Таксотер®

General characteristics. Structure:

Active agent: dotsetakset, trihydrate (the quantity is equivalent to an anhydrous dotsetaksel) - 20 mg.
Excipient: polysorbate 80 to 0,5 ml.
Composition of the enclosed solvent (13% ethanol solution in water for injections): ethanol of 95% (V/V) - 191,1 mg, water for injections to 1,5 ml.
Taksoter, a concentrate for preparation of solution for infusions of 80 mg / 2 ml. Contains in 1 bottle:
Active agent: dotsetakset, trihydrate (the quantity is equivalent to an anhydrous dotsetaksel) - 80 mg.
Excipient: polysorbate 80 to 2,0 ml.
Composition of the enclosed solvent (13% ethanol solution in water for injections): ethanol
95% (V/V) - 764,4 mg, water for injections to 6,0 ml.
Description. A concentrate for preparation of solution for infusions of 20 mg / 0,5 ml and 80 mg / 2 ml: Transparent, oily solution from yellow till brownish-yellow color. Solvent:
Transparent colourless solution.

Pharmacological properties:

Pharmacodynamics. Dotsetaksel - antineoplastic drug of a plant origin (from group of toxoids). Accumulates тубулин in microtubules, interferes with their disintegration that breaks process of division of tumor cells. Dotsetaksel long time remains in cells where concentration it reaches high values. Besides, dotsetakset shows activity concerning some, though not everything, the cells producing the R-glycoprotein (P-gP) coded by a gene of multiple resistance to chemotherapeutic drugs in excess quantity. In vivo dotsetakset has a wide range of activity concerning tumors of mice and the intertwined tumor cells of the person.
Efficiency of a dotsetaksel was proved at a breast cancer, not small-celled cancer of a lung, ovarian cancer, a gormonorezistentny prostate cancer, a carcinoma of the stomach, cancer of the head and neck.

Pharmacokinetics. Pharmacokinetics at adults. The pharmacokinetics of a dotsetaksel is dozozavisimy and corresponds to three-phase pharmacokinetic model with elimination half-lives for and, P and at phases - 4 min., 36 min. and 11,1 h, respectively.
After hourly infusion of a dotsetaksel in a dose of 100 mg/sq.m average values of the maximum concentration of a dotsetaksel in plasma (Cmax) made 3,7 mkg/ml with the respective area under a curve "concentration time" (AUC) 4,6 ¼¬ú*þ/ml. Average values for the general clearance and volume of distribution in an equilibrium state made 21 l/h/sq.m and 113 l, respectively. Values of the general clearance of a dotsetaksel at different patients differed approximately for 50%.
Dotsetaksel more than for 95% contacts proteins of a blood plasma.
Dotsetaksel after oxidation is grated - butyl radio group by means of system of isoenzymes P450 within 7 days is brought through kidneys, with urine (6% of the entered dose) and through digestive tract, with a stake (75% of the entered dose). About 80% of the entered dose of a dotsetaksel within 48 hours are removed with a stake in the form of metabolites (the main inactive metabolite and three less significant inactive metabolites) and in very insignificant quantity - in not changed look. The pharmacokinetics of a dotsetaksel does not depend on age and a sex of the patient. At poorly expressed abnormal liver functions (activity of alaninaminotranspherase (ALT) and aspatataminotransferaz (nuclear heating plant) no more than 1,5 their upper bounds of norm (UBN) in combination with activity of an alkaline phosphatase no more than 2,5 VGN) the general clearance of a dotsetaksel decreases on average by 27%. At a weak or 2nd moderate delay of liquid the clearance of a dotsetaksel does not change; there are no data on its clearance at a vyrazhennoyzaderzhka of liquid.
At the combined use dotsetakset does not influence clearance of doxorubicine and plasma concentration of a doksorubitsinol (a doxorubicine metabolite). Pharmacokinetic indicators of a dotsetaksel, doxorubicine and cyclophosphamide did not change at their simultaneous use.
Kapetsitabin does not influence pharmacokinetics of a dotsetaksel (Stakh, AUC), and dotsetakset, in turn, does not influence pharmacokinetics of a kapetsitabin and most important metabolite of a kapetsitabin (5-DFUR).
The clearance of a dotsetaksel at a combination therapy with Cisplatinum does not change in comparison with its clearance at monotherapy. The pharmacokinetic profile of Cisplatinum of the dotsetaksel entered soon after infusion did not differ from that at introduction of one Cisplatinum.
Prednisonum does not influence pharmacokinetics of the dotsetaksel entered after standard premedication by dexamethasone.
The combination therapy dotsetaksely, Cisplatinum and ftoruratsily does not change their pharmacokinetic indicators. Pharmacokinetics at children
Children have pharmacokinetic indicators at monotherapy dotsetaksely and therapies dotsetaksely in a combination with Cisplatinum and ftoruratsily were similar to that at adults.

Indications to use:

Breast Cancer (BC)
Resectable RMZh (Taksoter® in a combination with doxorubicine and cyclophosphamide, adjuvant chemotherapy):
• resectable RMZh with damage of regional lymph nodes;
• resectable RMZh without damage of regional lymph nodes at patients to whom carrying out chemotherapy according to the established international selection criteria for primary chemotherapy of early stages of RMZh (in the presence of one or more factors of high risk of development of a recurrence is shown: the size of a tumor is more than 2 cm, the negative status of estrogenic and progesteronovy receptors, high histologic degree of a zlokachestvennost of a tumor (degree 2 - 3), age less than 35 years).
Metastatic and/or locally-spread RMZh:
- locally-spread or metastatic RMZh (Taksoter® in a combination with doxorubicine, therapy of the 1st line);
- metastatic RMZh with a tumoral hyper expression of HER2 (Taksoter® in a combination with trastuzumaby, therapy of the 1st line);
- locally-spread or metastatic RMZh at inefficiency of the previous chemotherapy including anthracyclines or the alkylating means (Taksoter® in monotherapy) or at inefficiency of the previous chemotherapy including anthracyclines (Taksoter® in a combination with kapetsitabiny).
Not small-celled cancer of a lung
- Locally-spread or metastatic not small-celled cancer of a lung at inefficiency of the previous chemotherapy (Taksoter® in monotherapy).
- Nerezektabelny locally-spread or metastatic not small-celled cancer of a lung (Taksoter® in a combination with Cisplatinum, therapy of the 1st line).
Ovarian cancer
- Metastatic ovarian cancer at inefficiency of the previous therapy of the 1st line (Taksoter® in monotherapy, therapy of the 2nd line).
Prostate cancer
- Metastatic gormonorezistentny (an androgen - independent) a prostate cancer (Taksoter® in a combination with Prednisonum or Prednisolonum).
Carcinoma of the stomach
- A metastatic carcinoma of the stomach, including cancer of a zone of esophageal and gastric transition (Taksoter® in a combination with Cisplatinum and ftoruratsily, therapy of the 1st line).
Cancer of the head and neck
- Locally-spread planocellular cancer of the head and neck (Taksoter® in a combination with Cisplatinum and ftoruratsily, induction therapy).

