Новотакс®

General characteristics. Structure:

Active ingredient: 20 mg or 40 mg of a dotsetaksel anhydrous.

Excipients: polysorbate-80, ethanol anhydrous.

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 (R-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 is 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 α, β and γ 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 aspartate aminotransferase (ACT) 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 moderate delay of liquid the clearance of a dotsetaksel does not change; there are no data on its clearance at the expressed delay 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 (Cmax, 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 entered soon after infusion of a dotsetaksel 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).
Adjuvant therapy. Resectable RMZh (the drug Novotaks® in a combination with doxorubicine and cyclophosphamide):
 
- 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/nuclear degree of a zlokachestvennost of a tumor (degree 2-3), age less than 35 years).
 
Resectable RMZh with a tumoral hyper expression of HER2 (doxorubicine and cyclophosphamide with the subsequent use of the drug Novotaks® in a combination with trastuzumaby (scheme AC-TH)).
 
Neoadjuvant therapy. Resectable and locally-spread RMZh (doxorubicine and cyclophosphamide with the subsequent use of the drug Novotaks®)
 
Metastatic and/or locally-spread RMZh:
 
- locally-spread or metastatic RMZh (the drug Novotaks® in a combination with doxorubicine, therapy of the 1st line);
 
- metastatic RMZh with a tumoral hyper expression of HER2 (the drug Novotaks® 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 (the drug Novotaks® in monotherapy) or at inefficiency of the previous chemotherapy including anthracyclines (the drug Novotaks® 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 (the drug Novotaks® in monotherapy);
 
- nerezektabelny locally-spread or metastatic not small-celled cancer of a lung (the drug Novotaks® in combinations with Cisplatinum, the drug Novotaks® with karboplatiny presents alternative option of treatment for the therapy based on Cisplatinum to combinations, therapy of the 1st line).
 
Ovarian cancer:
 
- metastatic ovarian cancer at inefficiency of the previous therapy of the 1st line (the drug Novotaks® in monotherapy, therapy of the 2nd line).
 
Prostate cancer:
 
- metastatic gormonorezistentny (an androgen - independent) a prostate cancer (the drug Novotaks® 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 (the drug Novotaks® 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 (the drug Novotaks® in a combination with Cisplatinum and ftoruratsily, induction therapy).

Route of administration and doses:

Treatment by the drug Novotaks® 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, all patient receiving the drug Novotaks® (except patients with cancer prostatic glands recommendations about premedication at which see below), in case of lack of contraindications, before its introduction premedication is carried out by glucocorticosteroids, for example, dexamethasone inside in a dose of 16 mg/days (on 8 mg two times a day) within 3 days, beginning in 1 day prior to administration of the drug Novotaks®.

At the patients with a prostate cancer 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 Novotaks® is carried out.

For decrease in risk of development of hematologic complications are recommended preventive introduction of a granulotsitarny colony stimulating factor (G-KSF). ^{The drug Novotaks®} is administered intravenously kapelno within 1 hour of 1 times in 3 weeks.

Breast Cancer (BC). Adjuvant therapy. 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 Novotaks® 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 TAS). Only 6 cycles (see also further "Correction of the mode of dosing").

Adjuvant therapy of resectable RMZh with a tumoral hyper expression of HER2 in combination with anti-HER2 therapy

According to the scheme AC-TH:

- EXPERT (cycles 1-4): doxorubicine (A) of 60 ^mg/sq.m with the subsequent administration of cyclophosphamide (C) to 600 ^mg/sq.m there are each 3 weeks, 4 cycles.

- TN (cycles 5-8): dotsetakset (T) of 100 ^mg/sq.m of 1 times in 3 weeks, 4 cycles and трастузумаб (N), entered weekly according to the following scheme: a cycle 5 (begins in 3 weeks after the last cycle EXPERT): day 1 трастузумаб 4 mg/kg (a load dose), day 2 dotsetakset 100 ^mg/sq.m, day 8 and 15 - трастузумаб 2 mg/kg. Cycles 6-8: day 1 dotsetakset 100 ^mg/sq.m and трастузумаб 2 mg/kg, day 8 and 15 - трастузумаб 2 mg/kg. In 3 weeks after day of 1 cycle 8: трастузумаб 6 mg/kg each 3 weeks. Trastuzumab is entered in total during 1 year.

