Taxotere

Active material: Docetaxel
When ATH: L01CD02
CCF: Anticancer drug
ICD-10 codes (testimony): C16, C34, (C) 49.0, C50, C56, C61
When CSF: 22.03.01.01
Manufacturer: AVENTIS PHARMA S.A. (France)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Concentrate for solution for infusion as a clear, oily solution from yellow to brownish yellow; enclosed solvent – clear, colorless.

Excipients: polysorbate 80.

Solvent: 13% Ethanol district in water d/and (1.98 ml).

0.61 ml – colorless glass vials (1) together with the solvent (fl. 1 PC.) – packings Valium planimetric (1) – packs cardboard.

Concentrate for solution for infusion as a clear, oily solution from yellow to brownish yellow; enclosed solvent – clear, colorless.

Excipients: polysorbate 80.

Solvent: 13% Ethanol district in water d/and (7.33 ml).

2.36 ml – colorless glass vials (1) together with the solvent (fl. 1 PC.) – packings Valium planimetric (1) – packs cardboard.

Pharmacological action

Antitumor cytostatic drug of plant origin from the taxo group. Active substance formulation – docetaxel – accumulates tubulum in microtubules, prevents their decay, which leads to a violation of the phase of mitosis and inter -phase processes in tumor cells. Docatoxel lasts a long time in cells, where its high concentrations are achieved. Docatoxel is active in relation to some (But not all) cell, producing in excess P-glycoprotein, which is encoded by the multiple stability gene.

In vivo, Docatoxel has a wide range of activity against mouse tumors and distorted human tumor cells.

Pharmacokinetics

Pharmacokinetics of docksel is dose -dependent and corresponds to a three -phase pharmacokinetic model from t_1/2 4 m, 36 Mines and 11.4 h, respectively.

Linking plasma protein is more 95%.

Metabolism and excretion

During 7 Docatoxel days are withdrawn in urine and feces after oxidation of the Teret-tube ether group with the participation of cytochrome P450. The excretion in the urine is 6% radioactive dose, with feces – 75%. About 80% radioactive drug, displayed with feces, Discovered during 48 h in the form of the main inactive metabolite and three less significant inactive metabolites and, in a very small amount, in unchanged form.

Pharmacokinetics in special clinical situations

Pharmacokinetics of docksel does not depend on the age and gender of the patient.

With mild impaired liver function (AST and ALT PH8.5 VGN in combination with an increase in the activity of the SCF≥2.5 VGN) The general clearance is reduced by 27% Compared to the average.

Docatoxel clearance did not change in patients with mild or moderate liquid delay. Data on the clearance of the drug in patients with a pronounced liquid delay.

Testimony

- adjuvant therapy for the operating cancer of the mammary gland with damage to regional lymph nodes in combination with doxorubicin and cyclophosphamide;

-Local-fan or metastatic cancer of the mammary gland (In combination with doxorubicin as primary chemotherapeutic treatment as a preparation of the 1st line; or as therapy of the 2nd line – in monotherapy, with the ineffectiveness of previous treatment, included anthracycline or alkylating agents, and in combination with Capecitabin, if previous therapy has included anthracycline);

- metastatic cancer of the mammary gland with tumor expression HER2 in combination with trastuzumab, in the absence of previous chemotherapy;

- Inoperative, Local-fed or metastatic non-alcoholic lung cancer (in combination with cimplatin or carboplatin) as the treatment of the 1st line or in monotherapy as therapy of the 2nd line with the ineffectiveness of chemotherapy, Platinum;

- Metastatic ovarian cancer after failure of prior therapy 1st line (therapy 2 lines);

-Inoperable local-produced flat cell cancer of the head and neck (c combinations C cispatinoma and 5-Ftruraciloma) quality of therapy of the 1st line;

- metastatic plane cell cancer of the head and neck with the ineffectiveness of previous therapy (therapy 2 lines);

- Metastatic, hormone-refractory prostate cancer (in combinations with prednisone or prednisolone);

- metastatic stomach cancer, Including the cardial department (c combinations C cispatinoma and 5-Ftruraciloma) quality of therapy of the 1st line.