Route of administration and doses:

Treatment by the drug Taksoter® should be carried out only under observation of the doctor having experience of carrying out antineoplastic chemotherapy in the conditions of a specialized hospital.
For the prevention of hypersensitivity reactions, and also for the purpose of reduction of a delay of liquid by all patient receiving Taksoter® (except patients with a prostate cancer recommendations about premedication at whom see below), in case of lack of contraindications before its introduction premedication is carried out by a glucocorticosteroid, for example, dexamethasone inside in a dose of 16 mg/days (on 8 mg twice a day) within 3 days, beginning in 1 day prior to administration of the drug Taksoter®. At the patients with cancer of a prostate receiving the accompanying treatment by Prednisonum or Prednisolonum premedication by dexamethasone in a dose of 8 mg in 12, 3 and 1 hour prior to administration of the drug Taksoter® is carried out.
For decrease in risk of development of hematologic complications preventive introduction of a granulotsitarny colony stimulating factor (G-KSF) is recommended.
Таксотер® it is entered intravenously kapelno within 1 hour of 1 times in 3 weeks.

Breast Cancer (BC).
At adjuvant therapy of resectable RMZh with damage of regional lymph nodes and resectable RMZh without damage of regional lymph nodes, the recommended dose of the drug Taksoter® makes 75 mg/sq.m in 1 hour after administration of doxorubicine (50 mg/sq.m) and cyclophosphamide (500 mg/sq.m) each three weeks (scheme TAC). Only 6 cycles (see also further "Dose adjustment").
At locally-spread or metastatic RMZh as therapy of the first line dotsetakset 75 mg/sq.m it is entered into combinations with doxorubicine of 50 mg/sq.m; as therapy 2 lines the recommended dose of a dotsetaksel in monotherapy makes 100 mg/sq.m.
For a combination of Taksoter® plus трастузумаб the recommended dose of the drug Taksoter® makes 100 mg/sq.m each 3 weeks with weekly introduction of a trastuzumab. Initial infusion of a dotsetaksel is carried out next day after introduction of the first dose of a trastuzumab. The subsequent doses of a dotsetaksel are entered directly after the end of infusion of a trastuzumab (at good tolerance of the previous dose of a trastuzumab). For obtaining information on doses and a way of introduction of a trastuzumab see the instruction on a medical use of a trastuzumab.
At a combination with kapetsitabiny the recommended dose of a dotsetaksel makes 75 mg/sq.m each 3 weeks, and a kapetsitabina - 1250 mg/sq.m inside two times a day (within 30 minutes after food) within 2 weeks with the subsequent one-week period of rest. For calculation of a dose of a kapetsitabin according to body surface area see the application instruction of a kapetsitabin. Not small-celled cancer of a lung
At the patients who were not receiving earlier chemotherapy the following scheme of treatment is recommended: dotsetakset 75 mg/sq.m, right after it introduction of Cisplatinum of 75 mg/sq.m within 30-60 minutes.
For treatment after inefficiency of chemotherapy on the basis of platinum drugs, monotherapy dotsetaksely in a dose of 75 mg/sq.m is recommended. Metastatic ovarian cancer
For therapy of the 2nd line of ovarian cancer the dose of a dotsetaksel of 100 mg/sq.m everyone is recommended
3 weeks in monotherapy.
Prostate cancer
For treatment of patients with a prostate cancer the recommended dose of the drug Taksoter® makes 75 mg/sq.m of times in three weeks. Prednisonum or Prednisolonum are appointed it is long on 5 mg in 2 times a day. Carcinoma of the stomach
For cancer therapy of a stomach the recommended dose of the drug Taksoter® makes 75 mg/sq.m in the form of hourly infusion with the subsequent infusion of Cisplatinum of 75 mg/sq.m within 1-3 hours (both drugs only in the first day of each cycle of chemotherapy). Upon completion of introduction of Cisplatinum carry out 24-hour infusion of a ftoruratsil of 750 mg/sq.m/days within 5 days. Treatment repeats each 3 weeks. Patients have to receive premedication antiemetic drugs and the corresponding hydration for introduction of Cisplatinum. For reduction of risk of hematologic toxicity (see dose adjustment) with the preventive purpose introduction of G-KSF is shown.

Cancer of the head and neck
Patients have to receive premedication antiemetics, the corresponding hydration has to be carried out by him (before introduction of Cisplatinum). It is necessary to carry out prevention of development of neytropenichesky infections. All patients receiving Taksoter®-soderzhashchiye of the scheme of treatment preventively received antibiotics.
The induction chemotherapy with the subsequent radiation therapy For induction therapy at locally-spread inoperable planocellular cancer of the head and neck the recommended dose of the drug Taksoter® makes 75 mg/sq.m in the form of hourly infusion with the subsequent introduction of Cisplatinum in a dose of 75 mg/sq.m within 1 hour (both drugs are administered only in the first day of each cycle of chemotherapy). After that continuous infusion of a ftoruratsil in a dose of 750 mg/sq.m/days within 5 days is carried out. This scheme repeats each 3 weeks during 4 cycles. After chemotherapy patients have to receive radiation therapy. The induction chemotherapy with the subsequent himioluchevy therapy For induction therapy of locally-spread planocellular cancer of the head and a neck (technically nerezektabelny, with low probability of surgical treatment or at the solution of preservation of body) the recommended dose of the drug Taksoter® makes 75 mg/sq.m in the form of hourly intravenous infusion with the subsequent 0,5-3-hour infusion of Cisplatinum of 100 mg/sq.m (both drugs are administered only in the first day of each cycle of chemotherapy) and with the subsequent continuous infusion of a ftoruratsil in a dose of 1000 mg/sq.m/days from 1 to 4 day. This scheme of treatment repeats each 3 weeks, only 3 cycles. After chemotherapy patients have to receive himioluchevy therapy. For obtaining data on correction of doses of Cisplatinum and a ftoruratsil, see application instructions of these drugs. Dose adjustment General principles
Таксотер® it has to be entered at quantity of neutrophils in peripheral blood> 1500/mkl. In case of development of a febrile neutropenia, number of neutrophils <500/mkl lasting more than one week expressed or cumulative (amplifying at repeated introductions) skin reactions, or the expressed peripheral neuropathy against the background of therapy dotsetaksely, its dose at the following introductions has to be lowered from 100 mg/sq.m to 75 mg/sq.m and/or from 75 mg/sq.m to 60 mg/sq.m. If similar reactions remain also at a dose of a dotsetaksel of 60 mg/sq.m, they should stop treatment.