Neoadjuvant therapy. For performing neoadjuvant therapy of patients with a resectable and locally-spread breast cancer the drug Novotaks® doses provided below are recommended:

- EXPERT (cycles 3-4): doxorubicine (A) of 60 ^mg/sq.m with the subsequent administration of cyclophosphamide (C) to 600 ^mg/sq.m there are each 3 weeks, 4 cycles.

- T (cycles 5-8): dotsetakset (T) of 100 ^mg/sq.m of 1 times in 3 weeks, 4 cycles.

Locally-spread or metastatic RMZh. 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 drug Novotaks® combination plus трастузумаб the recommended dose of the drug Novotaks® makes 100 ^mg/sq.m each 3 weeks with weekly introduction of a trastuzumab. Initial intravenous infusion of a dotsetaksel is carried out next day after the first dose of a trastuzumab. The subsequent doses of a dotsetaksel are entered directly after the end of intravenous infusion of a trastuzumab (at good tolerance of the previous dose of a trastuzumab). For obtaining information on doses and a route of administration of a trastuzumab see the instruction on a medical use of a trastuzumab.

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 the infections caused by a neutropenia. All patients receiving containing dotsetakset schemes of treatment, preventively received antibiotics.

The drug Novotaks® in the chemotherapeutic scheme AS-T. At a resectable and locally-spread breast cancer after an episode of a febrile neutropenia or an infection against the background of neoadjuvant therapy according to the scheme AS-T it is necessary with the preventive purpose to apply G-KSF on all subsequent cycles, and the dose of the drug Novotaks® has to be lowered from 100 ^mg/sq.m to 75 ^mg/sq.m.

The drug Novotaks® in a combination with anti-HER2 therapy. At a resectable breast cancer with a tumoral hyper expression of HER2 after an episode of a febrile neutropenia or an infection against the background of adjuvant therapy it is necessary with the preventive purpose to apply G-KSF on all subsequent cycles, and the dose of a dotsetaksel has to be lowered from 100 ^mg/sq.m to 75 ^mg/sq.m. It is necessary to consider the risk associated with a neutropenia, to be guided by the standard recommendations it if necessary to apply G-KSF. In a case the dotsetaksela developed stomatitis 3 or 4 severity a dose it is necessary to reduce from 100 ^mg/sq.m to 75 ^mg/sq.m.

The drug Novotaks® in a combination with kapetsitabiny. For dose adjustment of a kapetsitabin at its combination with the drug Novotaks® see the instruction on a medical use of a kapetsitabin.

At use of the drug Novotaks® in a combination with kapetsitabiny at the first emergence of toxicity 2 severity which remains by the beginning of the following cycle Novotaks®/kapetsitabinom 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 3 severity at any time of a cycle treatment is postponed by the first development of toxicity until decrease in toxicity to 0-1 severity, then treatment by the drug Novotaks® 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 Novotaks® has to be stopped.

The drug Novotaks® in a combination with Cisplatinum or karboplatiny. At patients who originally received dotsetakset in a dose 75 ^mg/sq.m in a combination with Cisplatinum or karboplatiny 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 or a karboplatin see application instructions of these drugs.

The combination therapy including the drug Novotaks® at not small-celled cancer of a lung. The drug Novotaks® in a combination with Cisplatinum or karboplatiny. At patients who originally received dotsetakset in a dose 75 ^mg/sq.m in a combination with Cisplatinum or karboplatiny 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 or a karboplatin see application instructions of these drugs.

The drug Novotaks® in a combination with Cisplatinum and ftoruratsily at a carcinoma of the stomach or cancer of the head and neck. The patients receiving the drug Novotaks® 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 use of G-KSF, there is a febrile neutropenia, a long neutropenia or the infection caused by a neutropenia, the dose of the drug Novotaks® 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 Novotaks® dose from 60 ^mg/sq.m to 45 ^mg/sq.m. At development of thrombocytopenia 4 severity a dose of the drug Novotaks® 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 the drug Novotaks® 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 Novotaks® dose by 20%.
Diarrhea 4 severity	First episode: to reduce doses of the drug Novotaks® and FAUGH by 20% Repeated episode: to stop treatment.
Stomatitis / мукозит 3 severity	First episode: to reduce a dose FAUGH by 20% Repeated episode: to stop only reception FAUGH in all subsequent cycles. Third episode: to reduce a drug Novotaks® dose by 20%
Stomatitis / мукозит 4 severity	First episode: to stop only reception FAUGH in all subsequent cycles Repeated episode: to reduce a drug Novotaks® dose by 20%.

