibiting the metabolism of drugs that are substrates of other isoenzymes CYP (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP2D6), as well as in vitro Cabazitaxel does not induce isoenzymes of the subfamily CYP1A, isoenzyme CYP2C9, and isozymes of the subfamily CYP3A.

    Studies on human interaction have shown that cabazitaxel (administered as a one-hour intravenous infusion at a dose of 25 mg / m2 surface area of ​​the body) did not alter the plasma concentrations of midazolam, the reference substrate of the isozymes of the subfamily CYP3A. In this way, in vivo cabazitaxel does not inhibit isozymes of the subfamily CYP3A.

    Strong inductors or inhibitors of the isoenzymes of the subfamily CYP3A can change the concentration of cabazitaxel in blood plasma, since cabazitaxel is mainly metabolized with the participation of isoenzyme CYP3A.

    Prednisolone, when applied at a dose of 10 mg / day does not change the pharmacokinetics of cabazitaxel.

    In vitro cabazitaxel does not inhibit multiple resistant proteins to chemotherapeutic agents (MRP1 and MRP2) or an organic cation carrier (OCT1). Cabazitaxel inhibits the transport of P-glycoprotein (P-gP) (digoxin, vinblastine), proteins of resistance to chemotherapeutic drugs for breast cancer (BCRP) (methotrexate) and polypeptides transporting organic anions (OATP1B3) (cholecystokinin - CCK8), in concentrations at least 15 times higher than those observed in clinical settings, and also inhibits the transport of OATP1B1 (estradiol-17p-glucuronide) in concentrations of only 5 times higher than those observed in clinical settings. Therefore, in a dose of 25 mg / m2 body surface area risk of interaction kabasitaxel in vivo with substrates MRP, OST1, P-gp. BCRP and OATP1B3 is unlikely. The risk of interaction between cabazitaxel and the OATP1B1 transporter is possible, especially during intravenous infusion (1 hour) and up to 20 min after the end of the infusion.

    Excretion

    After a one-hour intravenous infusion [14C] -catabasitaxel (labeled with radioisotope cabazitaxel) at a dose of 25 mg / m2 body surface area in cancer patients approximately 80% of the administered dose is excreted within two weeks. Cabazitaxel mainly, is excreted from the body through the intestine (with feces) in the form of numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and its metabolites is less than 4% of the administered dose (2.3% of the administered dose is excreted unchanged in urine).

    Cabazitaxel has a high plasma clearance of 48.5 l / h (26.44 l / h / m2 body surface area in patients with median body surface area 1.84 m2), and a long half-life of 95 h.

    Special patient groups

    Elderly patients

    In a population analysis of the pharmacokinetic data of patients aged 65 years and older, there was no age effect on the pharmacokinetics of cabazitaxel.

    Patients of childhood

    The safety and effectiveness of kabasitaxel in children and adolescents under 18 years of age have not been established.

    Liver failure

    Cabazitaxel is excreted from the body mainly through hepatic metabolism. Hepatic insufficiency is mild (total serum bilirubin> 1 and ≤1.5 x VGN (upper limit of normal) or ACT (aspartate aminotransferase) of blood serum> 1.5 x VGN) and the mean (total bilirubin> 1.5 and ≤ 3.0 x VGN) did not exert a severity rating influence on the pharmacokinetics of cabazitaxel in patients in a special study. In patients with severe hepatic insufficiency (total bilirubin> 3.0 x VGN), a decrease in clearance of cabazitaxel by 39% was observed, which indicates the effect of severe hepatic insufficiency on the pharmacokinetics of the drug.

    Renal insufficiency

    Cabazitaxel is slightly excreted by the kidneys (2.3% of the dose).

    Population pharmacokinetic analysis based on data from 170 patients, 59 patients with mild renal insufficiency (creatinine clearance 50-80 ml / min) and 14 patients with moderate renal insufficiency (creatinine clearance 30-50 ml / min ), showed that renal failure of mild to moderate severity did not have a significant effect on the pharmacokinetics of cabazitaxel. This was confirmed by a comparative study of pharmacokinetics in patients with solid tumors with normal renal function (8 patients),patients with moderate renal insufficiency (8 patients) and patients with severe renal failure (9 patients) who received treatment with cabazitaxel in the form of intravenous infusion up to 25 mg / m2 body surface area. In the study, there were two patients with a creatinine clearance <15 mL / min / 1.73 m2 (8 ml / min / 1.73 m2 and 14 ml / min / 1.73 m2). Therefore, there are limited data on the use of cabazitaxel in patients with terminal renal failure. The results of a study of the pharmacokinetics and safety of cabazitaxel in 8 patients showed that severe renal failure did not have a significant effect on the pharmacokinetics and safety of cabazitaxel.

    Pharmacokinetic interaction with other drugs

    Kabasitaxel is mainly metabolized by isozymes of the subfamily CYP3A.

    The course of ketoconazole (400 mg twice daily), a strong inhibitor of the isozymes of the subfamily CYP3A, led to a decrease in the clearance of cabazitaxel by 20% with a corresponding increase in its AUC on 25%. Simultaneous use of aprepitant, a moderate inhibitor of isoenzymes of the subfamily CYP3A, did not affect the clearance and systemic exposure of cabazitaxel.