Adjuvant therapy of a breast cancer
Introduction of G-KSF is recommended to the patients with cancer of a mammary gland receiving adjuvant therapy by the drug Taksoter® in a combination with doxorubicine and cyclophosphamide (scheme TAC) for the purpose of primary prevention. Patients who transferred a febrile neutropenia or a neytropenichesky infection in all subsequent cycles need to reduce a drug Taksoter® dose to 60 mg/sq.m. At patients at whom stomatitis 3 or 4 severity developed the dose decline of a dotsetaksel to 60 mg/sq.m is necessary. Таксотер® in a combination with Cisplatinum
At patients who originally received dotsetakset in a dose 75 mg/sq.m in a combination with Cisplatinum and at which the quantity of thrombocytes in the previous cycle decreased to 25000/mkl, or at patients at whom the febrile neutropenia, or at patients with heavy not hematologic toxicity developed, the dose of a dotsetaksel in the subsequent cycles has to be lowered to 65 mg/sq.m.
For dose adjustment of Cisplatinum see the application instruction of Cisplatinum.

Таксотер® in a combination with kabetsitabiny
- For dose adjustment of a kapetsitabin at its combination with the drug Taksoter® see the instruction on a medical use of a kapetsitabin.
- At the first emergence of toxicity 2 severity which remains by the beginning of the following cycle Taksoter®/kapetsitabin the following cycle of treatment can be postponed until decrease in toxicity to 0-1 severity, at the same time during the following cycle of treatment 100% of an initial dose are entered.
- Patients with repeated development of toxicity have 2 severity or the first development of toxicity 3 severity of a cycle at any time, treatment is postponed until decrease in toxicity to 0-1 severity, then treatment by the drug Taksoter® is resumed in a dose of 55 mg/sq.m.
- At any subsequent emergence of toxicity or emergence of any toxicity 4 severity administration of the drug Taksoter® has to be stopped.
Таксотер® in a combination with trastuzumaby
For dose adjustment of a trastuzumab see information in the application instruction of a trastuzumab.
Таксотер® in a combination with Cisplatinum and ftoruratsily
The patients receiving Taksoter® in a combination with Cisplatinum and ftoruratsily according to the existing standard recommendations have to receive antiemetic drugs and sufficient hydration. It is necessary to apply G-KSF to reduction of risk of the complicated neutropenia.
If, despite reception of G-KSF, there are episodes of a febrile neutropenia, a long neutropenia or a neytropenichesky infection, the dose of the drug Taksoter® should be reduced from 75 to 60 mg/sq.m. At the subsequent development of episodes of the complicated neutropenia it is recommended to reduce a drug Taksoter® dose from 60 mg/sq.m to 45 mg/sq.m. At development of thrombocytopenia 4 severity a dose of the drug Taksoter® is recommended to be reduced from 75 mg/sq.m to 60 mg/sq.m. The subsequent cycles using a dotsetaksel are possible at quantity of neutrophils> 1500/mkl and thrombocytes> 100000/mkl. At persistent preservation of these toxic manifestations treatment should be stopped.
The recommended correction of doses at development of toxicity in the patients receiving Taksoter® in a combination with Cisplatinum and ftoruratsily (FAUGH).

Toxicity                                       Correction of the mode of dosing
Diarrhea 3 severity         First episode: to reduce a dose FAUGH by 20%
                                                 Repeated episode: to reduce a drug Taksoter® dose by 20%.
Diarrhea 4 severity          First episode: to reduce doses of the drug Taksoter® and FAUGH by 20%
                                                 Repeated episode: to stop treatment.
Stomatitis / мукозит 3 degrees       First episode: to reduce a dose FAUGH by 20% 
weights                                     Repeated episode: to stop only reception FAUGH

                                                 in all subsequent   cycles.
                                                                           
Stomatitis / мукозит 4 degrees      Third episode: to reduce a drug Taksoter® dose by 20%
  weights                                              First episode: to stop only reception FAUGH in all subsequent cycles
                                                 Repeated episode: to reduce a drug Taksoter® dose by 20%.