For obtaining recommendations about correction of doses of Cisplatinum and a ftoruratsil see instructions for their use.

Patients with planocellular 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 of a cycle of chemotherapy).

Use for special groups of patients. Children. Safety and efficiency of a dotsetaksel at children is not studied. There is a limited experience of use of a dotsetaksel for children. It is not established yet efficiency and safety of use dotsetakset at nasopharynx cancer at children and teenagers from 1 month to 18 years. Dotsetaksel 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).

Patients of advanced age. Proceeding from data of the population pharmacokinetic analysis, there are no special instructions on use of a dotsetaksel for patients of advanced age.

Patients have 60 years and are more senior at a combination of a dotsetaksel 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 a dotsetaksel in monotherapy in a dose of 100 ^mg/sq.m at patients with activity of ALT and/or ACT> 1,5 VGN or activity of an alkaline phosphatase> 2,5 VGN, the recommended dose of the drug Novotaks® makes 75 ^mg/sq.m. Patients with increase have concentration of bilirubin in blood (> 1 VGN) and/or with increase in activity of ALT and ACT (> 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 combination dotsetakset with Cisplatinum and ftoruratsily at treatment of patients with cancer of a stomach was not applied at patients with increase in activity of ALT and/or ACT (> 1,5 VGN) in combination with increase in activity of an alkaline phosphatase (> 2,5 VGN) and increase in concentration 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 a dotsetaksel 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 renal failures of heavy degree.

Features of use:

Pregnancy and lactation. Use of the drug Novotaks® is contraindicated during pregnancy and during breastfeeding. Women in case of pregnancy at them during treatment should report about it to the attending physician urgently.

Neutropenia. It is necessary to make careful observation of clinical blood test at the patients receiving therapy by the drug Novotaks®. At development of the expressed neutropenia (<500/mkl within 7 days) during a therapy course the drug Novotaks® recommends to lower a drug dose on the subsequent cycles or to apply adequate symptomatic measures. To continue treatment by the drug Novotaks® perhaps after recovery of number of neutrophils to 1500/mkl.
 
In case of introduction of G-KSF to the patients receiving the drug Novotaks® in a combination with Cisplatinum and ftoruratsily the febrile neutropenia and/or neytropenichesky infections develop less often. Therefore at use of this combination introduction 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 use of the drug Novotaks® 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 TAS 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 the chemotherapeutic scheme TAS carefully.
 
Hypersensitivity reactions. For the purpose of identification of hypersensitivity reactions of patients it is necessary to observe carefully, especially during the first and second infusion. Development of reactions of hypersensitivity is possible in the very first minutes of infusion of a dotsetaksel therefore at its introduction it is necessary to have medicines and the equipment for treatment of arterial hypotension 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 were observed, such as the expressed lowering of arterial pressure, bronchospasm or generalized rash / erythema and it is very rare - fatal anaphylactic reactions.

Emergence of reactions of hypersensitivity demands the immediate termination of administration of the drug Novotaks® and performing the corresponding therapy. The patients who transferred heavy reactions of hypersensitivity should not resume treatment by the drug Novotaks®.
 
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 "hepatic" transaminases (ALT and/or ACT), more than by 1,5 times the exceeding VGN, in combination with increase in activity of an alkaline phosphatase in blood serum 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 functional trials of a liver the recommended dose of the drug Novotaks® 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 Novotaks®. At patients with the increased concentration of bilirubin and/or a superactivity of ALT and ACT (> 3,5 VGN) in combination with increase in activity of an alkaline phosphatase> 6 VGN, the drug Novotaks® is not recommended to be used.
 
At the moment there are no uses of a dotsetaksel 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 use of diuretics.

Leukemia. At use of a combination dotsetakset with doxorubicine and cyclophosphamide concerning resectable RMZh risk of development delayed myelodisplasias and/or myeloid leukemia demands hematologic observation of patients.
 
Heart failure. At the patients receiving dotsetakset in a combination with anti-HER2 the therapy especially later containing chemotherapy anthracyclines (doxorubicine or эпирубицин), development of heart failure which can be moderately severe or heavy and lead to death is possible.

When treatment dotsetaksely in a combination of anti-HER2 is shown to the patient by therapy, it has to undergo cardiological inspection prior to therapy; 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 the corresponding anti-HER2 drugs.
 
