Джевтана®
Producer: Sanofi-Aventis Private Co.Ltd (Sanofi-Aventis Pravit. Co. Ltd.) France
Code of automatic telephone exchange: L01CB04
Release form: Liquid dosage forms. A concentrate for preparation of solution for infusions.
General characteristics. Structure:
Active ingredient: kabazitakset an acetonic solvate (in terms of kabazitakset) - 60,00 mg;
excipient: polysorbate-80 (рН 3,5) - 1,56 g.
1 ml of a concentrate contains 40 mg of a kabazitaksel of an acetonic solvate (in terms of kabazitakset).
With solvent contains in 1 bottle:
ethanol of 96% - 573,3 mg, water for injections to 4,5 ml.
Description. A concentrate for preparation of solution for infusions: transparent oily liquid from yellow till brownish-yellow color. Solvent: transparent colourless liquid.
Pharmacological properties:
Pharmacodynamics. Kabazitaksel is antineoplastic means which works by destruction of a cellular network of microtubules. Kabazitaksel communicates with tubuliny and promotes assembly of a tubulin in microtubules and at the same time inhibits their disassembly. It leads to stabilization of microtubules that as a result inhibits mitotic and interfazny activity of a cell.
Kabazitaksel showed a wide range of antineoplastic activity concerning late stages of tumors of the person, ksenotransplantirovanny to mice. Kabazitaksel is active concerning tumors, sensitive to a dotsetaksel. Besides kabazitakset showed activity concerning tumoral models, insensitive to chemotherapy, including dotsetakset.
Assessment of efficiency and safety of the drug Dzhevtana® with Prednisonum or Prednisolonum was carried out to combinations at the patients with a gormonorezistentny metastatic prostate cancer who were earlier receiving chemotherapy with inclusion of a dotsetaksel (in total 755 patients).
Patients received kabazitakset 25 mg/sq.m of a body surface intravenously each 3 weeks during at most 10 cycles in combination with daily intake of Prednisonum or Prednisolonum of 10 mg/days. In group of comparison patients received митоксантрон 12 mg/sq.m of a body surface intravenously each three weeks in combination with daily intake of Prednisonum or Prednisolonum of 10 mg/days.
The general survival was more long in group of a kabazitaksel from 30% decrease in risk of death in comparison with group of a mitoksantron (a median of survival of 15,1 (14,1-16,3) and 12,7 (11,6-13,7) months, respectively).
Increase in duration of survival up to progressing of a disease in group of the drug Dzhevtana® in comparison with group of a mitoksantron 2,8 (2,4-3,0) months against 1,4 (1,4-1,7) months, respectively was observed.
The patients receiving the drug Dzhevtana® had authentically big frequency of remissions of a disease, a component of 14,4% in comparison with 4,4% for patients in group of a mitoksantron.
There were no statistically significant distinctions in both groups in the relation
progressing of pain or remission of pain.
Pharmacokinetics. The population analysis of pharmacokinetic indicators was carried out at 170 patients, including patients with locally widespread solid tumors, a metastatic breast cancer and a metastatic prostate cancer. These patients received doses of a kabazitaksel in the range of 10-30 mg/sq.m of a body surface weekly or each 3 weeks.
Absorption
After hourly intravenous infusion of a kabazitaksel in a dose of 25 mg/sq.m of a body surface at patients with a metastatic prostate cancer the maximum concentration of a kabazitaksel in a blood plasma (Stakh) was reached by the end of hourly infusion (Tmax), average value Stakh made 226 ng/ml. Average value of the area under a pharmacokinetic curve "concentration time" (AUC) made 991 ¡ú.þ/ml.
At patients with locally-spread solid tumors big deviations in a dozoproportsionalnost of concentration of a kabazitaksel in a blood plasma in the range of doses of 10-30 mg/sq.m of a body surface were not observed.
Distribution
Distribution volume in an equilibrium state (Vss) made 4870 l (2640 l/sq.m for patients with a median of the surface area of a body leaving 1,84 sq.m). In vitro communication of a kabazitaksel with human serum proteins made 89 - 92% and was not saturable to concentration of 50000 ng/ml which exceeds Stakh, observed at a clinical use of drug. Kabazitaksel, mainly, contacts a seralbumin (82,0%) and lipoproteids (87,9% for lipoproteids of high density, 69,8% for lipoproteids of low density and 55,8% for lipoproteids of very low density). In vitro in human blood of a ratio of concentration in blood and concentration in a blood plasma are in range of 0,90-0,99 that indicates identical distribution of a kabazitaksel in blood and a blood plasma.