For obtaining recommendations about correction of doses of Cisplatinum and a ftoruratsil watch instructions for their use.
Patients with not small-celled cancer have heads and necks at which the complicated neutropenia developed (including the prolonged neutropenia, a febrile neutropenia or an infection), in all subsequent cycles with the preventive purpose use of G-KSF is recommended (for example, from 1 to 15 day). Special groups of patients Children
Safety and efficiency of the drug Taksoter® at children is studied insufficiently. There is a limited experience of use of the drug Taksoter® for children. Efficiency and safety of use of the drug Taksoter® at cancer is not established yet
9 nasopharynxes at children and teenagers from 1 month to 18 years. Таксотер® it was not applied at children according to indications: a breast cancer, not small-celled cancer of a lung, a prostate cancer, a carcinoma of the stomach and cancer of the head and neck, except for the low-differentiated cancer of a nasopharynx (type I and II). Elderly people
Proceeding from data of the population pharmacokinetic analysis, there are no special instructions on use of the drug Taksoter® for elderly people. Patients have 60 years and are more senior at a drug Taksoter® combination with kapetsitabiny the dose decline of a kapetsitabin for 25% is recommended (see the application instruction of a kapetsitabin).
Patients with a liver failure
Proceeding from the pharmacokinetic data obtained for the drug Taksoter® in monotherapy in a dose of 100 mg/sq.m at patients with activity of ALT and/or nuclear heating plant> 1,5 VGN or activity of an alkaline phosphatase> 2,5 VGN, the recommended dose of the drug Taksoter® makes 75 mg/sq.m. At patients with the increased content of bilirubin in blood (> 1 VGN) and/or with increase in activity of ALT and nuclear heating plant (> 3,5 VGN) in combination with increase in activity of an alkaline phosphatase (> 6 VGN), the dose decline cannot be recommended and it is not necessary to apply without strict indications dotsetakset.
The drug Taksoter® combination with Cisplatinum and ftoruratsily at treatment of patients with a carcinoma of the stomach was not applied at patients with increase in activity of ALT and/or nuclear heating plant (> 1,5 VGN) in combination with increase in activity of an alkaline phosphatase (> 2,5 VGN) and the increased content of bilirubin in blood (> 1 VGN); at such patients the dose decline cannot be recommended and it is not necessary to apply without strict indications dotsetakset.
At the moment there are no uses of the drug Taksoter® given relatively in a combination with other drugs at patients with abnormal liver functions. Patients with renal failures.
There are no data on use of a dotsetaksel for patients with heavy renal failures.
Preparation of infusion solution
Concentrate for preparation of solution for infusions on 20 mg / 0,5 ml: actual content in a bottle of 24,4 mg / 0,61 ml that allows to offset the losses of liquid at preparation of previously mixed solution caused by foaming, adhesion to walls of a bottle and existence of "dead space". Thus, excess of drug in a bottle guarantees that after cultivation of its contents the enclosed 10th solvent the minimum volume of the gathered previously mixed solution will make 2 ml containing 10 mg/ml of a dotsetaksel that corresponds to 20 mg (the dose specified on the label of a bottle).
Concentrate for preparation of solution for infusions on 80 mg / 2 ml: actual content in a bottle of 94,4 mg / 2,36 ml that allows to offset the losses of liquid at preparation of previously mixed solution caused by foaming, adhesion to walls of a bottle and existence of "dead space". Thus, excess of drug in a bottle guarantees that after cultivation of its contents the enclosed solvent the minimum volume of the gathered previously mixed solution will make 8 ml containing 10 mg/ml of a dotsetaksel that corresponds to 80 mg (the dose specified on the label of a bottle).
It is IMPOSSIBLE to apply Taksoter®, a concentrate for preparation of infusion solution (20 mg / 0,5 ml and 80 mg / 2 ml) consisting of two bottles (a concentrate and solvent) together with forms of production of the drug Taksoter® in 1 bottle (20 mg / 1 ml and 80 mg / 4 ml).
a) Preparation of previously mixed drug Taksoter® solution (concentration dotsetakset 10 mg/ml)
The concentrate for preparation of solution for infusions of Taksoter® needs to be parted previously in the enclosed solvent.
If bottles with drug and solvent were stored in the refrigerator, then before their cultivation it is necessary to sustain within 5 minutes at the room temperature (below 25 °C).
All contents of a bottle with solvent in aseptic conditions are gathered by means of a needle in the syringe (the bottle is placed slightly at an angle) and entered into a bottle with the drug Taksoter®.
After extraction of a needle bottle contents with the received mix are mixed by a bottle turning during 45 up and down with (Not to stir up!) also leave for 5 min. at the room temperature then solution is checked for homogeneity and transparency (availability of foam even in 5 minutes is norm because of the content of polysorbate 80 as a part of drug).
Previously mixed solution contains dotsetakset 10 mg/ml in concentration and has to be immediately used for preparation of solution for infusions.
b) Preparation of solution for infusion
The necessary volume of previously mixed solution according to required
by dose it is entered into a bag for infusions or the bottle containing  250 ml of 5% of solution
Dextrosums   or 0,9% of solution of sodium of chloride. If the required dose dotsetakset
11 exceeds 200 mg, it is necessary to use the bigger volume of liquid for infusion that concentration of a dotsetaksel was not higher than 0,74 mg/ml.
Bag contents for infusions or a bottle should be mixed by means of vrashchetelny movements. The received solution needs to be used within 4 hours by intravenous hourly infusion at the room temperature and usual conditions of illumination.
Previously mixed solution of the drug Taksoter® and solution for infusion, as well as any other drugs for parenteral use, it is necessary to examine before introduction; in the presence of a deposit solution should be destroyed.
The remains of drug and all materials used for its cultivation and introduction should be utilized according to standard instructions.

Features of use:

