Novotax - instructions for use, doses, side effects, contraindications

Docetaxel is an antitumor drug of plant origin (from the taxoid group). Accumulates tubulin in microtubules, prevents their disintegration, which disrupts the process of dividing the tumor cells. Docetaxel long time is stored in cells, where its concentration reaches high values. Besides, docetaxel is active in relation to some, though not all, cells producing in excess P-glycoprotein (P-gP), encoded by a gene of multiple resistance to chemotherapeutic drugs. In vivo docetaxel has a wide spectrum of activity against tumors of mice and transplanted human tumor cells.

The efficacy of docetaxel has been proven in breast cancer, non-small cell lung cancer, ovarian cancer, hormone-resistant prostate cancer, stomach cancer, head and neck cancer.

Pharmacokinetics:

Pharmacokinetics the of adults

The pharmacokinetics of docetaxel is dose-dependent and corresponds to a three-phase pharmacokinetic model with half-lives for α, β and γ phases - 4 min, 36 min and 11.1 h respectively. After a one-hour infusion of docetaxel at a dose of 100 mg / m2mean values of the maximum concentration of docetaxel in plasma (CmOh) were 3.7 μg / ml with the corresponding area under the concentration-time curve (AUC) 4.6 μg.h / ml. The average values for the total clearance and the volume of distribution in the equilibrium state were 21 l / h / m2 and 113 liters, respectively. The values of total clearance of docetaxel in different patients differed by approximately 50%. Docetaxel more than 95% binds to blood plasma proteins.

Docetaxel after oxidation of the tert-butyl ether group using the isoenzyme system P450 for 7 days is excreted through the kidneys, with urine (6% of the administered dose) and through the gastrointestinal tract, with feces (75% of the administered dose). About 80% of the administered dose of docetaxel is excreted within 48 hours with feces in the form of metabolites (the main inactive metabolite and three less significant inactive metabolites) and in a very small amount - unchanged.

The pharmacokinetics of docetaxel does not depend from age and sex patient.

At mildly expressed violations of liver function (activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) no more than 1.5 of their upper bounds of norm (VGN) in combination with activity of alkaline phosphatase no more than 2.5 VGN)) the total clearance of docetaxel is reduced by an average of 27%.With mild or moderate fluid retention, clearance of docetaxel does not change; there is no information on its clearance with a pronounced fluid retention.

With combined use docetaxel does not affect the ground clearance doxorubicin and the plasma concentration of doxorubicinol (doxorubicin metabolite).

The pharmacokinetic parameters of docetaxel, doxorubicin and cyclophosphamide did not change with their simultaneous application.

Capecitabine does not affect the pharmacokinetics of docetaxel (Cmax, AUC), a docetaxel, in turn, does not affect the pharmacokinetics of capecitabine and the most important metabolite of capecitabine (5'-DFUR).

Docetaxel clearance with combination therapy with cisplatin does not change in comparison with its clearance in monotherapy. The pharmacokinetic profile of cisplatin, administered shortly after the infusion of docetaxel, did not differ from that of single cisplatin.

Prednisone does not affect the pharmacokinetics of docetaxel administered after standard premedication with dexamethasone.

Combination Therapy docetaxel, cisplatin and fluorouracil does not change their pharmacokinetic parameters.

Pharmacokinetics the children

In children, pharmacokinetic parameters in monotherapy with docetaxel and docetaxel in combination with cisplatin and fluorouracil were similar to those in adults.

Indications:

Breast Cancer (BC)

Adjuvant therapy

Operational breast cancer (Novotax® in combination with doxorubicin and cyclophosphamide):

- operable breast cancer with involvement of regional lymph nodes;

- operative breast cancer without affecting regional lymph nodes in patients who undergo chemotherapy according to established international screening criteria for primary chemotherapy of early breast cancer (with one or more factors of high recurrence risk: tumor size> 2 cm, negative status of estrogen and progesterone receptors, high histological / nuclear grade of tumor malignancy (degree 2-3), age less than 35 years).

Operable breast cancer with tumor overexpression HER2 (doxorubicin and cyclophosphamide with the subsequent application of Novotax® in combination with trastuzumab (scheme AC-TH)).

Neoadjuvant therapy

Operational and locally advanced breast cancer (doxorubicin and cyclophosphamide followed by Novotax®)

Metastatic and / or locally advanced breast cancer

- locally advanced or metastatic breast cancer (Novotax® in combination with doxorubicin, 1st line therapy);

- metastatic breast cancer with tumor overexpression HER2 (Novotax ® in combination with trastuzumab, 1st line therapy);

- locally advanced or metastatic breast cancer with ineffectiveness of previous chemotherapy involving anthracyclines or alkylating agents (Novotax® in monotherapy) or with ineffectiveness of previous chemotherapy involving anthracyclines (Novotax® in combination with capecitabine).