Dosage regimen

In order to prevent hypersensitivity reactions, and also in order to reduce fluid retention to all patients (excluding prostate cancer patients) Before the administration of the drug taxi^® The premedication of GKS is carried out, For example, dexamethasone in the dose 16 mg / day (by 8 mg 2 times / day) inside, during 3 days, starting over 1 day before the introduction of taxoster^®.

In patients with cancer of the prostate gland, receiving concomitant treatment with prednisone or prednisolone, premedication of dexamethasone in the dose is carried out 8 mg for 12, 3 and 1 h before the introduction of taxoster^®.

To reduce the risk of developing hematological complications, the preventive introduction of a granulocytic colony -nistile factor is recommended (G-CSF).

Taxor^® introduced in the form of one -hour V/in infusion every 3 of the week.

Mammary cancer

With adjuvant therapy of patients with the operating form of breast cancer, the recommended dose of taxoster^® is 75 mg / m² through 1 hour after the introduction of doxorubicin (50 mg / m²) and cyclophosphamide (500 mg / m²) every 3 of the week. Total 6 cycles.

With monotherapy taxi^® administered at a dose of 100 mg / m² every 3 of the week. With a combination with doxorubicin (50 mg / m²) or capecitabine (1250 mg / m² inside 2 times / day for 2 weeks followed by one week apart) Taxor^® administered at a dose of 75 mg / m² every 3 of the week.

With a combination with trastuzumab, a recommended dose of taxoster^® is 100 mg / m² every 3 of the week. Doses and methods of introducing trastuzumab are determined by the instructions for the use of trastuzumab.

At small cell lung cancer Taxor^® administered at a dose of 75 mg / m² with monotherapy and 75 mg / m² In combination with platinum preparations every 3 of the week. With ineffective combination with platinum preparations taxi^® used in the form of monotherapy.

At metastatic ovarian cancer Taxor^® administered at a dose of 100 mg / m² every 3 of the week.

At Local-fan-gathered placket cancer of the head and neck Taxor^® administered at a dose of 75 mg / m². After a taxi infusion^® On the same day, cisplatin infusion is carried out in a dose 75 mg / m² during 1 no, followed by infusion of 5-fluoruracyl in the dose 750 mg / m²/day in the form of a 24-hour infusion during 5 days. This mode is prescribed 1 once every 3 weeks and repeat to 4 cycles. After the course of chemotherapy, radiation therapy is prescribed.

At Metastatic plane -cellet cancer of the head and neck Taxor^® administered at a dose of 100 mg / m² every 3 of the week.

At metastatic hormone -resistant cancer of the prostate gland Taxor^® administered at a dose of 75 mg / m² 1 once every 3 of the week. Prednisone or prednisone is prescribed inside 5 mg 2 times/day for a long time for the entire period of course treatment.

At metastatic cancer of the stomach, Including the cardial department, Taxor^® administered at a dose of 75 mg / m² 1 once every 3 of the week. After a taxi infusion^® On the same day, cisplatin infusion is carried out in a dose 75 mg / m² during 1-3 no, followed by infusion of 5-fluoruracyl in the dose 750 mg / m²/day in the form of a 24-hour infusion during 5 days, Starting from the end of cisapaplatin infusion.

Dose adjustment

Taxor^® Introduce with the number of neutrophils ≥1500/μl. When the number of neutrophils falls <500/l, which has been observed for more than a week, or the development of febrile neutropenia, or the development of pronounced skin reactions, or pronounced peripheral neuropathy during therapy with dotsakel, the dose of this drug for the next introduction should be reduced from 100 to 75 mg / m² and / or 75 to 60 mg / m². If such complications arise when applying the docetaxel dose 60 mg / m², treatment should be discontinued.