Neutropenia
It is necessary to make careful observation of clinical blood test at the patients receiving therapy by the drug Taksoter®. At development of the expressed neutropenia (<500/mkl within 7 days) during a therapy course the drug Taksoter® recommends to lower a drug dose on the subsequent cycles or to apply adequate symptomatic measures. To continue treatment by the drug Taksoter® perhaps after recovery of number of neutrophils to 1500/mkl.
In case of receiving G-KSF by the patients receiving Taksoter® in a combination with Cisplatinum and ftoruratsily the febrile neutropenia and/or neytropenichesky infections develop less often. Therefore at use of this combination purpose of G-KSF is necessary for reduction of risk of development of the complicated neutropenia (a febrile neutropenia, a long neutropenia, a neytropenichesky infection) with the preventive purpose. It is necessary to watch a state and laboratory indicators of the patients receiving this chemotherapeutic scheme carefully. If patients receive primary prevention of G-KSF (from the first cycle) at purpose of the drug Taksoter® with doxorubicine and cyclophosphamide (TAS chemotherapy mode) the febrile neutropenia and/or a neytropenichesky infection develop in combinations less often. Therefore at adjuvant chemotherapy of a breast cancer according to the scheme TAC for reduction of risk of development of the complicated neutropenia (a febrile neutropenia, a long neutropenia, a neytropenichesky infection) it is necessary to consider a question of preventive introduction of G-KSF from the first cycle. It is necessary to watch a condition of the patients receiving TAS carefully. Hypersensitivity reactions
With the purpose of identification of hypersensitivity reactions of patients it is necessary to observe carefully, especially during the first and second infusions. Development of reactions of hypersensitivity is possible in the very first minutes of infusion of the drug Taksoter® therefore at its introduction it is necessary to have medicines and the equipment for treatment of arterial hypotonia and a bronchospasm. Easy manifestations of hypersensitivity (face reddening or the localized skin reactions) do not demand interruption of administration of drug. Despite premedication, at patients heavy reactions of hypersensitivity, such as the expressed lowering of arterial pressure, bronchospasm or generalized rash / erythema and very seldom fatal anaphylactic reactions were observed. Emergence of reactions of hypersensitivity demands the immediate termination of administration of the drug Taksoter® and performing the corresponding therapy. Repeated administration of the drug Taksoter® at the patients who transferred heavy reactions of hypersensitivity is forbidden. Patients with a liver failure
At the patients who are receiving monotherapy dotsetaksely in a dose of 100 mg/sq.m and having a superactivity of serumal transaminases (ALT and/or nuclear heating plant), more than by 1,5 times the exceeding VGN, in combination with increase in serumal level of an alkaline phosphatase VGN is more than 2,5 times higher, the risk of development of heavy side effects, such as sepsis, gastrointestinal bleedings, a febrile neutropenia, infections, thrombocytopenia, crushing toxic damages of skin up to a lethal outcome, and also stomatitis and an adynamy is extremely high. In this regard at such patients with the raised indicators of function of a liver the recommended dose of the drug Taksoter® makes 75 mg/sq.m. Functional trials of a liver have to be carried out prior to treatment and before each subsequent cycle of therapy by the drug Taksoter®. At patients with the increased level of bilirubin and/or a superactivity of ALT and nuclear heating plant (> 3,5 VGN) in combination with increase in level of an alkaline phosphatase> 6 VGN, Taksoter® is not recommended to be applied. At the moment there are no uses of the drug Taksoter® given relatively in a combination with other drugs at patients with abnormal liver functions. Liquid delay
Careful observation of patients with the expressed liquid delay is necessary: with an exudate in a pleural cavity, a pericardium or with ascites. At emergence of hypostases - restriction of the salt and drinking mode and purpose of diuretics.
Leukemia
At use of a combination of the drug Taksoter® with doxorubicine and cyclophosphamide concerning resectable RMZh the risk of development delayed myelodisplasias and/or myeloid leukemia demands hematologic observation of patients.
Heart failure
At the patients receiving Taksoter® in a combination with trastuzumaby concerning metastatic RMZh with a tumoral hyper expression of HER2 especially later containing chemotherapy anthracyclines (doxorubicine or эрирубицин), development of heart failure is possible, it can be moderately severe or heavy and lead to death. When treatment by the drug Taksoter® in a combination with trastuzumaby is shown to the patient, it has to undergo initial cardiological inspection. Each three months it is necessary to control cordial function that allows to reveal patients at whom heart failure can develop. In more detail see the Application instruction of a trastuzumab. Patients of advanced age
In comparison with patients 60 years at patients at the age of 60 years are younger and are more senior, receiving the combined chemotherapy of Taksoter® + капецитабин, increase in frequency 3 and 4 severity connected with treatment serious the NPR and early cancellation of treatment owing to development of the NPR connected with treatment of the adverse phenomena was observed.
There are limited data on use of a combination of a dotsetaksel with doxorubicine and cyclophosphamide for patients 70 years are more senior.
Patients have 65 years and are more senior, receiving treatment by the drug Taksoter® each 3 weeks concerning a prostate cancer, the frequency of changes of nails on> was higher than 10%, than at patients of younger age, and patients have 75 years and the frequency of fever, diarrhea, anorexia and peripheral hypostases on> 10% is more senior was higher, than at patients of younger age.
At use of a combination dotsetakset with Cisplatinum and ftoruratsily the following side reactions (all severity): the lethargy (drowsiness, block, catalepsy), stomatitis,  a neytropenichesky infection, at patients is more senior than 65 years met on> 10% more often than at patients of younger age. Therefore patients are more senior than 65 years receiving this combination need careful observation. Need of contraception
Men and women of childbearing age during treatment by the drug Taksoter® need to apply reliable methods of contraception. As in preclinical trials it was shown that dotsetakset has genotoksichesky action and can break male fertility (ability to conceive), the men receiving treatment dotsetaksely are recommended to abstain from conception of the child during treatment dotsetaksely and within not less than 6 months after the termination of chemotherapy and to advise to make sperm preservation before treatment.
Of pregnancy at them during treatment follows women in case of emergence urgently
to report about it to the attending physician.
Neurotoxicity
Development of heavy touch neuropathy demands a drug Taksoter® dose decline. Ethanol content.
The drug Taksoter® contains ethanol in concentration of 50 volume % (that is to 0,385 mg (0,5 ml) of anhydrous ethanol in a bottle of 20 mg / 1 ml and to 1,58 g (2 ml) of anhydrous ethanol in a bottle of 80 mg / 4 ml). It should be taken into account at use of drug for patients with alcoholism and patients from risk group (patients with diseases of a liver and epilepsy).
The address and precautionary measures at the treatment of the drug Taksoter® Taksoter® is antineoplastic drug; as well as in case of other potentially toxic substances, it is necessary to be careful at its use and preparation of solutions. It is recommended to use gloves. If solution of the drug Taksoter® or infusion solution of the drug Taksoter® gets on skin, then it should be washed up immediately carefully water with soap. At hit of a concentrate, or infusion solution of the drug Taksoter® on their mucous membranes it is necessary to wash out immediately carefully water.
Influence on ability to manage vehicles and to be engaged in other potentially dangerous types of activity.
Special researches were not conducted. However development of side reactions from a nervous system, an organ of sight, digestive tract, etc., and also existence in composition of drug of ethanol can be led to reduction of speed psychomotor reaction and attention. In this regard it is not recommended by the drug Taksoter® to drive during treatment the car and to be engaged in other potentially dangerous types of activity.