Researches on animals showed that kabazitakset and its metabolites are excreted
in breast milk, and kabazitakset gets through a placental barrier.
Metabolism
Kabazitaksel is intensively metabolized in a liver (> 95%), mainly, by means of CYP3A4 isoenzyme (80-90%). Kabazitaksel is the main connection circulating in a blood plasma. In addition to it in a blood plasma 7 metabolites were identified (including 3 active metabolites which are formed as a result of O-demethylation). Concentration in a main thing blood plasma makes 5% of concentration in a blood plasma of not changed kabazitaksel of them. About 20 metabolites of a kabazitaksel are removed by kidneys (with urine) and intestines (with a stake).
The potential risk of inhibition kabazitaksely in clinically significant concentration of hepatic metabolism is possible concerning drugs which mainly, are CYP3A isoenzyme substrates. However there is no potential risk of inhibition of metabolism of drugs which are substrates of other isoenzymes of CYP (1A2, 2B6, 2C8, 2C9, 2C19, 2E1 and 2D6), and also there is no potential risk of induction kabazitaksely metabolism of the drugs which are substrates of isoenzymes CYP1A, CYP2C9, and CYP3A.
Powerful inductors or inhibitors of an isoenzyme CYP3A can change plasma concentration of a kabazitaksel in a blood plasma as kabazitakset generally is metabolized by means of CYP3A isoenzyme.
Prednisolonum or Prednisonum accepted in a dose of 10 mg/days do not change pharmacokinetics of a kabazitaksel.
In vitro kabazitakset does not inhibit a squirrel of multiple resistance to chemotherapeutic drugs (MRP1 and MRP2). Kabazitaksel inhibits transport of the R-glycoprotein (P-gP) (digoxin, vinblastine) and resistance proteins to chemotherapeutic drugs at a breast cancer (BCRP) (methotrexate) in the concentration, by 38 times exceeding the concentration observed in clinical conditions. Therefore the risk of interaction of a kabazitaksel in a dose of 25 mg/sq.m of a body surface with MRP, P-gP and BCRP in vivo substrates is improbable.
Removal
After hourly intravenous infusion [^^-кабазитаксела (marked a radioisotope of a kabazitaksel) in a dose of 25 mg/sq.m of a body surface the oncological patient about 80% of the entered dose it is removed within 2 weeks. Kabazitaksel, mainly, is brought from an organism through intestines (with a stake) in the form of numerous metabolites (76% of a dose); while renal excretion kabazitakset and its metabolites makes less than 4% of the entered dose (2,3% of the entered dose are removed with urine in not changed look).
Kabazitaksel has the high plasma clearance making 48,5 l/h (patients have 26,44 l/h/sq.m with a median of surface area of a body of 1,84 sq.m), and the long elimination half-life making 95 hours. Special groups of patients
Patients of advanced age
In the population analysis of pharmacokinetic these patients at the age of 65 years is also more senior any influence of age on pharmacokinetics of a kabazitaksel was not observed. Patients of children's age.
Safety and efficiency of the drug Dzhevtana® at children and teenagers up to 18 years are not established.
Liver failure
Official pharmacokinetic researches at patients with a liver failure were not conducted. However because kabazitakset it is brought out of an organism in generally metabolic way, at patients with a liver failure it is possible to expect increase in system exposure of a kabazitaksel. Renal failure
Kabazitaksel is slightly brought by kidneys (2,3% of a dose). No official pharmacokinetic researches of a kabazitaksel at patients with a renal failure were conducted. However the population pharmacokinetic analysis which is carried out according to 170 patients as a part of whom there were 14 patients with a renal failure of moderate severity (clearance of creatinine within 30-50 ml/min.) and 59 patients with a renal failure of easy severity (clearance of creatinine of 50-80 ml/min.) showed that the renal failure easy and moderate severity had no significant effect on pharmacokinetics of a kabazitaksel.
Indications to use:
Gormonorezistentny metastatic prostate cancer at the patients who were earlier receiving chemotherapy with inclusion of a dotsetaksel (in a combination with Prednisolonum or Prednisonum).