Patients with operating form of breast cancer, receiving adjuvant therapy, With the development of febrile neutropenia, G-CSFs for all subsequent cycles should receive. While maintaining febrile neutropenia, it is necessary to reduce the dose of taxi^® to 60 mg / m² and continue taking G-CSF. If G-CSF is not used, to the dose of taxor^® should be reduced with 75 mg / m² to 60 mg / m². In patients with stomatitis 3 or 4 degree is necessary to reduce the dose to 60 mg / m².

The first appearance of toxicity 2 degrees, which remains until the next cycle of treatment with a taxi^®/Capecitabin, The next treatment cycle can be postponed to a decrease in toxicity to 0-1 degrees, At the same time, during the next treatment cycle is introduced 100% The initial dose of the taxi^®.

In patients with re -development of toxicity 2 degree or first development of toxicity 3 degree at any time of the therapy cycle, treatment is put off until a decrease in toxicity to 0-1 degrees, Then the use of taxi^® resumes at the dose 55 mg / m².

With any subsequent manifestations of toxicity or the appearance of any type of toxicity 4 degree the introduction of taxi^® It should be discontinued.

Capecitabin dose correction when combined with a taxi^® Conducted according to the instructions for the use of capacitabin.

At Combined therapy for patients, which initially receive taxi^® dose 75 mg / m² in combination with cimplatin or carboplatin, in which the amount of platelets in the previous treatment cycle has decreased to <25 000/l (cisplatin) and to <75 000/l (with carblatin), or in patients, which developed febrile neutropenia, or in patients with serious manifestations of non -metatological toxicity, the dose of taxoster^® The next cycle should be reduced to 65 mg / m². When correcting the dose of cisplatin, it is necessary to follow the instructions for the use of cisplatin.

At Combinations of taxi^® with cisplate and 5-ftoruracil (5-FU) In the case of the development of febrile neutropenia or the connection of infection despite the use of G-CXF, Dose of taxor^® It should be reduced to 60 mg / m². With the subsequent development of episodes of complicated neutropenia, it is recommended to reduce the dose of taxi^® from 60 mg / m² to 45 mg / m². With the development of thrombocytopenia 4 degrees dose of fee^® It is recommended to reduce with 75 mg / m² to 60 mg / m². Subsequent cycles using docksel are possible with the number of neutrophils > 1500/l and platelet > 100 000/l. When maintaining toxicity, treatment should be discontinued.

With the development of other types of toxicity, the dose correction of the taxoster^® carried out in accordance with the recommendations, in the table.

Dose correction of cisplatin is carried out according to the instructions for the use of cisplatin.

To patients with impaired liver function at alt or AST levels, exceeding more than 1.5 times VGN, or the level of the SCF, exceeding more than 2.5 times VGN, The recommended dose is 75 mg / m². Patients with elevated bilirubin levels and / or increased activity of ALT and AST (>3.5 VGN) In combination with an increase in the level of the SCF (>6 VGN) Apply taxi^® not recommended.

There are currently no data regarding the use of taxoster^® in combination with other drugs in patients with impaired liver function.

Taking into account the analysis of pharmacokinetic data, any special instructions for the use of taxi^® in elderly patients no. With a combination with capacitabin in older patients 60 years It is recommended to reduce the starting dose of capacitabin (In accordance with the instructions for the use of capacitabin).

Terms preparing solutions

Concentrate for solution for infusion 20 Mg / 0.5 ml: real content in a bottle 24.4 Mg / 0.61 ml, which allows you to compensate for fluid loss when preparing a pre -mixed solution, due to foaming, adhesion to the walls of the bottle and the presence “dead” Space. Thus, Excess the drug in the bottle guarantees, that after breeding its contents, the minimum volume of the pre -mixed solution of the pre -mixed solution will be 2 ml, containing 10 Mg / ML of the doctaxel, corresponding 20 mg (dose, a bottle indicated on the label).

Concentrate for the preparation of a solution for infusion 80 Mg / 2 ml: real content in a bottle 94.4 Mg / 2.36 ml, which allows you to compensate for fluid loss when preparing a pre -mixed solution, due to foaming, adhesion to the walls of the bottle and the presence “dead” Space. Thus, Excess the drug in the bottle guarantees, that after breeding its contents, the minimum volume of the pre -mixed solution of the pre -mixed solution will be 8 ml, containing 10 Mg / ML of the doctaxel, corresponding 80 mg (The dose is indicated on the label label).