    The course reception of rifampin (600 mg once a day), a strong inducer of isoenzymes of the subfamily CYP3A, led to an increase in clearance by 21% and a corresponding decrease AUC on 17%.

    Indications:

    Metastatic castration-resistant prostate cancer in patients who previously received chemotherapy with the inclusion of docetaxel (in combination with prednisolone).

    Contraindications:

    - Anamnesis for severe hypersensitivity reactions to cabazitaxel or other taxanes, or excipients of the formulation.

    - The number of neutrophils in peripheral blood is less than 1500 / mm3.

    - Severe hepatic insufficiency (total serum bilirubin> 3 x VGN.

    - Simultaneous use with the vaccine against yellow fever, as well as with other live attenuated vaccines (see section "Interaction with other drugs").

    - Children and adolescents under 18 years of age (safety and efficacy not established).

    Carefully:

    - In patients with terminal renal failure (creatinine clearance <15 mL / min) (due to their condition and limited data, treatment should be conducted with caution and with careful medical supervision during treatment (see the sections "Pharmacokinetics", "Application Dosages").

    - In patients with hepatic insufficiency mild (total serum bilirubin> 1 and ≤1.5 x VGN or ACT serum> 1.5 x VGN) and medium (total bilirubin> 1.5 and ≤3.0 x VGN) severity (see the sections "Pharmacokinetics", "Method of administration and dose" and "Special instructions").

    - In patients with a hemoglobin content in peripheral blood <10 g / dl.

    - Patients with conditions or conditions predisposing to neutropenia and / or complications with prolonged neutropenia (age over 65, low overall status, low body weight, previous episodes of febrile neutropenia, previous intensive radiation therapy, and other serious co-morbidities) (requires careful medical supervision during treatment, possibly preventive introduction of granulocyte colony-stimulating factor (G-CSF)).

    - In patients with a high risk of developing gastrointestinal complications: patients with neutropenia; elderly patients; patients concomitantly taking non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents or anticoagulants; patients with diseases of the gastrointestinal tract,such as ulcerative lesions of the gastrointestinal tract and gastrointestinal hemorrhages in the anamnesis.

    - In patients with alcoholism, patients with liver disease and epilepsy (since the included solvent includes ethanol) - see section "Special instructions".

    - In patients with previous radiotherapy of the abdominal and pelvic region (see section "Special instructions").

    - In patients who simultaneously take strong / moderate inhibitors of the isoenzymes of the subfamily CYP3A and strong inductors of the isoenzymes of the subfamily CYP3A (see the sections "Pharmacokinetics", "Method of administration and dose", "Interaction with other drugs", "Special instructions").

    - In patients who simultaneously take St. John's wort (see the sections "Pharmacokinetics", "Method of administration and dose", "Interaction with other drugs", "Special instructions").

    Dosing and Administration:

    The use of cabazitaxel should be performed only in specialized oncology units under the supervision of a doctor who has special training in antitumor chemotherapy.The department should have the necessary conditions and medications to help with the emergence of hypersensitivity reactions, such as lowering blood pressure (BP) and bronchospasm.

    Secondary remediation

    To reduce the risk of development and severity of hypersensitivity reactions prior to the administration of cabazitaxel, premedication is carried out with the following intravenous drugs:

    - antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or the like in equivalent doses);

    - glucocorticosteroids (GCS): dexamethasone 8 mg or equivalent doses of another SCS;

    - blockers of H2-histamine receptors (ranitidine or a similar preparation in equivalent doses).

    Prophylactic use of antiemetics is recommended inside or, if necessary, intravenously.

    Dosing regimen

    The recommended dose of cabazitaxel is 25 mg / m2 of the body surface area, which is administered by a one-hour intravenous infusion every 3 weeks against the backdrop of administering glucocorticosteroids at a dose of 10 mg per prednisolone daily during the entire period of treatment with cabazitaxel.

    Correction of the administered dose

    Recommended changes in the administered dose due to the development of adverse reactions in patients receiving cabazitaxel

    Adverse Reactions

    Change in the administered dose

    Long-term (more than 1 week) neutropenia ≥3 severity, despite the use of appropriate treatment, including the introduction of G-CSF.

    Postponement of the next treatment cycle until the number of neutrophils in the peripheral blood is restored to more than 1500 cells / mm3, then lowering the dose in subsequent cycles with 25 mg / m2 body surface area up to 20 mg / m2 body surface area.

    Febrile neutropenia or neutropenic infection.

    Postponement of the next treatment cycle to reduce or resolve febrile neutropenia and to restore the number of neutrophils in peripheral blood to more than 1500 cells / mm3, then lowering the dose in subsequent cycles with 25 mg / m2 body surface area up to 20 mg / m2 body surface area.

    Diarrhea ≥3 severity or persistent diarrhea, despite appropriate therapy and replenishment of fluid and electrolyte losses.