Route of administration and doses:
Use of the drug Dzhevtana® has to be carried out only in specialized oncological departments under observation of the doctor having special preparation on antineoplastic chemotherapy. In department there have to be necessary conditions and medicines for assistance at emergence of reactions of hypersensitivity, such as lowering of arterial pressure and bronchospasm. Premedication
For reduction of risk of development and weight of reactions of hypersensitivity before administration of the drug Dzhevtana® premedication is carried out by the following medicines entered intravenously:
- antihistamines (дексхлорфенирамин 5 mg or дифенгидрамин 25 mg or similar drug in equivalent doses);
- glucocorticosteroids (dexamethasone of 8 mg or equivalent doses of other glucocorticosteroid);
- blockers of ^-histamine receptors (ranitidine or similar drug in equivalent doses).
Preventive use of antiemetics inside or, if necessary, intravenously is recommended.
Dosing mode
The recommended dose of the drug Dzhevtana® makes 25 mg/sq.m of a body surface which is entered by hourly intravenous infusion each 3 weeks into combinations with Prednisolonum intake (or Prednisonum) 10 mg daily during the entire period of treatment by the drug Dzhevtana®.
Correction of the entered dose
The recommended changes of the entered dose because of development of adverse reactions in the patients receiving the drug Dzhevtana®.
Adverse reactions Change of the entered dose
Long (more than 1 week) the Delay of the following cycle of treatment before recovery
neutropenia> 3 severity, quantities of neutrophils in peripheral blood to more
despite use of 1500 cells/mm3, then a dose decline in the subsequent cycles
the corresponding treatment, including from 25 mg/sq.m of a body surface to 20 mg/sq.m of a body surface.
introduction of G-KSF.
Febrile neutropenia or Delay of the following cycle of treatment before reduction or
neytropenichesky infection. permissions of a febrile neutropenia and to
recovery of quantity of neutrophils in
peripheral blood to more than 1500 cells/mm3, then
dose decline in the subsequent cycles from 25 mg/sq.m
body surfaces to 20 mg/sq.m of a body surface.
Diarrhea> 3 severity or persistently the Delay of the following cycle of treatment before reduction or
the proceeding diarrhea, despite permissions of diarrhea, then a dose decline in the subsequent
performing the corresponding therapy and cycles from 25 mg/sq.m of a body surface to 20 mg/sq.m
completion of losses of liquid and body surface.
electrolytes.
Peripheral neuropathy> 2 degrees a treatment Delay before reduction of symptoms, then
weights a dose decline in the subsequent cycles from 25 mg/sq.m
body surfaces to 20 mg/sq.m of a body surface.
If at the patient continue to arise any of the reactions stated above at administration of drug in a dose of 20 mg/sq.m of a body surface treatment by the drug Dzhevtana® should be stopped. Special groups of patients Children and teenagers up to 18 years
Safety and efficiency of the drug Dzhevtana® at children and teenagers up to 18 years are not established now. Patients of advanced age
Special correction of the mode of dosing at use of the drug Dzhevtana® for patients of advanced age is not required. Patients with a liver failure
The drug Dzhevtana® is intensively metabolized in a liver. As a precautionary measure the drug Dzhevtana® should not be used at patients with a liver failure (serumal concentration of bilirubin> 1 x VGN, activity of nuclear heating plant and/or ALT in blood serum> 1,5 x VGN). Patients with a renal failure
Джевтана® it is removed by kidneys in the minimum degree. At patients with a slight renal failure (clearance of creatinine: 50-60 ml/min.) are not required to correction of the mode of dosing. Data on use of drug for patients with a renal failure of moderate severity (clearance of creatinine of 30-50 ml/min.) are limited, and at patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.) and an end-stage of a renal failure - are absent. Therefore treatment of such patients should be carried out with care and under careful medical control during treatment. Way of introduction Intravenous infusion.
During administration of infusion solution of a kabazitaksel use the filter inserted about system for intravenous infusions with a nominal diameter of time of 0,22 microns. The drug Dzhevtana®, a concentrate for preparation of solution for infusions, before addition in infusion solution it is necessary to dissolve with the enclosed solvent always.
The drug Dzhevtana® should not mix up with other medicines and solutions, except for 5% of solution of a dextrose and 0,9% of solution of sodium of chloride. The drug Dzhevtana® contains in the structure polysorbate-80 which, as we know, increases the speed of extraction of di - (2 ethylhexyl) phthalate from polyvinylchloride (PVC). In this regard it is impossible to use containers for infusional liquids from PVC and sets for performing infusions of polyurethane for preparation and administration of infusion solution of a kabazitaksel.
Preparation of solution for infusions and the treatment of drug
As well as during the work with other antineoplastic drugs, it is necessary to be careful and use gloves during the work with the drug Dzhevtana® and at preparation of its infusion solution.