The concentrate for the preparation of an infusion solution for parenteral use should be previously diluted in the attached solvent.

Preparation of a pre -mixed taxi solution^® (docetaxel 10 mg / ml)

Before breeding, the vials with the drug and solvent are necessary during 5 Min hold at room temperature.

The entire contents of the bottle with a solvent are typed using a needle in a syringe (The bottle is placed slightly at an angle) and entered into a bottle with a taxi^®.

Turn the bottle with the mixture during 45 sec (do not shake!) And leave on 5 min at room temperature, After that, the solution is checked for homogeneity and transparency (the presence of foam even through 5 Min is the norm).

A pre -mixed solution is recommended to be used for the preparation of a solution for infusion immediately after preparing it. Pre -mixed taxi solution^® can be stored in the refrigerator (at a temperature of from 2 ° to 8 ° C.) or at room temperature for 8 no.

Preparation of a solution for infusion

The required volume of a pre -mixed solution in accordance with the required dose is introduced into the bag for infusions or bottle, comprising 250 ml 5% dextrose solution or 0.9% sodium chloride solution. If the required dose of dotachesel exceeds 200 mg, then you should use a larger volume of fluid for infusion, so that the concentration of pre -chasel is not higher 0.74 mg / ml.

It is necessary to mix the contents of the bag for infusion or bottle. The resulting solution should be used during 4 h for iv in a single -hour infusion at room temperature and ordinary illumination conditions.

Pre -mixed taxi solution^® and a solution for infusion must be examined before the introduction; In the presence of sediment, the solution should be destroyed.

Side effect

From the hematopoietic system: common – Reversible neutropenia (in patients who did not receive G-CSF), In some cases, accompanied by fever, joining infections, and sometimes the development of sepsis and pneumonia. The number of neutrophils is reduced to minimal values on average through 7 days (patients, receiving chemotherapy previously, This period can be shorter), The average duration of pronounced neutropenia (<500/l) Also constitutes 7 days. It is possible to develop thrombocytopenia and anemia. Bleeding rarely occurs, mainly due to thrombocytopenia.

Allergic reactions: Light or moderate reactions of increased sensitivity usually occur within a few minutes after the start of infusion (tides, rash, itch, chest tightness, backache, breathlessness, drug fever, chills); rarely – Lyell's syndrome, Stevens-Johnson syndrome. Heavy reactions are possible (hypotension, bronchospasm, Generalized rash and erythema), which disappeared after the cessation of infusion and the appointment of adequate therapy.

Dermatological reactions: alopecia, Light and moderate skin reactions; rarely – A pronounced rash, accompanied by itching, or limited leather erythema of the palms and feet with edema and subsequent desquamation, as well as swelling of the hands, faces and chests, Hypo- Or hyperpigmentation of nails, onixolizis.

Metabolism: fluid retention – Cases of development of peripheral edema are described, pleural or pericardial effusion, ascita, weight gain. Peripheral edema usually appear on the lower extremities, and then they can become generalized, leading to an increase in body weight to 3 kg or more. The frequency and severity of fluid retention increases with the repeated administration of the drug; average total doses of taxi^®, in which the liquid delay was observed, compiled during the premedication 818.9 mg / m² and 489.7 mg / m² – Without premedication. However, in some cases, swelling arose during the first courses of therapy. The delayed liquid was not accompanied by acute episodes of oliguria or arterial hypotension. In rare cases, the development of dehydration and pulmonary edema was reported.

From the digestive system: nausea, vomiting, diarrhea, anorexia, constipation, stomatitis, taste disturbance, esophagitis, epigastric pain; colitis, Including ischemic, enterocolitis, perforation of the stomach or intestines; rarely – gastrointestinal bleeding, ileus. In patients, receiving monotherapy with a taxi^® dose 100 mg / m², Increasing serum activity ACT , ALT , SCF and concentrations of bilirubin in the blood serum more, than 2.5 times the ULN, It is noted less, than 5% cases. In some cases, – hepatitis (death was observed in patients with liver diseases).