    Postponement of the next treatment cycle to reduce or resolve diarrhea, then reduce the dose in subsequent cycles with 25 mg / m2 body surface area up to 20 mg / m2 body surface area.

    Peripheral Neuropathy ≥2 degrees of severity.

    Delay treatment until symptoms decrease, then lowering the dose in subsequent cycles with 25 mg / m2 body surface area up to 20 mg / m2 body surface area.

    If the patient with the introduction of the drug at a dose of 20 mg / m2 body surface area continue to occur any of the above reactions, it is recommended to reduce the dose of the drug to 15 mg / m2 body surface area or discontinue drug treatment. Data on the use of the drug in a dose of less than 20 mg / m2 body surface area are limited.

    Special patient groups

    Children and teenagers under 18 years of age

    The safety and efficacy of kabasitaxel in children and adolescents under 18 years of age have not been established.

    Elderly patients

    No special correction of the dosing regimen is required when using cabazitaxel in elderly patients.

    Patients with hepatic insufficiency

    In patients with mild hepatic insufficiency (total serum bilirubin> 1 and ≤1.5 x VGN or ACT serum> 1.5 x VGN) dose of cabazitaxel should be reduced to 20 mg / m2 body surface area, with care being required, careful monitoring of patients' condition and monitoring of adverse reactions (cm.section "Pharmacokinetics", "With caution" and "Special instructions").

    In patients with moderate hepatic insufficiency (total serum bilirubin> 1 and ≤3 x VGN), the maximum tolerated dose is 15 mg / m2 body surface area. If patients with hepatic insufficiency of moderate severity are prescribed, the dosage of cabazitaxel should not exceed 15 mg / m2 body surface area. However, there are limited data on the effectiveness of this dose (see the "Precautions" and "Special instructions" sections). Cabazitaxel is contraindicated in patients with severe hepatic insufficiency (total serum bilirubin> 3 x VGN (see section "Pharmacokinetics", "Contraindications" and "Special instructions").

    Patients with renal insufficiency

    Cabazitaxel is excreted by the kidneys to a minimal extent.

    There is no need for correction of the dosing regimen in patients with renal insufficiency without hemodialysis. However, in patients with end-stage renal failure (QC less than 15 ml / min), due to their condition and limited data, treatment should be conducted with caution and with careful medical supervision during treatment (see the section "Pharmacokinetics", "With caution").

    The simultaneous use of cabazitaxel with inducers and inhibitors of the isoenzymes of the subfamily CYP3A

    It is necessary to avoid simultaneous use of medicines that are strong inductors of isoenzymes of the subfamily CYP3A or strong inhibitors isoenzymes of the subfamily CYP3A (see the sections "Pharmacokinetics" and "Interaction with other drugs"). However, if the patient needs simultaneous use of cabazitaxel and strong inhibitors of the isoenzymes of the subfamily CYP3A. should consider reducing the dose of cabazitaxel by 25% (see the sections "Pharmacokinetics" and "Interaction with other drugs").

    Method of administration

    Intravenous infusion.

    During the intravenous infusion solution of cabazitaxel, use a filter inserted into the intravenous infusion system with a nominal pore diameter of 0.22 μm.

    Cabazitaxel, a concentrate for the preparation of a solution for infusions, should always be diluted with ALL the contents of the supplied solvent before adding to the infusion solution.

    Cabazitaxel should not be mixed with other drugs and solutions, with the exception of 5% dextrose and 0.9% sodium chloride solution.The preparation contains polysorbate 80, which, as is known, increases the rate of extraction of di- (2-ethylhexyl) phthalate from polyvinyl chloride (PVC). In this regard, you can not use containers for infusion liquids from PVC and kits for infusion of polyurethane for the preparation and administration of an infusion solution of cabazitaxel.

    Preparation of solution for infusion and handling of the drug

    As with other antitumor drugs, care should be taken and gloves used when working with cabazitaxel and when preparing its infusion solution.

    If the solution of cabazitaxel at any stage of work with it has got on the skin, it should be washed immediately and thoroughly with soap and water, and if - on the mucous membrane, then with one water.

    Work with kabazitakselom should only personnel who have skills in handling cytotoxic drugs.

    Carefully read ALL of the following information on preparing the preparation for intravenous administration before mixing and dilution.

    Each flask with concentrate contains 60 mg of cabazitaxel in E5 ml (nominal volume) (with a volume of filling the E83 ml bottle containing 73.2 mg of cabazitaxel). Each vial with solvent contains 4.5 ml (nominal volume) (volume filling 5.7 ml of solvent).

    Note

    These filling volumes were established during the development of the preparation in order to compensate for fluid loss during the preparation of the premix (the solution obtained as a result of the primary dilution of the concentrate with the applied solvent). Thus, the vials of both kabazitaxel and solvent concentrate contain an excessive amount of active substance and solvent to compensate for fluid loss during solution preparation. This excess amount of active substance and solvent ensures that after diluting the concentrate of cabazitaxel to ALL of the contents of the solvent vial contained in the package, the premix will contain a solution of cabazitaxel at a concentration of 10 mg / ml. The kabasitaxel concentrate needs two dilutions before administration. Follow the cooking instructions below.