If drug Dzhevtana® solution at any stage of work with it got on skin, it is necessary to wash out immediately and carefully it water with soap and if - on a mucous membrane, then one water.
Only the personnel owning skills have to work with the drug Dzhevtana®
treatment of cytotoxic drugs.
Pregnant women should not work with this drug.
Preparations of solution for infusions it is carried out in aseptic conditions in 2 steps. Stage 1. Initial cultivation of the drug Dzhevtana®, a concentrate for preparation of solution for infusions, the applied solvent.
- Get a bottle of a concentrate of Dzhevtana® and the solvent which is applied to it. In case of storage properly drug has to be transparent.
- Take all contents of the applied solvent by means of the syringe, having partially inclined a bottle, and enter into a bottle with a concentrate of Dzhevtana®. For the maximum reduction of foaming at introduction through a needle to a bottle with a concentrate of solvent direct a needle to an internal wall of a bottle and you enter solvent slowly.
- Remove the syringe and a needle and mix bottle contents approximately within 45 seconds, carefully repeatedly overturning a bottle, before receiving transparent and homogeneous solution.
- Leave to stand the received solution within several minutes (approximately within 5 minutes) and then check solution for homogeneity and transparency. During this time preservation of a small amount of foam normal is possible.
The mix which turned out as a result has concentration of a kabazitaksel of 10 mg/ml (the taken volume makes 6 ml). She has to be immediately in addition divorced for receiving solution for infusions (see a stage 2). Stage 2. Preparation of solution for infusions
Take necessary amount of originally divorced drug Dzhevtana® (10 mg/ml of a kabazitaksel) by means of the graduated syringe (because of a possibility of contents in a bottle of foam you enter the hypodermic needle during extraction of solution into the middle of a stopper of a bottle) and enter it into a sterile container with infusion solution (except a container from PVC) (5% solution of a dextrose or 0,9% chloride sodium solution). Concentration of infusion solution of a kabazitaksel has to be from 0,10 mg/ml to 0,26 mg/ml.
For introduction of the ordered dose more than one bottle of originally divorced solution can be required.
Take the syringe and mix contents of an infusional container or a bottle manually the shaking movements.
As well as all other solutions for parenteral administration, the solution which turned out as a result has to be visually examined before use. The patient cannot enter solution which contains precipitated calcium superphosphates, and it should be utilized according to national requirements for utilization of such substances. Dzhevtana® infusion solution has to be entered immediately. However under special conditions (see below) time of its storage can be more long.
Unused drug or expendables have to be utilized according to national requirements for utilization of such substances. Storage conditions of divorced solution
Stability of originally divorced concentrate the applied solvent After initial cultivation of the drug Dzhevtana® the applied solvent the mix which turned out as a result concentrated solvent remains chemically and physically stable within 1 hour at storage at a usual temperature (15 °C - 30 °C). From the microbiological point of view mix concentrated solvent has to be used immediately after preparation. If it is not used immediately after preparation, then responsibility for time and conditions of its storage is born by the user. Usually it is not necessary to store it more than 24 hours at a temperature of 2 °C of -8 °C provided that cultivation was carried out in controlled and validirovanny aseptic conditions.
Stability of finally divorced solution in infusional capacity After final cultivation in infusional capacity / bottle chemical and physical stability of solution was shown within 8 hours at the room temperature (including 1-hour infusion) and within 48 hours at storage in the refrigerator.
From the microbiological point of view infusion solution has to be entered immediately after preparation. If it is not entered immediately after preparation, then responsibility for time and conditions of its storage is born by the user. Usually it is not necessary to store it more than 24 hours at a temperature of 2 °C - 8 °C provided that cultivation was carried out in controlled and validirovanny aseptic conditions.
As infusion solution is supersaturated, it can crystallize over time. In this case, solution should not be entered and has to be utilized according to national requirements for utilization of such substances.
Features of use:
Hypersensitivity reactions
All patients before administration of the drug Dzhevtana® have to receive premedication (see the section "Mode of Dosing and Route of Administration").
Patients have to be observed carefully regarding development of reactions of hypersensitivity, especially during the first several minutes after the beginning of infusion of a kabazitaksel therefore it is necessary to have all necessary equipment and medicines for rendering acute management at a lowering of arterial pressure or development of a bronchospasm. Heavy reactions, such as generalized rash / erythema, a lowering of arterial pressure and a bronchospasm can develop. At development of heavy reactions of hypersensitivity the immediate termination of infusion of a kabazitaksel and performing necessary treatment is required. The patients who had heavy reaction of hypersensitivity in the anamnesis cannot carry out repeated administration of the drug Dzhevtana®.