Non-small cell lung cancer

- mdisseminated or metastatic non-small cell lung cancer with ineffectiveness of previous chemotherapy (Novotax® in monotherapy);

- Mr.Injectable, locally advanced or metastatic non-small cell lung cancer (Novotax® in combination with cisplatin, Novotax® in combination with carboplatin presents an alternative treatment option for cisplatin-based therapy, 1st line therapy).

Ovarian Cancer

- métastatic ovarian cancer with ineffectiveness of previous therapy of the 1st line (Novotax® in monotherapy, 2nd line therapy).

Prostate Cancer

- muteratic hormone-resistant (androgen-independent) prostate cancer (Novotax® in combination with prednisone or prednisolone).

Stomach cancer

- muteratic gastric cancer, including cancer of the esophageal-gastric junction (Novotaks® in combination with cisplatin and fluorouracil, 1st line therapy).

Head and neck cancer

- Locally spread squamous cell carcinoma of the head and neck (Novotax® in combination with cisplatin and fluorouracil, induction therapy).

Contraindications:

- Pronounced hypersensitivity reactions to docetaxel or polysorbate 80;

- anda similar number of neutrophils in peripheral blood <1500 / μl;

- atmarked violations of the liver;

- bPregnancy and period of breastfeeding;

- dEthnic age under 18;

- PWhen Novotax® is used in combination with other drugs, contraindications to their use should also be considered.

Pregnancy and lactation:

Novotax® is contraindicated during pregnancy and during breastfeeding. Women in case of occurrence of their pregnancy during treatment should immediately inform their doctor about this.

Dosing and Administration:

Treatment with Novotax® should be done only under the supervision of a doctor who has experience in conducting antitumor chemotherapy in a specialized hospital.

To prevent reactions of hypersensitivity and to reduce fluid retention, all patients receiving Novotax® (except for patients with prostate cancer, recommendations for premedication in which see below), in the absence of contraindications, prior to its introduction, glucocorticosteroid precedication , for example, dexamethasone inside at a dose of 16 mg / day (8 mg twice daily) for 3 days, starting 1 day before Novotax®.

In patients with prostate cancer receiving concomitant treatment with prednisone or prednisolone, premedication with dexamethasone at a dose of 8 mg for 12, 3 and 1 hour before beginning of Novotax®.

To reduce the risk of developing hematological oslorations recommended prthe introduction of granulocyte colony-stimulating factor (G-CSF).

Novotaks drug® is administered intravenously drip for 1 hour 1 time per 3 weeks.

Cancer breast cancer (breast cancer)

Adjuvant therapy

With adjuvant therapy of operative breast cancer with regional lymph nodes and operable breast cancer without regional lymph nodes, the recommended dose of Novotax® is 75 mg /m² 1 hour after the administration of doxorubicin (50 mg /m²) and cyclophosphamide (500 mg /m²) every three weeks (TAC scheme). A total of 6 cycles (see also "Correction of the dosing regimen").

Adjuvant therapy of operable breast cancer with tumor overexpression of HER2 in combination with anti-HER2 therapy

According to the scheme AC-TN:

- AC (cycles 1-4): doxorubicin (A) 60 mg /m² followed by administration of cyclophosphamide (C) 600 mg /m² every 3 weeks, 4 cycles.

- TH (cycles 5-8): docetaxel (T) 100 mg /m² Once every 3 weeks, 4 cycles and trastuzumab (H), entered weekly according to the following scheme: cycle 5 (starts 3 weeks after the last cycle of the AU): day 1 trastuzumab 4 mg / kg (loading dose), day 2 docetaxel 100 mg /m², day 8 and 15 - trastuzumab 2 mg / kg.Cycles 6-8: Day 1 docetaxel 100 mg /m² and trastuzumab 2 mg / kg, day 8 and 15 - trastuzumab 2 mg / kg. 3 weeks after the day of cycle 1 8: trastuzumab 6 mg / kg every 3 weeks. Trastuzumab is introduced for a total of 1 year.

Neoadjuvant therapy

To carry out neoadjuvant therapy for patients with operable and locally advanced breast cancer, the following doses of Novotax® are recommended:

- AU (cycles 3-4): doxorubicin (A) 60 mg /m² followed by administration of cyclophosphamide (C) 600 mg /m² every 3 weeks, 4 cycles.

- T (cycles 5-8): docetaxel (T) 100 mg /m² 1 time in 3 weeks, 4 cycles.