    Preparation of a solution for infusions is carried out in aseptic conditions in 2 stages.

    Step 1. Initial dilution of the concentrate to prepare a solution for infusion with the applied solvent.

    - Inspect the kabasitaxel concentrate flask and the solvent supplied with it. The concentrate solution should be transparent.

    - Remove ALL the contents of the supplied solvent with a syringe, slightly tilting the vial, and insert into a vial of concentrate. To minimize the pricing when introducing the solvent through the needle into the vial of concentrate, direct the needle to the inner wall of the vial and inject the solvent slowly.

    - Remove the syringe and needle and mix the contents of the vial for about 45 seconds, gently turning the vial several times until a clear and homogeneous solution is obtained.

    - Allow the solution to stand for a few minutes (about 5 minutes) and then check the solution for homogeneity and clarity. During this time, a small amount of foam can normally be maintained.

    The resulting mixture (premix) has a concentration of cabazitaxel 10 mg / ml (the extract volume is 6 ml). The premix should be immediately diluted additionally to obtain a solution for infusions (see step 2).

    Stage 2. Preparation of a solution for infusions

    Extract the required amount of the initially diluted preparation (solution with a concentration of 10 mg / ml cabazitaxel) with a graduated syringe (because of the possibility of containing a foam in the vial of the syringe, insert the syringe needle during extraction solution into the middle of the bottle stopper) and insert it into a sterile container with an infusion solution (except for the PVC container) (5% dextrose solution or 0.9% sodium chloride solution). The concentration of the infusion solution of cabazitaxel should be from 0.10 mg / ml to 0.26 mg / ml.

    To administer the prescribed dose, more than one vial of the initially diluted solution may be required.

    Remove the syringe and mix the contents of the infusion container or vial manually with jiggling movements.

    Like all other solutions for parenteral administration, the resulting solution should be visually inspected before use. The solution containing precipitates can not be administered to the patient and should be disposed of in accordance with national requirements for the disposal of such substances.

    The infusion solution of cabazitaxel should be administered immediately after preparation.However, under special conditions (see below), the storage time may be longer.

    Unused product or consumables must be disposed of in accordance with national requirements for the disposal of such substances.

    Storage conditions for diluted solution

    Stability of the initially diluted concentrate with the applied solvent (premix) in the vial

    After the initial dilution of cabazitaxel with the applied solvent, the resulting concentrate-solvent mixture (premix) remains chemically and physically stable for 1 hour when stored at normal temperature (15 ° C to 30 ° C). From a microbiological point of view, the concentrate-solvent mixture should be used immediately after preparation. If it is not used immediately after preparation, the user is responsible for the time and conditions of its storage. Normally, it should not be stored for more than 24 hours at a temperature of 2 ° C to 8 ° C, provided that the dilution was carried out in controlled and validated aseptic conditions.

    Stability of the finally diluted solution in the infusion tank

    After the final dilution in the infusion tank / vial, the chemical and physical stability of the solution was demonstrated for 8 hours at room temperature (including a 1-hour infusion) and for 48 hours when stored in a refrigerator.

    From the microbiological point of view, the infusion solution should be administered immediately after cooking. If it is not entered immediately after preparation, the responsibility for the time and conditions of its storage is borne by the user. Normally it should not be stored for more than 24 hours at a temperature of 2 ° C to 8 ° C. provided that the dilution was carried out in controlled and validated aseptic conditions.

    Since the infusion solution is supersaturated, it can crystallize over time. In this case, the solution should not be introduced and should be disposed of in accordance with the national requirements for the disposal of such substances.

    Side effects:

    The safety of cabazitaxel in combination with prednisolone or a combination with prednisolone or prednisone was evaluated in 371 patients with metastatic castration-resistant prostate cancer.The median of the patients' cycles of cabazitaxel was 6 cycles.

    Very frequent (≥10%) adverse reactions (HP) of all degrees of severity were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, weakness, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, spinal pain, arthralgia, anorexia, peripheral neuropathy (including peripheral sensory and motor neuropathies), pyrexia , dyspnea, dysgeusia, cough and alopecia,

    Frequent (≥ 5%) HP ≥3 degrees of severity with the use of cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, weakness and asthenia. Termination of treatment due to development HP 18.3% of patients receiving patients treated with cabazitaxel. The most common HP, leading to discontinuation of treatment with cabazitaxel, were neutropenia and renal insufficiency.

    The most frequent HP, leading to death in patients treated with cabazitaxel, were infections. Most adverse reactions in the form of fatal infections developed after a single injection of the drug.

    Below are the HP. Separated according to the system-organ classes according to the classification of the Medical dictionary for normative-legal activity (MedDRA). Heaviness HP classified according to generally accepted terminology criteria for HP (СТСАЕ 4.0) (severity ≥ 3 = G ≥ 3).