Risk of a neutropenia
According to recommendations of the American society of clinical oncology and/or the modern approved managements for reduction of risk of emergence or treatment of neytropenichesky complications (a febrile neutropenia, a long neutropenia or a neytropenichesky infection) the patients receiving the drug Dzhevtana® can with the preventive purpose receive G-KSF. It is necessary to consider a question of primary prevention of a neutropenia by means of G-KSF at patients of high risk (the age is more senior than 65 years, a bad general state, the previous episodes of a febrile neutropenia, the intensive previous radiation therapy, subnutrition, or other serious associated diseases), who do patients predisposed to increase in complications at a long neutropenia. It was shown that use of G-KSF reduces the frequency of emergence and weight of a neutropenia.
The neutropenia is the most often found adverse reaction at drug Dzhevtana® use. During the first cycle (cycle 1) of treatment and before each new cycle of treatment weekly control of quantity of uniform elements of blood (the general blood test) is required if necessary to reduce a dose in the following cycle.
At development of a febrile neutropenia or long neutropenia, despite the carried-out corresponding treatment, treatment kabazitaksely it can be continued only after increase in quantity of neutrophils in peripheral blood to> 1500/mm3. Risk of nausea, vomiting, diarrhea and dehydration
If at patients diarrhea after administration of the drug Dzhevtana® develops, they should carry out treatment by usually used antidiarrheal drugs. It is necessary to take the appropriate measures on recovery of losses of liquid and definition and correction of electrolytic composition of blood serum, especially concentration of potassium ions. Diarrhea can develop more often at the patients who received earlier abdominal пельвикальную radiation therapy. Dehydration develops at patients of 65 years more often and is more senior. At development of diarrhea 3 severity can be required a delay of the following cycle of treatment or reduction of a dose (see the section "Mode of Dosing and Route of Administration"). If at the patient nausea and vomiting is observed, use of antiemetics is possible. Peripheral neuropathy
At the patients receiving kabazitakset, cases of peripheral neuropathy, peripheral touch neuropathy (paresthesia, a dizesteziya) and peripheral motor neuropathy were observed. To the patients receiving kabazitakset, it is necessary to recommend to inform before continuation of treatment the attending physician on the symptoms of neuropathy which developed at them, such as pain, burning sensation, pricking, numbness. The doctor has to estimate existence or strengthening of symptoms of neuropathy before each cycle of treatment. Introduction of a kabazitaksel has to be postponed until reduction of symptoms. At persistent peripheral neuropathy> 2 severity the dose of a kabazitaksel has to be decrease from 25 mg/sq.m of a body surface to 20 mg / м2поверхности bodies.
Risk of development of a renal failure
It was reported about renal failures in combination with sepsis, heavy dehydration owing to diarrhea and vomiting and an obstructive uropathy. Development of a renal failure, including cases from the death was observed. It is necessary to take the appropriate measures for identification of the reason and to carry out an intensive care of patients with the developing renal failure. It is necessary to monitorirovat function of kidneys.
At treatment kabazitaksely it is necessary to carry out adequate hydration of the patient. The patient should recommend to report immediately about any changes in volume allocated during a day of urine. It is necessary to determine the content of creatinine before treatment, at each research of the general blood test and in case of the message of the patient on change of release of urine. In case of development of a renal failure> 3 severity treatment kabazitaksely has to be stopped. Risk of development of disturbances of a heart rhythm
It was reported about development of disturbances of a heart rhythm, most often ciliary arrhythmia and tachycardia.
Patients of advanced age
Patients of advanced age (> 65 years) can be more predisposed to some adverse reactions, including a neutropenia and a febrile neutropenia. Patients with a liver failure
Treatment by the drug Dzhevtana® contraindicated as kabazitakset intensively is metabolized in a liver, and at a liver failure increase in concentration of a kabazitaksel in blood is possible.
Patients with anemia
It is recommended to apply with care kabazitakset at patients with a hemoglobin content in peripheral blood <10 g/dl and it is necessary to hold the relevant medical activities directed to increase in concentration of hemoglobin in peripheral blood. Reproductive function
Owing to possible adverse effects on men's gametes and possible intake of drug in semen, the patients receiving kabazitakset, and their sexual partners have to use effective ways of contraception during treatment and within 6 months after introduction of the last dose of a kabazitaksel. Due to the possible receipt of a kabazitaksel in semen, the men receiving kabazitakset, during treatment have to prevent contact of an ejaculate with tissues of other person.