From the central and peripheral nervous system: Peripheral neuropathy in the form of easily or moderate paresthesia, hyperesthesia, dysesthesia or pain, Including burning. Motor disorders were characterized by weakness. In the event of these symptoms, dose correction is necessary. If symptoms persist, then treatment should be stopped. Rarely – convulsions, The transient loss of consciousness.

Cardio-vascular system: abnormal heart rhythm (sinus tachycardia, atrial fibrillation), unstable angina, heart failure, arterïalnaya hypo- or hypertension; rarely – venous thromboembolism and myocardial infarction.

The respiratory system: rarely – acute respiratory distress syndrome and interstitial pneumonia, pulmonary fibrosis and increased reaction to irradiation.

On the part of the musculoskeletal system: arthralgia, myalgia, muscular weakness.

On the part of the organ of vision: rarely – development of lacrimation in combination with conjunctivitis (or without it), Transmitted visual disorders (flashes of light in the eyes, The appearance of cattle), usually arising during the administration of the drug and combined with the development of hypersensitivity reactions, which usually disappear after the cessation of infusion; rarely, mainly in patients, receiving at the same time other antitumor drugs, it is possible to develop an occlusion of a lacrimal canal, leading to excessive lacrimation.

Local reactions: Moderate hyperpigmentation, inflammation, redness, xerosis, phlebitis, hemorrhage, swelling of the veins.

Other: asthenia, breathlessness, generalized or local pains, including chest pain, not related to diseases of the heart or lungs.

When applying taxi^® in Combinations with capitabin There was a more frequent development of undesirable phenomena from the digestive system, Ladomary-senior syndrome (hyperemia of the skin of the limbs / palms and stop / followed by edema and deskvamation), degidratacii, lacrimation, artralgii, severe thrombocytopenia and anemia, giperʙiliruʙinemii, but a more rare development of severe neutropenia, Alopecia, violations by nails, astenii, mialgii, edema of the lower extremities.

Patients over the age of 60 years, who received combined therapy with a taxi^® and capecitabine, Compared to patients of younger age, more frequent development of toxicity is noted 3-4 degrees.

In patients receiving Combined treatment with trastuzumab a large frequency of adverse reactions and more frequent development of toxicity was revealed 4 degrees, Compared to monotherapy taxi^®. Cases of development of heart failure were identified, especially when supplemented to therapy of anthracyclines (doxorubicin or epirubicin).

When applying taxi^® in Combinations C cispatatinoma and 5-Fruraciloma February neutropenia and/or neutropenic infectious complications arise in a lower percentage of cases with the preventive prescription of G-CSF.

Contraindications

- The initial number of neutrophils <1500/l;

- Expressed human liver;

- Pregnancy;

- Lactation (breast-feeding);

- Hypersensitivity to the drug.

Pregnancy and lactation

Taxor^® contraindicated during pregnancy and lactation (breast-feeding).

Women and men of childbearing age Conception should be avoided, Using reliable contraceptive methods, during the use of the drug and at least during 3 months after its cancellation.

Cautions

Taxi treatment^® It is carried out only with the participation of an experienced specialist in antitumor chemotherapy in a specialized hospital.

With the development of severe neutropenia (<500/MKL during 7 days or more) During the course of therapy by taxi^® It is recommended to reduce the dose of the drug in subsequent courses or use adequate symptomatic measures. Continue^® possible after restoring the number of neutrophils up to 1500/μl.

In order to identify reactions of increased sensitivity of patients, you should carefully observe, especially during the first and second infusions. The development of reactions of increased sensitivity is possible in the first minutes of the infusion of taxoster^®. Mild symptoms of hypersensitivity (redness of the face, Localized skin reactions) do not require interruption of therapy. Severe hypersensitivity reactions (hypotension, bronchospasm, generalized rash, эritema) require immediate abolition of the administration of the drug and conducting appropriate medical measures. Repeated purpose of the taxi^® In such patients, it is not allowed.