    Classification of frequency of occurrence HP World Health Organization: very often (≥ 10%); often (≥ 1% and <10%); infrequently (≥ 0.1% and <1%); rarely (≥ 0.01% and <0.1%); very rarely (<0.001%), an unknown frequency (according to available data, to determine the frequency of occurrence HP does not seem possible).

    Within each group by frequency of occurrence HP, the latter are given in order of decreasing their severity.

    Infectious and parasitic diseases

    Often: septic shock (all cases ≥ 3 degrees of severity); sepsis (all cases ≥3 degrees of severity); inflammation of subcutaneous fat, urinary tract infections of all severity; flu; cystitis; upper respiratory tract infection; herpes zoster; candidiasis.

    Infrequently: inflammation of subcutaneous fat, ≥3 degree of severity, cystitis ≥3 degrees of severity.

    Violations of the blood and lymphatic system

    Very often: neutropenia of all severity levels, including neutropenia with clinical manifestations ≥3 degrees of severity; anemia of all severity; leukopenia of all degrees of severity; thrombocytopenia.

    Often: febrile neutropenia, all cases ≥3 degrees of severity, thrombocytopenia ≥3 degrees of severity. Neutropenic complications included neutropenic infection, neutropenic sepsis, and septic shock, which in some cases resulted in death.

    It has been shown that the use of G-CSF reduces the incidence and severity of neutropenia (see the sections "Dosing and Administration" and "Special instructions").

    Immune system disorders

    Often: hypersensitivity reactions, including severe reactions, such as generalized rash / erythema, lowering blood pressure (BP) and bronchospasm.

    Metabolic disorders

    Very often: anorexia.

    Often: dehydration of all degrees of severity, hyperglycemia, hypokalemia.

    Infrequently: anorexia ≥3 degrees of severity, hyperglycemia> 3 degrees of severity, hypokalemia ≥3 degrees of severity.

    Disorders of the psyche

    Often: anxiety, confusion.

    Disturbances from the nervous system

    Very often: dysgeusia (perversion of taste).

    Often: peripheral neuropathy: peripheral sensory neuropathy (paresthesia, dysesthesia, hypoesthesia) and peripheral motor neuropathy; dizziness, headache, lethargy, sciatica.

    Infrequent: peripheral neuropathy ≥3 degrees of severity; peripheral sensory neuropathy ≥3 degrees of severity, lethargy ≥3 degrees of severity, sciatica ≥3 degrees of severity.

    Disturbances on the part of the organ of sight

    Often: conjunctivitis, increased tearing.

    Hearing disorders and labyrinthine disorders

    Often: ringing in the ears, vertigo (feeling of deflection or twisting of one's own body or surrounding objects).

    Heart Disease

    Often: atrial fibrillation (atrial fibrillation), tachycardia, (no cases of tachycardia ≥3 degrees of severity).

    Infrequent: atrial fibrillation (atrial fibrillation) ≥3 degrees of severity.

    When taking cabazitaxel, there were cases of developing heart failure (in two patients). One patient in the cabazitaxel group died of heart failure. Fatal ventricular fibrillation was observed in 1 patient and heart failure in 2 patients.However, none of these cases was regarded by researchers as related to the use of cabazitaxel.

    Vascular disorders

    Often: reduction of blood pressure, deep vein thrombosis of all severity, increased blood pressure, orthostatic hypotension, "hot flashes" of the blood to the face skin with a feeling of heat, hyperemia. Infrequently: a decrease in blood pressure ≥3 degrees of severity, an increase in blood pressure ≥3 degrees of severity, orthostatic hypotension ≥3 degrees of severity.

    Disturbances from the respiratory, thoracic and mediastinal organs

    Very often: shortness of breath, cough.

    Often: dyspnea ≥3 degrees of severity, pain in the mouth and throat, pneumonia of all severity.

    There have been cases of interstitial pneumonia / pneumonitis, interstitial lung disease, acute respiratory distress syndrome, including fatal.

    Disorders from the gastrointestinal tract

    Very often: diarrhea, nausea, vomiting, constipation, abdominal pain.

    Often: diarrhea ≥3 degrees of severity, nausea ≥3 degrees of severity, vomiting ≥3 degrees of severity, constipation ≥3 degrees of severity, abdominal pain ≥3 degrees of severity, dyspepsia, epigastric pain, hemorrhoids, gastroesophageal reflux disease, bleeding from rectum, dryness of the oral mucosa, bloating.

    Infrequent: rectal bleeding ≥3 degrees of severity, dryness of oral mucosa ≥3 degrees of severity, bloating ≥3 degrees of severity.

    Unknown frequency: reported on the development of colitis, enterocolitis, gastritis, neutropenic enterocolitis, gastrointestinal bleeding and perforation of the gastrointestinal tract, intestinal obstruction and intestinal obstruction.

    Disturbances from the skin and subcutaneous tissues

    Very often: alopecia.

    Often: dry skin, erythema.

    Disturbances from musculoskeletal and connective tissue

    Very often: pain in the spine, arthralgia.

    Often: pain in the spine ≥3 degrees of severity, arthralgia ≥3 degrees of severity, pain in the extremities of all degrees of severity, muscle spasms, myalgia, musculoskeletal pain in the thorax, pain along the lateral surfaces of the trunk.