Disturbances from an organ of sight. At the patients receiving treatment dotsetaksely, and also other taxons, it was reported about development of cystous hypostasis of macular area. Patients who have vision disorders urgently have to undergo full ophthalmologic inspection. In case of diagnosing of cystous hypostasis of macular area treatment dotsetaksely should be stopped, and to the patient the corresponding treatment has to be begun.
 
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 dotsetakset + 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 dotsetaksely 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 dotsetaksely 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.
 
Women in case of approach of pregnancy at them during treatment should report about it to the attending physician urgently.
 
Neurotoxicity. Development of heavy touch neuropathy demands a drug Novotaks® dose decline.
 
Ethanol content. In the drug Novotaks® in a bottle from 20 mg / 1,0 the ml of a concentrate contains ethanol of anhydrous 0,395 g, in a bottle from 40 mg / 2,0 concentrate ml - 0,790 g, in a bottle from 80 mg / 4,0 concentrate ml - 1,580 g, in a bottle from 120 mg / 6,0 concentrate ml - 1,975 g, in a bottle from 140 mg / 7,0 concentrate ml - 2,370 g, after a bottle from 160 mg / 8,0 concentrate ml - 2,765 g. 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).
 
Precautionary measures at use. The drug Novotaks® 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 Novotaks® or infusion solution of the drug Novotaks® 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 Novotaks® on their mucous membranes it is necessary to wash out immediately carefully water.
 
Neoadjuvant therapy of a breast cancer. At achievement of full or partial morphological regress of a tumor on neoadjuvant chemotherapy, the surgical oncotomy is carried out and at an opportunity an axillary limfodissektion. Carrying out additional adjuvant chemotherapy after achievement of full or partial morphological regress does not improve survival of patients. Therefore carrying out adjuvant chemotherapy is not proved for the patients who reached full or partial morphological regress of a tumor after neoadjuvant chemotherapy.

If the answer is minimum after several cycles of neoadjuvant chemotherapy, or the disease progresses at any time, it is necessary to consider the alternative mode of chemotherapy and/or preoperative radiation therapy with the subsequent surgical intervention, in the form of a mastectomy with an axillary limfodissektion. Postoperative adjuvant therapy for these patients consists of end of the planned chemotherapy if it not was is complete to surgical intervention, with the subsequent hormonal therapy at women with the positive status of estrogenic and/or progesteronovy receptors.

At patients with cancer of a mammary gland with a tumoral hyper expression of HER2 it is appointed трастузумаб up to one year.

Influence on ability to manage vehicles and mechanisms. 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 Novotaks® to manage during treatment vehicles and to be engaged in other potentially dangerous types of activity.

Side effects:

For the indication of frequency of development of the undesirable side reactions (USR) classification of the NPR of World Health Organization is 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).
 
Monotherapy dotsetaksely (75 mg/sq.m and 100 mg/sq.m). Disturbances from blood and lymphatic system. Very often: 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 with 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. Often: 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). Infrequently: heavy thrombocytopenia.
 
Disturbances from immune system. Very often: allergic reactions which usually arise within several minutes after the beginning of intravenous infusion of a dotsetaksel 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). Often: 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 intravenous infusion and performing 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 often: 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 intravenous 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. Often: heavy skin reactions, such as rashes with the subsequent desquamation, including a heavy palmar and bottom syndrome which can demand interruption or the termination of treatment dotsetaksely. Infrequently: heavy alopecia.
 
Disturbances from digestive tract. Very often: nausea, vomiting, diarrhea, anorexia, stomatitis. Often: heavy nausea; heavy vomiting; heavy diarrhea; lock; heavy stomatitis, esophagitis; pains in epigastriums, including strong; gastrointestinal bleedings. Infrequently: heavy gastrointestinal bleedings, heavy locks, heavy esophagitis.
 
Disturbances from a liver and biliary tract. Often: increase in serumal activity of ACT, ALT, an alkaline phosphatase and concentration of bilirubin in blood, more than by 2,5 times the exceeding VGN.
 
Disturbances from a nervous system. Very often: the easy or moderately expressed neurosensory reactions: paresthesia, a dizesteziya, pains, including burning sensation; the neuromotor reactions which mainly are shown muscular weakness; disturbance of flavoring feelings. Often: heavy neurosensory and neuromotor reactions (3-4 severity). Infrequently: 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).
 
Disturbances from heart. Often: disturbances of a cordial rhythm. Infrequently: heart failure.
 
Disturbances from vessels. Often: increase or lowering of arterial pressure, bleeding.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum. Very often: asthma. Often: heavy asthma.
 