Patients to whom treatment kabazitaksely is planned are recommended to carry out a sperm cryopreservation before an initiation of treatment. Medicinal interactions
Simultaneous with kabazitaksely use of powerful inhibitors and inductors of an isoenzyme CYP3A it is necessary to avoid as they can increase or reduce plasma concentration of a kabazitaksel, respectively. Excipients
Ethanol is a part of the applied solvent that should be considered at use of drug for patients with alcoholism, and also at patients of high risk (patients with diseases of a liver and epilepsy).
Influence on ability to manage vehicles and to be engaged in other potential and dangerous types of activity
It is necessary to refrain from control of vehicles and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions during treatment.
Side effects:
Safety of the drug Dzhevtana® with Prednisolonum or Prednisonum was estimated at combinations at 371 patients with a gormonorezistentny prostate cancer. The median of the cycles of the drug Dzhevtana® received by patients made 6 cycles. Very often meeting (> 10%) the adverse side reactions (ASR) of all severity were anemia, a leukopenia, a neutropenia, thrombocytopenia, diarrhea, weakness, nausea, vomiting, a lock, an adynamy, abdominal pains, a hamaturia, backbone pains, an arthralgia, anorexia, a pyrexia, short wind, cough and an alopecia. Often meeting (> 5%) adverse reactions> 3 severity at use of the drug Dzhevtana® were a neutropenia, a leukopenia, anemia, a febrile neutropenia, diarrhea, peripheral neuropathy (including peripheral touch and motor neuropathy), weakness and an adynamy.
The termination of treatment owing to development of the NPR took place at 68 patients (18,3%) receiving the drug Dzhevtana®. The neutropenia was the most often found adverse reaction leading to the treatment termination by the drug Dzhevtana®.
The adverse side reactions (ASR) classified according to terms of system and organ classification of the Medical dictionary for normative and legal activity (MedDRA) and gradation of frequency of emergence of the NPR of World Health Organization are given below. Within each group on the frequency of occurrence of the NPR, they are given as reduction them to gravity. Weight of the NPR was classified according to the Standard terminological criteria for the adverse phenomena (CTCAE 4.0) (severity> 3 = G> 3). The following gradation of frequency of emergence of the NPR were used: very often> 10%; often> 1 and <10%; infrequently> 0,1 and <1%; seldom> 0,01 and <0,1%; very seldom <0,01%; unknown frequency (it is not possible to determine the frequency of occurrence of the NPR by the available data). Infectious and parasitic diseases
Often: septic shock (all cases> 3 severity); sepsis (all cases> 3 severity); cellulitis, infections of urinary tract of all severity; flu; cystitis; upper respiratory tract infections; herpes zoster; candidiasis.
Infrequently: cellulitis> 3 severity, cystitis> 3 severity. Disturbances from blood and lymphatic system
Very often: a neutropenia of all severity, including a neutropenia with clinical manifestations> 3 severity; anemia of all severity; leukopenia of all severity; thrombocytopenia.
Often: febrile neutropenia, thrombocytopenia> 3 severity. Neytropenichesky infections, neytropenichesky sepsis and septic shock in certain cases led to death.
It was shown that use of G-KSF reduces the frequency of emergence and weight of a neutropenia.
Disturbances from immune system
Often: hypersensitivity reactions, including heavy reactions, such as generalized rash / erythema, lowering of arterial pressure and bronchospasm. Disturbances from a metabolism Very often: anorexia.
Often: dehydration of all severity, hyperglycemia, hypopotassemia.
Infrequently: anorexia > 3 severity, hyperglycemia > 3 severity,
hypopotassemia> 3 severity.
Disturbances of mentality
Often: concern, confusion of consciousness.
Disturbances from a nervous system
Very often: dysgeusia (food faddism).
Often: peripheral neuropathy: peripheral touch neuropathy (paresthesia, dizesteziya, hypesthesia) and peripheral motor neuropathy; dizziness, headache, lethargy, sciatica.
Infrequently: peripheral neuropathy> 3 severity; peripheral touch neuropathy> 3 severity, lethargy> 3 severity, sciatica> 3 severity.
Disturbances from an organ of sight
Often: conjunctivitis, the strengthened slezootdeleniye.
Disturbances from an acoustic organ and labyrinth disturbances
Often: a ring in ears, вертиго (feeling of a deviation or spinning of own body or surrounding objects).
Disturbances from heart
Often: ciliary arrhythmia (fibrillation of auricles), tachycardia. Infrequently: ciliary arrhythmia (fibrillation of auricles)> 3 severity.