Side effects:

For the indication of frequency of development of undesirable side reactions (NIR) classification of NIR of World Health Organization is used: very frequent> 10%; frequent> 1 and <10%; infrequent> 0,1 and <1%; rare> 0,01 and <0,1%; very rare <0,01%, unknown frequency (when according to the available data it is not possible to estimate the frequency of development of the NPR).
Monotherapy by the drug Taksoter® (75 mg/sq.m and 100 mg/sq.m) of Disturbance from blood and lymphatic system Very frequent
Reversible and non-cumulative (not amplifying at repeated introductions) the neutropenia observed at 96,6% of the patients who were not receiving G-KSF. The number of neutrophils decreases to the minimum values on average in 7 days (at patients of c the intensive previous chemotherapy this period can be shorter), the average duration of the expressed neutropenia (<than 500 cells / мкл) also makes 7 days. Febrile neutropenia, infections. Frequent
The heavy infections which are combined with decrease in quantity of neutrophils in peripheral blood <500/mkl; heavy infections, including sepsis and pneumonia, including from the death; thrombocytopenia <100000/mkl; the bleedings which are combined with thrombocytopenia <50000/mkl and anemia (hemoglobin <11 g/dl), including with heavy anemia (hemoglobin <8 g/dl). Infrequent
Heavy thrombocytopenia.
Disturbances from immune system
Very frequent
Allergic reactions which usually arise within several minutes after the beginning of infusion of the drug Taksoter® and happen easily or moderately expressed (a hyperemia of integuments; rash in combination with an itch and without it; feeling of constraint in a breast; dorsodynia; asthma; medicinal fever or fever). Frequent
The heavy allergic reactions which are characterized by a lowering of arterial pressure and/or  a bronchospasm or generalized rash / erythema, disappearing later the terminations of infusion and purpose of the corresponding therapy. Disturbances from skin and hypodermic fabrics
In certain cases additional impact on emergence of these reactions was exerted by a combination of several factors, such as the accompanying infections, the accompanying therapy and a basic disease. Very frequent
Reversible skin tests, usually poorly or moderately expressed: the localized rashes, mainly, on hands and legs, and also on a face and a thorax which often are followed by an itch. Rashes usually arose within one week after infusion of a dotsetaksel.
Disturbances from nails  are characterized hypo - and a hyperpegmentation, pain and
onikholizisy (loss of nails from free edge of a nail).
Alopecia.
Frequent
Heavy skin reactions, such as rashes with the subsequent desquamation, including a heavy syndrome of damage of palms and stop which can demand interruption or the termination of treatment dotsetaksely. Infrequent Heavy alopecia.
Disturbances from digestive tract Very frequent
Nausea, vomiting, diarrhea, anorexia, stomatitis. Frequent
Heavy nausea; heavy vomiting; heavy diarrhea; lock; heavy stomatitis; esophagitis;
pains in epigastriums, including strong; gastrointestinal bleedings.
Infrequent
Heavy gastrointestinal bleedings, heavy locks, heavy esophagitis.
Disturbances from a liver and biliary tract Frequent
Increase in serumal activity of nuclear heating plant, ALT, alkaline phosphatase and content of bilirubin in blood, more than by 2,5 times the exceeding VGN. Disturbances from a nervous system Very frequent
The easy or moderately expressed neurosensory reactions: paresthesia, a dizesteziya, pains, including burning sensation; and the neuromotor reactions which mainly are shown muscular weakness; disturbance of flavoring feelings. Frequent
Heavy neurosensory and neuromotor reactions (3-4 severity); Not frequent
Heavy disturbance of flavoring feelings.
At emergence of these neurologic symptoms it is necessary to carry out correction of the mode of dosing.
If neuropathy symptoms persistently remain, then treatment should be stopped. Average time to spontaneous permission of neurotoxic reactions made 81 days from their beginning (from 0 to 741 days) of Disturbance from heart Frequent
Disturbances of a cordial rhythm. Infrequent
Heart failure. Disturbances from vessels Frequent
Increase or lowering of arterial pressure, bleeding.
Disturbances from respiratory system, bodies of a thorax and a mediastinum
Very frequent
Asthma.
Frequent
Heavy asthma.
Disturbances from skeletal and muscular and connecting fabric
Very frequent
Mialgiya.
Frequent
Arthralgia.
The general frustration and disturbances in an injection site Very frequent
Adynamy, including a heavy adynamy; the generalized and localized pain syndrome, including pains in a thorax of not cardial genesis.
Liquid delay: it was reported about development of peripheral hypostases and increases in body weight and it is less frequent about emergence of an exudate in a pleural and pericardiac cavity, ascites. Peripheral hypostases usually began with the lower extremities and could pass into body weights, generalized with an increase, to 3 kg and more. The delay of liquid is cumulative (increases at repeated administrations of drug). The delay of liquid was not followed by acute episodes of an oliguria or a lowering of arterial pressure. Frequent
The reactions in a drug injection site which are usually poorly expressed and shown in the form of a hyperpegmentation, an inflammation, reddening or a xeroderma, phlebitis, hemorrhages from a punktirovanny vein or hypostasis of a vein.
The generalized and localized pain syndrome which is sharply expressed; including pains in a thorax of not cardial genesis. Severe forms of a delay of liquid.
At the patients receiving treatment dotsetaksely in monotherapy in a dose of 100 mg/sq.m, the median of a total dose before the end of treatment because of a delay of liquid made more than 1000 mg/sq.m, and time median to liquid delay involution - 16,4 weeks (from 0 to 42 weeks). At patients to whom premedication was carried out the delay of the beginning of the moderated or expressed liquid delay (average total doses dotsetakset at which the liquid delay was observed, made when carrying out premedication 818,9 mg/sq.m, and without carrying out premedication - 489,7 mg/sq.m) was observed, however in certain cases the delay of liquid developed already in time of the first courses of therapy. Таксотер® in a combination with other drugs Taksoter® in a combination with doxorubicine
At use of the drug Taksoter® in a combination with doxorubicine in comparison with monotherapy the drug Taksoter® observed the big frequency of a neutropenia, including a heavy neutropenia; febrile neutropenia; thrombocytopenia, including heavy thrombocytopenia; anemias; infections, including heavy infections; nausea; vomitings; diarrheas, including heavy diarrhea; lock; stomatitis, including heavy stomatitis; heart failure; alopecias; but smaller frequency of allergic reactions;
skin reactions, including heavy; damages of nails, including heavy; liquid delays, including heavy; anorexias, neurosensory and neuromotor reactions, including severe forms; hypotensions; disturbances of a rhythm; increases in activity of hepatic transaminases, an alkaline phosphatase, content of bilirubin in blood; mialgiya; adynamy.
Таксотер® in a combination with doxorubicine and cyclophosphamide (scheme TAC) At use of this chemotherapeutic scheme in comparison with monotherapy the drug Taksoter® observed the smaller frequency of development of a neutropenia, heavy anemia, a febrile neutropenia, infections, allergic reactions, peripheral hypostases, neurosensory and neuromotor reactions, damages of nails, diarrheas, arrhythmias, but the big frequency of development of not heavy anemia, thrombocytopenia, nausea, vomiting, stomatitis, disturbances of taste, a lock, adynamy, arthralgia, alopecia was observed. Were in addition observed: colitis, a coloenteritis, perforation of a large intestine without lethal outcomes (the treatment termination was required from the 2nd of 4 patients), acute myeloid leukemia, acute leukemia.
Preventive use of G-KSF reduced the frequency of emergence of a neutropenia (by 60%) and neytropenichesky infections 3-4 severity. Таксотер® in a combination kapetsitabiny
At use of the drug Taksoter® in a combination with kapetsitabiny more frequent development of the undesirable phenomena from digestive tract is observed (stomatitis, diarrhea, vomiting, a lock, abdominal pains, disturbances of flavoring perception); arthralgias; heavy thrombocytopenia and anemia; hyperbilirubinemias; a palmar and-foot syndrome (a dermahemia of extremities (palms and feet) with the subsequent hypostasis and desquamation); but more rare development of a heavy neutropenia; alopecias; disturbances from nails, including онихолизис; adynamy; mialgiya; loss of appetite and anorexias. Dyspepsia, dryness in a mouth, a pharyngalgia, oral cavity candidiasis, dermatitis, erythematic rash, discoloration of nails, a pyrexia, extremity pains, pain, a dorsodynia, a lethargy (drowsiness, block, catalepsy), short wind, cough, nasal bleeding, paresthesia, dizziness, a headache, peripheral neuropathy, dehydration, dacryagogue, weight reduction were in addition observed. In comparison with patients of younger age at patients of 60 years is also more senior, receiving a drug Taksoter® combination with kapetsitabiny, toxicity development 3-4 severity is more often noted. Таксотер® in a combination with trastuzumaby
At the patients receiving a drug Taksoter® combination with trastuzumaby (in comparison with monotherapy by the drug Taksoter®) nausea, diarrhea, a lock, abdominal pains came to light more often, taste disturbances, a febrile neutropenia, an arthralgia, anorexia, the toxic phenomena 4 severity, cases of development of heart failure, especially at the patients who were previously receiving anthracyclines as adjuvant therapy, however were less often observed a neutropenia 3-4 severity, an adynamy, weakness, an alopecia, damage of nails, skin rashes, vomiting, stomatitis and a mialgiya. Were in addition observed: dacryagogue, conjunctivitis, inflammation of mucous membranes, nasopharyngitis, throat and throat pains, nasal bleeding, rhinorrhea, grippopodobny diseases, cough, pyrexia, fever, pains, thorax pains, extremity pain, dorsodynia, bone pains, lethargy (drowsiness, block, catalepsy), sleeplessness, short wind, erythema, dyspepsia, paresthesia, headache, hypesthesia.
In comparison with monotherapy dotsetaksely increase in frequency of emergence of heavy side reactions was observed.