Disturbances from skeletal and muscular and connecting fabric. Very often: mialgiya. Often: arthralgia.
 
The general frustration and disturbances in an injection site. Very often: an 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 in generalized, with a body weight 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. Often: 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.
 
Dotsetaksel in a combination with other drugs. Dotsetaksel in a combination with doxorubicine. At use of a dotsetaksel in a combination with doxorubicine in comparison with monotherapy dotsetaksely the big frequency of a neutropenia, including a heavy neutropenia was observed; 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 - allergic reactions; skin reactions, including heavy; damages of nails, including heavy; liquid delays, including heavy; anorexias, neurosensory and neuromotor reactions, including severe forms; arterial hypotension; disturbances of a rhythm; increases in activity of hepatic transaminases, an alkaline phosphatase, concentration of bilirubin in blood; mialgiya; adynamy.
 
Dotsetaksela in a combination with doxorubicine and cyclophosphamide (scheme TAS). At use of this chemotherapeutic scheme in comparison with monotherapy Dotsetaksel's drug 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, a miyelodisplastichesky syndrome.
 
Preventive use of G-KSF reduced the frequency of emergence of a neutropenia (by 60%) and neytropenichesky infections 3-4 severity.
 
Dotsetaksel in a combination with kapetsitabiny. At use of a dotsetaksel 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 bottom 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, an 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), an asthma, a thaw, 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 combination of a dotsetaksel with kapetsitabiny, toxicity development 3-4 severity is more often noted.
 
Dotsetaksel in a combination with trastuzumaby. At the patients receiving a combination of a dotsetaksel with trastuzumaby (in comparison with monotherapy dotsetaksely) 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 charging 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, ostealgia, 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.
 
Dotsetaksel in the scheme AC-TH (doxorubicine and cyclophosphamide with the subsequent use of a dotsetaksel with trastuzumaby). Use of such combinations in comparison with monotherapy dotsetaksely was followed by increase in frequency of emergence of many side effects: the alopecia, anemia, including anemia 3-4 severity, thrombocytopenia, including 3-4 severity, nausea, including 3-4 severity, stomatitis, vomiting, diarrhea, a lock, anorexia, abdominal pains, increase in activity of ACT, ALT and an alkaline phosphatase, a mialgiya, damage of nails, an arthralgia, infections 3-4 severity, heart failure were more often observed.

Increase in frequency of a febrile neutropenia was not observed.

Less often a neutropenia 3-4 severity, a liquid delay, neurosensory and neuromotor reactions, rash and desquamation, allergic reactions met.

Are in addition registered: sleeplessness, increase in concentration of creatinine in blood.
 
Dotsetakset combinations with Cisplatinum or karboplatiny. At use of this scheme of chemotherapy in comparison with monotherapy dotsetaksely there were thrombocytopenia, including thrombocytopenia 3-4 severity more often (more at use of a karboplatin); anemia, including anemia 3-4 severity; nausea, including nausea 3-4 severity; diarrhea 3-4 severity; anorexia, including anorexia 3-4 severity (more at use of Cisplatinum); reactions in an injection site.

However a neutropenia, including a neutropenia 3-4 severity were less often observed; anemia, including anemia 3-4 severity, infections; febrile neutropenia; allergic reactions; skin reactions; damage of nails; a liquid delay, including a liquid delay 3-4 severity (more at use of a karboplatin); stomatitis, neurosensory and, to a lesser extent, neuromotor neuropathy; alopecia; adynamy and mialgiya.
 
It was in addition observed: fever in the absence of an infection, including 3-4 severity; pain.
 
Combination dotsetakset with Prednisolonum or Prednisonum. At use of a dotsetaksel in a combination with Prednisolonum or Prednisonum in comparison with monotherapy dotsetaksely the frequency of emergence of side effects, such as considerably decreased: anemia, including 3-4 severity; infections; neutropenia, including 3-4 severity; thrombocytopenia; febrile neutropenia; weakness; allergic reactions; neurosensory and neuromotor reactions; alopecia; rash: desquamation; nausea; diarrhea; stomatitis; vomiting; anorexia; mialgiya; arthralgia; liquid delay; but disturbances of taste and heart failure were more often observed.
 
Were in addition observed: nasal bleeding, cough, asthma, weakness, dacryagogue.
 
The combination dotsetakset with Cisplatinum and ftoruratsily. At use of this combination in comparison with monotherapy dotsetaksely 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 heart rhythm.