    Infrequent: myalgia ≥3 degrees of severity, musculoskeletal pain in the thoracic region ≥3 degrees of severity, pain along the lateral surfaces of the trunk ≥3 degrees of severity.

    Disorders from the kidneys and urinary tract

    Very often: hematuria of all degrees of severity (in 2/3 of the cases, weighed down factors,such as disease progression, instrumental interventions, concomitant infections, simultaneous administration of anticoagulants, non-steroidal anti-inflammatory drugs, acetylsalicylic acid).

    Frequent: acute renal failure of all degrees of severity; renal insufficiency of all degrees of severity; dysuria: renal colic; hematuria ≥3 degrees of severity: pollakiuria; hydronephrosis; retention of urine; urinary incontinence; obstruction of the ureters of all degrees of severity.

    Infrequent: renal colic ≥3 degrees of severity, pollakiuria ≥3 degrees of severity, hydronephrosis ≥3 degrees of severity, urinary retention ≥3 degrees of severity.

    Violations of the genitals and mammary gland

    Often: pain in the pelvic area.

    Infrequent: pelvic pain ≥3 degrees of severity.

    General disorders and disorders at the site of administration

    Very often: weakness, asthenia, pyrexia.

    Often: weakness ≥3 degrees of severity: asthenia ≥3 degrees of severity; pyrexia ≥3 degrees of severity: peripheral edema; inflammation of the mucous membranes; pain of all degrees of severity; pain in the chest; edema; chills; malaise.

    Infrequent: peripheral edema ≥3 degrees of severity, inflammation of mucous membranes ≥3 degrees of severity, chest pain ≥3 degrees of severity, edema ≥3 degrees of severity.

    Laboratory and instrumental data

    Often: weight loss, increased activity of ALT in blood serum.

    Infrequent: increased serum bilirubin concentration, increased activity ACT in the blood serum.

    HP the special patient groups

    Elderly patients

    Of the 371 patients treated with cabazitaxel in a study on prostate cancer, 240 patients were 65 years of age or older, 70 of whom were older than 75 years of age. The following HP were ≥5% more common in patients 65 years of age and older than those of younger age: weakness, neutropenia, including neutropenia with clinical manifestations, asthenia, pyrexia. dizziness, urinary tract infections and dehydration.

    Frequency of the following HP ≥3 degrees of severity was higher in patients ≥65 years of age compared with younger patients: neutropenia based on laboratory tests, neutropenia with clinical manifestations and febrile neutropenia.

    Overdose:

    Symptoms

    Expected symptoms of overdose: increased dose-dependent side effects, such as symptoms of suppression of bone marrow hematopoiesis and disorders of the gastrointestinal tract.

    Treatment

    There is no known antidote of cabazitaxel. In case of an overdose, the patient should be placed in a specialized department under careful medical supervision. After becoming aware of an overdose, patients should start receiving G-CSF as soon as possible. Other symptomatic treatment should also be done.

    Interaction:

    Inhibitor inhibitors CYP3A

    The metabolism of cabazitaxel varies with the simultaneous use of substances known as potent inhibitors of the isoenzymes of the subfamily CYP3A (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

    The simultaneous use of strong inhibitors of the isoenzymes of the subfamily CYP3A. If simultaneous use of cabazitaxel can not be avoided and strong inhibitor of isoenzymes of the subfamily CYP3A consideration should be given to careful monitoring of the patient and a reduced dose of cabazitaxel (see sections "Dosing and Administration" and "Pharmacokinetics"). Caution should be exercised with the simultaneous use of cabazitaxel and moderate isozyme inhibitors of the subfamily CYP3A.

    Inductors of isoenzyme CYP3A

    The metabolism of cabazitaxel varies with the simultaneous use of substances known as strong inducers of the isozymes of the subfamily CYP3A (eg, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital).

    It should avoid the simultaneous use of strong inductors of the isoenzymes of the subfamily CYP3A, since they can reduce the systemic exposure of kabasitaxel (see sections "Dosing and Administration" and "Pharmacokinetics").

    St. John's wort

    Patients receiving cabazitaxel treatment should refrain from taking peritoneal herb preparations (since it is also an isoenzyme inducer CYP3A4).

    Substrates of the transport polypeptide of organic anions (OATP1B1)

    In vitro kabasitaxel also demonstrated the ability to inhibit OATP1B1.The risk of interaction with substrates of the OATP1B1 (for example, inhibitors of HMG-CoA reductase [statins], valsartan, repaglinide) is possible during intravenous infusion (1 hour) and up to 20 minutes after its termination, and at this time it is possible to increase the system exposure of substrates OATP1B1.

    It is recommended that the following time intervals are observed when using the substrates of OATP1B at the same time: take them 12 hours before administration of cabazitaxel and at least 3 hours after administration of cabazitaxel.

    Prednisolone

    Prednisolone, applied on 10 mg daily, does not affect the effects on the pharmacokinetics of cabazitaxel.