Drug Taksoter® combination with Cisplatinum
At use of this scheme of chemotherapy in comparison with monotherapy thrombocytopenia, including thrombocytopenia 3-4 severity arose the drug Taksoter® more often; anemia, including anemia 3-4 severity; nausea, including nausea 3-4 severity; diarrhea 3-4 severity; anorexia, including diarrhea 3-4 severity; reactions in an injection site. However a neutropenia, including a neutropenia 3-4 severity were less often observed; infections; febrile neutropenia; allergic reactions; skin reactions; damage of nails; liquid delay; including a liquid delay 3-4 severity; stomatitis, neurosensory and to a lesser extent neyromotorony neuropathy; alopecia; adynamy and mialgiya.
It was in addition observed: fever in the absence of an infection, including 3-4 severity; pain.

Drug Taksoter® combination with Prednisolonum or Prednisonum
At use of the drug Taksoter® in a combination with Prednisolonum or Prednisonum in comparison with monotherapy by the drug Taksoter® the frequency of emergence of side effects considerably decreased: anemias, including 3-4 severity; infections; neutropenias, including 3-4 severity; thrombocytopenia; febrile neutropenia; weaknesses; allergic reactions;  neurosensory and neuromotor reactions; alopecias; rashes; desquamations; nausea; diarrheas; stomatitis; vomitings; anorexias; mialgiya; arthralgias; liquid delays; but disturbances of taste and heart failure were more often observed.
Were in addition observed: nasal bleeding, cough, asthma, weakness, tearfulness.
Drug Taksoter® combination with Cisplatinum and ftoruratsily
At use of this combination in comparison with monotherapy by the drug Taksoter® were more often observed anemia including 3-4 severity; thrombocytopenia, including 3-4 severity; febrile neutropenia; neytropenichesky infections (even at use of G-KSF); nausea; vomiting; anorexia; stomatitis; diarrhea; esophagites/dysphagies/pains when swallowing; but infections were less often observed; allergic reactions; liquid delay; neurosensory and neuromotor reactions; mialgiya; alopecia; rash; itch; damage of nails; skin desquamation; disturbances of a rhythm. Were in addition observed fever in the absence of an infection; lethargy (drowsiness, block, catalepsy); hearing changes; dizziness; tearfulness; xeroderma; heartburn; myocardium ischemia; underlined venous drawing; cancer pains; conjunctivitis; decrease in body weight.
Preventive purpose of G-KSF reduces the frequency of development of a febrile neutropenia and/or neytropenichesky infectious complications. The data obtained at use of drug after its registration
The high-quality, malignant and not specified new growths (including cysts and polyps) Very rare.
The acute myeloid leukemia and miyelodisplastichesky syndrome connected with dotsetaksely at its use in combination with other chemotherapeutic means and/or radiation.
Disturbances from blood and lymphatic system
It was reported about oppression of a marrowy blood formation and other hematologic side reactions.
It was reported about development of a syndrome of the disseminated intravascular coagulation (IDCS), it is frequent in combination with sepsis or multiorgan insufficiency. Disturbances from immune system.
It was reported about exceptional cases of an acute anaphylaxis, sometimes from the death. At the patients receiving premedication, these cases came to an end with a lethal outcome very seldom.
Disturbances from a nervous system
The exceptional cases of development of spasms or passing loss of consciousness which sometimes developed in time of infusional administration of drug were observed. Disturbances from an organ of sight
It was reported about exceptional cases of development of dacryagogue in combination with conjunctivitis (or without it) and very exceptional cases of the obstruction of the lacrimal channel leading to its gap. The exceptional cases of passing visual frustration (flash of light in eyes, emergence of scotomas) which are usually arising during infusional administration of drug and combined with development of reactions of hypersensitivity which usually disappeared after the infusion termination were observed.
Disturbances from an acoustic organ and labyrinth disturbances
It was reported about exceptional cases of ototoksichesky effect of drug, a hearing disorder and/or a hearing loss.
Disturbances from heart and vessels
Exceptional cases of a thromboembolism and myocardial infarction.
Disturbances from respiratory system, bodies of a thorax and a mediastinum the Acute respiratory distress syndrome, intersticial pneumonia, pulmonary fibrosis. At simultaneous carrying out radiation exceptional cases of a radiation pulmonitis.
Disturbances from digestive tract
Were seldom observed dehydration, as a result of development of reactions from digestive tract; perforation of a stomach or intestines; colitis, including ischemic; neytropenichesky coloenteritis; exceptional cases of Ilheus (intestinal impassability) and intestinal obstruction.
Disturbances from a liver and biliary tract
It was reported about exceptional cases of development of hepatitis, sometimes from the death, it is preferential at patients with associated diseases of a liver. Disturbances from skin and hypodermic fabrics
Very exceptional cases of a skin lupus erythematosus, violent rash, and also mnogoformny
erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis. In
some cases in development of these states several factors made the contribution,
such as the accompanying infections, at the same time accepted other medicines and associated diseases. It was reported about development of similar to a scleroderma of changes to which lymphangiectatic usually precedes swelled. The general frustration and disturbances in an injection site
It was seldom reported about a phenomenon of return of local beam reaction in earlier irradiated area.
It was seldom reported about edematization of lungs.