Were in addition observed: fever in the absence of an infection; lethargy (drowsiness, block, catalepsy); hearing changes; dizziness; dacryagogue; xeroderma; heartburn; myocardium ischemia; underlined venous drawing; cancer pains; conjunctivitis; decrease in body weight.

Preventive use of G-KSF reduces the frequency of development of a febrile neutropenia and/or neytropenichesky infectious complications.
 
The data obtained at post-registration use of drugs of a dotsetaksel. The high-quality, malignant and not specified new growths (including cysts and polyps). Very seldom: the acute myeloid leukemia and a 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. Seldom: 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. Seldom: spasms or passing losses of consciousness which sometimes developed in time of intravenous infusional administration of drug.
 
Disturbances from an organ of sight. Seldom: dacryagogue in combination with conjunctivitis (or without it). Very seldom: cases of the obstruction of the lacrimal channel leading to its gap. Seldom: the passing visual frustration (flashes of light in eyes, emergence of scotomas) which are usually arising during intravenous infusional administration of drug and combined with development of reactions of hypersensitivity which usually disappeared after the termination of intravenous infusion.
 
At the patients receiving treatment dotsetaksely, and also other taxons, it was reported about cases of development of cystous hypostasis of macular area.
 
Disturbances from an acoustic organ and labyrinth disturbances. Seldom: ototoksichesky effect of drug, a hearing disorder and/or a hearing loss, including the cases which are associated with other ototoksichesky drugs.
 
Disturbances from heart and vessels. Seldom: cases of venous tromboembolic episodes and myocardial infarction.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum. Seldom: an acute respiratory distress syndrome, intersticial pneumonia / pneumonitis, an intersticial pulmonary disease, pulmonary fibrosis, respiratory insufficiency which could lead to a lethal outcome.
 
At simultaneous carrying out radiation exceptional cases of radiation pneumonia.
 
Disturbances from digestive tract. Seldom: 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. Seldom: cases of development of hepatitis, sometimes from the death, it is preferential at patients with associated diseases of a liver.
 
Disturbances from kidneys and urinary tract. It was reported about deterioration in function of the kidneys and development of a renal failure which in most cases are associated with simultaneous use of nephrotoxic drugs.
 
Disturbances from skin and hypodermic fabrics. Very seldom: Cases of a skin lupus erythematosus, violent rash, and also mnogoformny erythema, Stephens-Johnson's syndrome, toxic epidermal necrolysis. In certain cases in development of these states several factors, such as the accompanying infections, at the same time accepted other medicines and associated diseases made the contribution.

It was reported about development of similar to a scleroderma of changes to which peripheral lymphangiectatic usually preceded swelled.
 
General frustration and disturbances together introductions. Seldom: A phenomenon of return of local beam reaction in earlier irradiated area; fluid lungs.

Disturbances from a metabolism and food. It was reported about development of cases of a hyponatremia, mainly in combination with dehydration, vomiting and pneumonia.

Interaction with other medicines:

The researches in vitro showed that biotransformation of drug can change at simultaneous use of the substances inducing or inhibiting P4503A cytochrome isoenzymes, or which are metabolized (competitive inhibition) by means of isoenzymes of P4503A 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, интраконазол) 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, 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 valproic acid, do not break linkng of a dotsetaksel with 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 Novotaks® in a combination with other drugs it is also necessary to consider contraindications to their use.

With care. To apply with care at simultaneous use with the drugs inducing or inhibiting P4503A cytochrome isoenzymes, or which are metabolized by means of P4503A cytochrome isoenzymes such as cyclosporine, терфенадин, antifungal means from group of imidazoles (кетоконазол, интраконазол), erythromycin and тролеандомицин, protease inhibitors (ритонавир) (see the section "Possible Medicinal Interactions").

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 to 25 °C in the place protected from light. To store in the place, unavailable to children. Period of validity: For packing on 1 ml and 2 ml - 2 years. For packing on 4 ml, 5 ml, 6 ml, 7 ml and 8 ml - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 1,0, 2,0, 4,0, 5,0, 6,0, 7,0 or 8,0 ml of the drug Novotaks® in the bottles of colourless neutral glass corked by rubber bungs with a running in caps aluminum. On 1 bottle (on 1,0 or 2,0 ml of drug) place in a blister strip packaging from a PVC film. On 1 blister strip packaging with the application instruction in a pack from a cardboard. On 1 bottle (on 4,0, 5,0, 6,0, 7,0 or 8,0 ml of drug) with the application instruction in a pack from a cardboard.