At reception of a kabazitaksel cases of development of heart failure were observed (at two patients (0,5%)). One patient in group of a kabazitaksel died of heart failure. Were observed fatal fibrillation of ventricles at 1 patient (0,3%) and a cardiac standstill at 2 patients (0,5%). However any of these cases was not regarded by researchers as connected with kabazitaksely.
Disturbances from vessels
Often: a lowering of arterial pressure, a deep vein thrombosis of all severity, increase in arterial pressure, orthostatic hypotonia, "inflows" of blood to face skin with feeling of heat, a hyperemia.
Infrequently: lowering of arterial pressure> 3 severity, increase in arterial pressure> 3 severity, orthostatic hypotonia> 3 severity.
Disturbances from respiratory system, bodies of a thorax and a mediastinum
Very often: short wind, cough.
Often: an asthma> 3 severity, pain in an oral cavity and a pharyngeal cavity, pneumonia of all severity.
Disturbances from digestive tract
Very often: diarrhea, nausea, vomiting, lock, abdominal pains.
Often: diarrhea> 3 severity, nausea> 3 severity, vomiting> 3 severity, a lock> 3 severity, abdominal pains> 3 severity, dyspepsia, pains in epigastric area, hemorrhoids, a gastroesophagal reflux disease, a proctorrhagia, dryness in a mouth, abdominal distention.
Infrequently: a proctorrhagia> 3 severity, dryness in a mouth> 3 severity, abdominal distention> 3 severity. Disturbances from skin and hypodermic fabrics Very often: alopecia. Often: xeroderma, erythema.
Disturbances from skeletal and muscular and connecting fabric
Very often: backbone pains, arthralgia.
Often: backbone pains> 3 severity, an arthralgia> 3 severity, pains in extremities of all severity, muscular spasms, a mialgiya, musculoskeletal pains in a thorax, pains on the side surfaces of a trunk. Infrequently: a mialgiya> 3 severity, musculoskeletal pains in a thorax> 3 severity, pains on the side surfaces of a trunk> 3 severity.
Disturbances from kidneys and urinary tract
Very often: hamaturia
Frequent: acute renal failure of all severity; renal failure of all severity; dysuria; renal colic; hamaturia> 3 severity; pollakiuria; hydronephrosis; ischuria; urine incontience; obstruction of ureters of all severity.
Infrequently: renal colic> 3 severity, pollakiuria> 3 severity, hydronephrosis> 3 severity, ischuria> 3 severity. Disturbances from generative organs and a mammary gland Often: pains in a small pelvis.
Infrequently: pains in a small pelvis> 3 severity. The general frustration and disturbances in an injection site
Very often: weakness, adynamy, pyrexia.
Often: weakness> 3 severity; adynamy> 3 severity; pyrexia> 3 severity; peripheral hypostases; inflammation of mucous membranes; pains of all severity; thorax pains; hypostases; fever; indisposition.
Infrequently: peripheral hypostases> 3 severity, inflammation of mucous membranes> 3 severity, thorax pains> 3 severity, hypostases> 3 severity. Laboratory and tool data Often: decrease in body weight, increase in activity of nuclear heating plant.
Infrequent: increase in serumal concentration of bilirubin, increase in activity of ALT.
Other special groups of patients
Patients of advanced age
From 371 patients receiving the drug Dzhevtana® in a research on cancer therapy of a prostate, 240 patients were at the age of 65 years and are more senior, from them 70 patients - are more senior than 75-year age. The following adverse reactions, met on> 5% more often at patients at the age of 65 years and are more senior in comparison with patients of younger age: weakness, a neutropenia with clinical manifestations, an adynamy, a pyrexia, dizziness, infections of urinary tract and dehydration.
Frequency of the following adverse phenomena> 3 severity was higher at patients> the 65th summer age in comparison with patients of younger age: a neutropenia by results of laboratory analyses, a neutropenia with clinical manifestations and a febrile neutropenia.
Interaction with other medicines:
Official researches on interaction with other medicines were not conducted.