Interaction with other medicines:

The researches in vitro showed that biotransformation of drug can change at simultaneous use of the substances inducing or inhibiting isoenzymes of P450-3A cytochrome, or which are metabolized (competitive inhibition) by means of isoenzymes of P450-3A cytochrome, such as cyclosporine, терфенадин, кетоконазол, erythromycin and тролеандомицин. In this regard it is necessary to be careful at co-administration of similar drugs, considering a possibility of the expressed interaction.
At simultaneous use of a dotsetaksel with CYP3A4 inhibitors, such as antifungal drugs from group of imidazoles (кетоконазол, итраконазол) and inhibitors of proteases (ритонавир), it is necessary to be careful.
Dotsetakset the researches conducted at the patients who were at the same time receiving and кетоконазол, showed that at the same time the clearance of a dotsetaksel decreased by 50%, apparently, because the main way of metabolism of a dotsetaksel is his metabolism by means of CYP3A4 isoenzyme. In this case even at use of lower doses of a dotsetaksel deterioration in its portability is possible.
The pharmacokinetics of a dotsetaksel in the presence of Prednisolonum was studied at patients with a metastatic prostate cancer. In spite of the fact that dotsetakset it is metabolized by means of CYP3A4 isoenzyme, and Prednisolonum is CYP3A4 isoenzyme inductor 20, statistically reliable influence of Prednisolonum on pharmacokinetics of a dotsetaksel was not observed.
Dotsetaksel has high communication with proteins of a blood plasma (> 95%). In vitro the medicines which are strongly contacting proteins of a blood plasma such as erythromycin, дифенгидрамин, propranolol, пропафенон, Phenytoinum, salicylates, sulfamethoxazole and sodium Valproatum, do not break binding of a dotsetaksel proteins of a blood plasma. Dexamethasone also does not influence extent of linkng of a dotsetaksel with proteins of a blood plasma. Dotsetaksel does not influence linkng of digitoxin with proteins of a blood plasma. The pharmacokinetics dotsetakset, doxorubicine and cyclophosphamide did not change at their combined use.
There are data on interaction of a dotsetaksel and a karboplatin. At use of a combination of a karboplatin and dotsetaksel the clearance of a karboplatin increases by 50% in comparison with monotherapy karboplatiny.

Contraindications:

- The expressed hypersensitivity reactions to a dotsetaksel or polysorbate 80.
- Initial quantity of neutrophils in peripheral blood <1500/mkl.
- The expressed abnormal liver functions.
- Pregnancy and period of feeding by a breast.
- Children's age up to 18 years.

At use of the drug Taksoter® in a combination with other drugs it is also necessary to consider contraindications to their use.

With care
At simultaneous use of the drugs inducing or inhibiting isoenzymes of P450-3A cytochrome, or which are metabolized by means of isoenzymes of P450-3A cytochrome such as cyclosporine, терфенадин, antifungal means from group of imidazoles (кетоконазол, итраконазол), erythromycin and тролеандомицин, protease inhibitors (ритонавир) (see the section "Interaction with Other Medicines").

Overdose:

Symptoms: There is an insignificant number of messages on overdose.
The main manifestations of overdose were suppression of function of marrow, a peripheral neurotoxicity and mukozit (an inflammation of mucous membranes).

Treatment: Now the antidote to a dotsetaksel is not known. In case of overdose of the patient it is necessary to hospitalize in specialized department and to carefully control function of vitals. Patients should appoint G-KSF, as soon as possible. If necessary - symptomatic therapy.

Storage conditions:

At a temperature from 2 °C to 25 °C in the place protected from light. To store in the place, unavailable to children. Period of validity 24 months. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for infusions of 20 mg / 0,5 ml and 80 mg / 2 ml complete with solvent.
1. A concentrate for preparation of solution for infusions: on 0,61 ml (for the mg drug Таксотер® 20) or 2,36 ml (for drug Taksoter of 80 mg) drug in a bottle of colourless glass with a rubber bung and an aluminum cap with a plastic cover of green color (for the mg drug Таксотер® 20) or red color (for the mg drug Таксотер® 80).
2. Solvent (13% ethanol solution in water for injections): on 1,98 ml (for the mg drug Таксотер® 20) or 7,33 ml (for the mg drug Таксотер® 80) solvent in a bottle of colourless glass with a rubber bung and an aluminum cap with a plastic cover.
Bottle with drug together with a bottle with solvent in the blister strip packaging from PVC soldered by a polyethylene film. A blister strip packaging together with the application instruction in a cardboard pack.