    Warfarin

    Cabazitaxel does not inhibit in vitro the main pathway of biotransformation of warfarin to 7-hydroxyvarfarin, which is carried out with the help of isoenzyme CYP2C9. Therefore, no pharmacokinetic interaction between cabazitaxel and warfarin is expected in vivo.

    Vaccinations

    The use of live vaccines or weakened live vaccines in patients with immunosuppression, reduced as a result of treatment with chemotherapeutic drugs, lead to development of serious or fatal infections.Vaccination with live attenuated vaccines should be avoided in patients receiving cabazitaxel treatment. Killed or inactivated vaccines can be used: however, the body's response to such vaccines may be less pronounced.

    Special instructions:

    Inhibition of bone marrow hematopoiesis

    With the use of cabazitaxel oppression of bone marrow hematopoiesis manifests itself in the form of neutropenia, anemia, thrombocytopenia, or perhaps the development of pancytopenia {cm. below additional information in the sub-sections "Neutropenia" and "Anemia").

    Neutropenia

    In accordance with the recommendations of the American Society of Clinical Oncology and / or modern approved guidelines, patients receiving cabazitaxel therapy can be preventively administered G-CSF to reduce the risk of developing or treating neutropenic complications (febrile neutropenia, prolonged neutropenia, or neutropenic infection).

    Primary prophylaxis of neutropenia with G-CSF in patients with high risk factors for neutropenia should be considered.which increase the likelihood of complications from prolonged neutropenia (age over 65, poor general condition, previous episodes of febrile neutropenia, intense previous radiation therapy, reduced diet or other serious co-morbidities). It has been shown that the use of G-CSF reduces the incidence and severity of neutropenia.

    Neutropenia is the most common HP when using cabazitaxel. Weekly monitoring of the number of blood cells (a complete general blood test) during the first cycle (cycle 1) of treatment and then before each next treatment cycle is required in order to reduce the dose of the drug in the next cycle if necessary.

    With the development of febrile neutropenia or prolonged neutropenia, despite ongoing treatment, cabazitaxel treatment can be continued only after an increase in the number of neutrophils in peripheral blood to ≥1500 / mm3.

    Hypersensitivity reactions

    All patients should receive premedication before introducing cabazitaxel (see section "Method of administration and dose").

    Patients should be carefully observed for the development of hypersensitivity reactions, especially during the first and second intravenous infusion of cabazitaxel. Hypersensitivity reactions can develop during the first minutes after the initiation of intravenous infusion of cabazitaxel. therefore, it is necessary to have all necessary equipment and medicines to provide emergency care while lowering blood pressure or developing bronchospasm. Severe reactions can occur, such as generalized skin rash / erythema, decreased blood pressure and bronchospasm. With the development of severe hypersensitivity reactions, immediate discontinuation of intravenous infusion of cabazitaxel and necessary treatment are required.

    Patients who had a history of severe hypersensitivity reaction can not be re-administered kabasitaxel.

    Risk of nausea, vomiting, diarrhea and dehydration

    If patients develop diarrhea after administration of cabazitaxel, they should be treated with commonly used anti-diarrhea drugs. Appropriate measures should be taken to restore fluid loss and determine and correct the electrolyte composition of blood serum, especially the concentration of potassium ions.Diarrhea can develop more often in patients who previously underwent radiotherapy of the abdominal and pelvic region. Dehydration often develops in patients 65 years and older. With the development of diarrhea ≥3 degrees of severity, it may be necessary to postpone the next treatment cycle or dose reduction (see section "Method of administration and dose"). If the patient has nausea and vomiting, antiemetics may be used.

    The risk of developing serious reactions from the gastrointestinal tract

    The development of gastrointestinal bleeding and perforation, intestinal obstruction, colitis, including fatal cases in patients receiving cabazitaxel treatment has been reported. Caution should be exercised in patients with a high risk of developing gastrointestinal complications, namely: in patients with neutropenia, the elderly, concomitantly taking NSAIDs. receiving antiplatelet therapy or direct or indirect anticoagulants, as well as in patients with previous pelvic radial therapy, gastrointestinal diseases such as ulcerative gastrointestinal lesions and gastrointestinal bleeding in the anamnesis.

    Early signs of serious gastrointestinal toxicity may include symptoms such as pain and tenderness in the abdomen, fever, constipation, diarrhea with neutropenia or without neutropenia. It is necessary to check the presence of these symptoms on a regular basis, and in case of their occurrence, their treatment should be immediately carried out. It may be necessary to delay treatment with cabazitaxel or stop treatment with it.

    Peripheral Neuropathy

    In patients treated with cabazitaxel, peripheral neuropathy, peripheral sensory neuropathy (paresthesia, dysesthesia) and peripheral motor neuropathy were observed. Patients receiving cabazitaxel treatment should be advised before informing their attending physician of the symptoms of neuropathy developed in them, such as pain, burning sensation, tingling, numbness, or weakness. The physician should evaluate the presence or intensification of the symptoms of neuropathy before each treatment cycle. The administration of cabazitaxel should be delayed until symptoms decrease. With persistent peripheral neuropathy ≥2 degrees of severity, the dosage of cabazitaxel should be reduced from 25 mg / m2 body surface area up to 20 mg / m2 body surface area.