Patients, receiving docetaxel monotherapy at a dose of 100 mg / m² and high activity ALT and/or AST, more than 1.5 times higher than WHN, In combination with an increased level of ShHF more than in 2.5 times the ULN, The risk of developing severe side effects is extremely high: sepsis, gastrointestinal bleeding, febrile neutropenia, infection, thrombocytopenia, stomatitis, asthenia. In this regard, in such patients with increased indicators of the liver function, the recommended dose of taxoster^® is 75 mg / m². Functional liver tests should be determined before therapy begins and before each subsequent cycle of therapy by taxi^®. In patients with an increased level of bilirubin and/or increased activity of the ALT and AST (>3.5 VGN) In combination with an increase in the level of the SCF (>6 VGN) Taxor^® It is not recommended to be appointed. There are currently no data regarding the use of taxoster^® in combination with other drugs in patients with impaired liver function.

In connection with the possibility of developing edematous syndrome, it is necessary to observe patients with ascite, in efficiency into the pleural cavity or pericardium. When swelling appears, the restriction of salt and drinking regime and the purpose of diuretics are shown.

With combined therapy by taxi^®, Doxorubicin and cyclophosphamide the risk of acute leukemia is comparable to the risk of treatment, containing anthracycline/cyclophosphamide.

As with other potentially toxic substances, Caution must be careful when using a taxi^® and preparation of solutions. It is recommended to use gloves. If the concentrate gets, pre -mixed solution or solution for infusions on the skin should immediately wash it with water and soap. If the concentrate gets, pre -mixed solution or solution for infusion on the mucous membranes should immediately rinse them with water.

Monitoring of laboratory parameters

Systematic monitoring of a picture of peripheral blood is necessary in order to timely detect myelotoxicity.

Use in Pediatrics

Safety and efficiency of taxi use^® Children have not been studied enough. There is a limited experience in using taxi^® children.

Overdose

Symptoms: Suppression of the bone marrow, perifericheskaya neuropathy, mucositis.

Treatment: No specific antidote. Hospitalization is shown to the specialized department and thorough control of the function of vital organs. Appoint G-CSF as soon as possible. If necessary spend symptomatic therapy.

Drug Interactions

Studies in vitro have shown, that the biotransformation of the drug can change with the simultaneous use of substances, inducing, inhibitors of the cytochrome system P450Ili metabolized CYP3A isoenzymers (cyclosporine, terfenadine, ketoconazole, Erythromycin, troleandomiцin). In this regard, it is necessary to be careful while prescribing with similar drugs, given the opportunity to express interaction.

In vitro medicines, characterized by high binding with proteins (such as erythromycin, difengidramin, propranolol, propafenone, phenytoin, Salicylate, sulfamethoxazole, sodium valproat), did not affect the binding of pre -chasel with proteins.

Dexamethasone does not affect the degree of binding of pre -Socialsel with plasma proteins.

Docatoxel does not affect the binding of digitoxin with plasma proteins.

Pharmacokinetic interactions

With the use of docksel in combination with doxorubicin, the clearance of Docatoxel increases while maintaining its effectiveness. At the same time, doxorubicin clearance and concentration of doxorubicinol (Docsorubicine metabolite) it does not change in plasma.

Carboplatin clearance for combined therapy with pre -Stelesel increases by 50% Compared to monotherapy carboplatin.

No influence of docksel on pharmacokinetics was revealed (C_max, AUC) The main metabolite of Capecitabin (5DFUR) and influences pharmacokinetician capes (C_max, AUC) doctaxel.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be stored out of reach of children, the dark place at a temperature between 2° to 25° c.

The expiration date of the concentrate for the preparation of a solution for infusion, contains 20 mg doctaxel, – 24 Months. The expiration date of the concentrate for the preparation of a solution for infusion, contains 80 mg doctaxel, – 36 Months.