In vitro of a research showed that kabazitakset preferential is metabolized by means of CYP3A isoenzyme (80% of-90%) and inhibits CYP3A isoenzyme. CYP3A isoenzyme inhibitors
Though official researches on medicinal interaction were not conducted, at simultaneous use of a kabazitaksel with powerful inhibitors of an isoenzyme CYP3A (such as кетоконазол, итраконазол, кларитромицин, атазанавир, индинавир, нефазодон, нелфинавир, ритонавир, саквинавир, телитромицин, вориконазол) increase in concentration of a kabazitaksel in a blood plasma is expected. Therefore it is necessary to avoid simultaneous use of a kabazitaksel and powerful inhibitors of an isoenzyme CYP3A. It is necessary to be careful at simultaneous use of a kabazitaksel and moderate inhibitors of an isoenzyme CYP3A. CYP3A isoenzyme inductors
Though official researches on medicinal interaction were not conducted, at simultaneous use of a kabazitaksel with powerful inductors of an isoenzyme CYP3A (such as Phenytoinum, carbamazepine, rifampicin, рифабутин, rifapentine, phenobarbital) decrease in concentration of a kabazitaksel in a blood plasma is expected. Therefore it is necessary to avoid simultaneous use of a kabazitaksel and powerful inductors of an isoenzyme CYP3A. Besides the patients receiving kabazitakset, have to abstain from administration of drugs of a grass of a St. John's Wort. Prednisolonum/Prednisonum
Prednisolonum/Prednisonum, accepted on 10 mg daily, do not exert impact on pharmacokinetics of a kabazitaksel.
Warfarin
Kabazitaksel does not inhibit in vitro the main way of biotransformation of warfarin to 7 hydroxywarfarin which is carried out by means of CYP2C9 isoenzyme. Therefore any pharmacokinetic interaction of a kabazitaksel and in vivo warfarin is not expected. Vaccination
Use of live vaccines or the weakened live vaccines for patients with the immunity reduced as a result of treatment by chemotherapeutic drugs can lead to development of serious or fatal infections. It is necessary to avoid vaccination by live attenuated vaccines at the patients receiving treatment kabazitaksely. The killed or inactivated vaccines can be applied; however reaction of an organism to such vaccines can be less expressed.
Contraindications:
- Indications of the anamnesis on heavy reactions of hypersensitivity on kabazitakset either other taxons, or drug excipients (polysorbate-80).
- Quantity of neutrophils in peripheral blood less than 1500/mm3.
- Liver failure (bilirubin> 1 x UBN (upper bound of norm), aspartate aminotransferase of serum (nuclear heating plant) and/or alaninaminotranspherase of serum (ALT)> 1,5 x VGN).
- Simultaneous vaccination by a vaccine to yellow fever (see. "Interaction with other medicines").
- Pregnancy and period of a lactation.
- Children's and teenage age up to 18 years (safety and efficiency are not established).
With care
- At patients with a renal failure of moderate severity (clearance of creatinine of 30-50 ml/min.) (limitation of clinical data on drug use) and at patients with a heavy renal failure (clearance of creatinine less than 30 ml/min.) and an end-stage of a renal failure (lack of clinical data on drug use) (careful medical control is required during treatment).
- At patients with a hemoglobin content in peripheral blood <10 g/dl.
- At patients with states or diseases which do them predisposed to development of a neutropenia and/or increase in complications at a long neutropenia (the age is more senior than 65 years, low indicators of the general state, low body weight, the previous episodes of a febrile neutropenia, the previous intensive radiation therapy, other serious associated diseases) ( careful medical control is required during treatment, perhaps preventive introduction of a granulotsitarny colony stimulating factor (G-KSF)).
Overdose:
Symptoms
The expected overdose symptoms: strengthening of dozozavisimy side effects, such as symptoms of suppression of a marrowy hemopoiesis and disturbance from digestive tract. Treatment
There is no known antidote of a kabazitaksel. In case of overdose the patient has to be placed in specialized department under careful medical observation. After it will become known of overdose, patients have to, as soon as possible, begin to receive G-KSF. Also it is necessary to carry out other symptomatic treatment.
Storage conditions:
To store at a temperature not above 30 °C. Not to store in the refrigerator. To store in the place, unavailable to children. Period of validity 2 years. Not to use drug after the period of validity specified on packaging.
Issue conditions:
According to the recipe
Packaging:
Concentrate for preparation of solution for infusions of 40 mg/ml (complete with solvent).
On 1,5 ml of drug in the bottle from transparent glass (type I) corked by the stopper from chlorbutyl which is pressed out by the aluminum cap closed from above by a protective plastic lid like "flip-off".
On 4,5 ml of solvent in the bottle from transparent glass (type I) corked by the stopper from chlorbutyl which is pressed out by the aluminum cap closed from above by a protective plastic lid like "flip-off".
On 1 bottle with drug and to 1 bottle with solvent in transparent plastic packaging. On 1 plastic packaging together with the application instruction in a cardboard pack.