    Risk of developing kidney failure

    Reported violations of kidney function in combination with sepsis, severe dehydration due to diarrhea and vomiting and obstructive uropathy. There was a development of renal failure, including fatal cases. Appropriate measures should be taken to identify the cause of renal failure and to conduct intensive therapy of patients with developing renal failure. Kidney function should be monitored.

    When treating cabazitaxel, adequate hydration of the patient should be performed. The patient should be advised to immediately report any changes in the amount of urine released per day. The serum creatinine content should be determined before treatment, with each study of a general blood test and in the case of a patient reporting a change in urinary excretion. In case of development of renal insufficiency ≥3 degrees of severity, treatment with cabazitaxel should be discontinued.

    Risk of heart rhythm disturbances

    It was reported on the development of heart rhythm disorders, most often tachycardia and atrial fibrillation (cm.section "Side effect").

    Risk of development of disturbances from the respiratory system

    Cases of interstitial pneumonia / pneumonitis, interstitial lung disease, acute respiratory distress syndrome, including fatal cases, have been reported.

    When developing new symptoms from the respiratory system or worsening of existing symptoms, it is necessary to carefully monitor the condition of patients, promptly examine them and conduct appropriate treatment. It is recommended to abort therapy with cabazitaxel until the diagnosis is confirmed. Earlier application of the supporting therapy improves the patient's condition. The benefits of relapse therapy with cabazitaxel should be carefully evaluated.

    Elderly patients

    Older patients (≥65 years of age) may be more prone to some HP. including neutropenia and febrile neutropenia (see section "Side effect").

    Patients with hepatic insufficiency

    Cabazitaxel is contraindicated in patients with severe hepatic insufficiency (total bilirubin> 3 x VGN). In patients with mild hepatic insufficiency (total serum bilirubin> 1 - ≤ 1.5 x VGN or ACT > 1.5 x VGN) and moderate severity (total bilirubin> 1 to ≤ 3 x UGN) should reduce the dose of cabazitaxel (see sections "With caution", "Method of administration and dose"). In this case, you should be careful, carefully monitor the condition of patients and monitor adverse reactions.

    Anemia

    Patients receiving cabazitaxel treatment. reported on the development of anemia (see section "Side effect"). The parameters of hemoglobin and hematocrit should be checked before starting therapy with cabazitaxel, and also if patients have signs or signs of anemia or hemorrhage.

    It is recommended to use caution cabazitaxel in patients with a hemoglobin content in the peripheral blood <10 g / dL, and appropriate medical measures should be taken to increase the hemoglobin content in the peripheral blood.

    Reproductive function

    Due to the potential adverse effects on male gametes (gametes) and potential drug intake in seminal fluid, men receiving cabazitaxel treatment and their sexual partners with childbearing potential should use reliable contraceptive methods during treatment and within 6 months after the administration of the last dose of cabazitaxel .In connection with the potential intake of cabazitaxel in seminal fluid, men receiving cabazitaxel treatment during treatment should prevent the contact of the ejaculate with the tissues of another person, including pregnant and breast-feeding women. Patients who are scheduled for treatment with cabazitaxel are advised to cryopreserve sperm before starting treatment.

    Drug Interactions

    Simultaneous application of strong inhibitors and inducers of isoenzymes of the subfamily CYP3A with cabazitaxel should be avoided, as they can, respectively, increase or decrease the plasma concentration of cabazitaxel.

    Excipients

    The included solvent is ethanol 96%, which should be taken into account when using the drug in patients with alcoholism, as well as in patients at high risk (patients with liver disease and epilepsy).

    Effect on the ability to drive transp. cf. and fur:

    Based on the safety profile of cabazitaxel, it can have a moderate effect on the ability to drive vehicles or use other mechanisms, since it can cause weakness and dizziness.Patients should be advised during the treatment to refrain from driving and practicing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

    Form release / dosage:

    Concentrate for the preparation of a solution for infusions, 40 mg / ml (complete with a solvent).

    Packaging:

    For 1.5 ml of the preparation into a transparent glass bottle (type I) sealed with a chlorobutyl stopper, crimped with an aluminum cap, closed with a protective plastic lid of the type "flip-off".

    For 4.5 ml of solvent in a bottle of clear glass (type I), sealed with a stopper of chlorobutyl. Crimped aluminum cap, closed on top with a protective plastic lid type "flip-off".

    For 1 bottle with the drug and 1 bottle with a solvent, along with instructions for use in a pack of cardboard.

    Storage conditions:

    At a temperature of 15 to 25 ° C.

    Keep out of the reach of children!

    Shelf life:

    2 years.

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004783
    Date of registration:04.04.2018
    Expiration Date:04.04.2023
    The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India
    Manufacturer: & nbsp
    Representation: & nbspDr. Reddy`c Laboratoris Ltd.Dr. Reddy`c Laboratoris Ltd.
    Information update date: & nbsp25.04.2018
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