Locally advanced or metastatic breast cancer

With locally advanced or metastatic breast cancer as first-line therapy docetaxel 75 mg /m² is administered in combination with doxorubicin 50 mg /m²; as a 2 line therapy, the recommended dose of docetaxel in monotherapy is 100 mg /m².

For Novotax® plus trastuzumab recommended dose of the drug Novotax® is 100 mg /m²every 3 weeks with a weekly administration of trastuzumab. The initial intravenous infusion of docetaxel is carried out on the next day after the first dose of trastuzumab.Subsequent doses of docetaxel are administered immediately after the end of intravenous infusion of trastuzumab (with good tolerability of the previous dose of trastuzumab). For information on the doses and route of administration of trastuzumab, see the instructions for the medical use of trastuzumab.

When combined with capecitabine, the recommended dose of docetaxel is 75 mg /m² every 3 weeks, and capecitabine - 1250 mg /m²inside twice a day (within 30 minutes after eating) for 2 weeks with a subsequent one-week rest period. To calculate the dose of capecitabine in accordance with the surface area of the body, see the instructions for the use of capecitabine.

Non-small cell lung cancer

In patients who have not received previous chemotherapy, the following treatment regimen is recommended: docetaxel 75 mg /m², immediately following it, the administration of cisplatin 75 mg /m² for 30-60 minutes or carboplatin (AUC 6 mg / ml / min) for 30-60 minutes.

For treatment after the ineffectiveness of chemotherapy based on platinum drugs, monotherapy with docetaxel at a dose of 75 mg /m².

Metastatic ovarian cancer

For the treatment of the second line of ovarian cancer, a dose of docetaxel 100 mg /m² every 3 weeks in monotherapy.

Prostate Cancer

For treatment of patients with prostate cancer, the recommended dose of Novotax® is 75 mg /m² every three weeks. Prednisone or prednisolone use for a long time 5 mg orally 2 times a day.

Stomach cancer

To treat stomach cancer, the recommended dose of Novotax® is 75 mg /m² in the form of a one-hour intravenous infusion followed by intravenous infusion of cisplatin 75 mg /m² for 1-3 hours (both drugs only on the first day of each cycle of chemotherapy). Upon completion of cisplatin administration, a 24-hour intravenous infusion of fluorouracil 750 mg /m²/ day for 5 days. Treatment is repeated every 3 weeks. Patients should receive premedication with antiemetics and appropriate additional administration of fluid for the administration of cisplatin. To reduce the risk of hematological toxicity (see the section "Correction of the dosing regimen"), the introduction of G-CSF is indicated for prophylactic purposes.

Rak head and neck

Patients should receive premedication with antiemetics, they should be given appropriate hydration (before and after cisplatin administration).It is necessary to prevent the infections caused by neutropenia. All patients receiving docetaxel treatment regimens, prophylactically received antibiotics.

Induction chemotherapy followed by radiotherapy

For induction therapy for locally advanced inoperable squamous cell carcinoma of the head and neck, the recommended dose of Novotax® is 75 mg /m² in the form of a one-hour intravenous infusion with subsequent administration of cisplatin at a dose of 75 mg /m² for 1 hour (both drugs are administered only on the first day of each cycle of chemotherapy). After this, a continuous intravenous infusion of fluorouracil at a dose of 750 mg /m²/ day for 5 days. This pattern is repeated every 3 weeks for 4 cycles. After chemotherapy, patients should undergo radiation therapy.

Induction chemotherapy followed by chemoradiotherapy

For induction therapy of locally advanced squamous cell carcinoma of the head and neck (technically unresectable, with low probability of surgical cure or in organ preservation), the recommended dose of Novotax® is 75 mg /m² a one-hour intravenous infusion followed by a 0.5-3 hour intravenous infusion of cisplatin 100 mg /m² (both drugs are administered only on the first day of each cycle of chemotherapy) and subsequent continuous intravenous infusion of fluorouracil at a dose of 1000 mg /m²/ day from 1 to 4 days. This treatment regimen is repeated every 3 weeks, only 3 cycles. After chemotherapy, patients should receive chemoradiotherapy. For information on correcting doses of cisplatin and fluorouracil, see instructions for using these drugs.

Preparation of a solution for infusion

Novotaks® preparation, concentrate for solution for infusion (40 mg / 1 ml) in forms of release in a single vial, can not be used for one intravenous infusion, together with Novotax® dosage forms in two bottles (concentrate and solvent).

Novotaks® concentrate for solution for infusion (20 mg / 0.5 mL, 40 mg / 1 mL, 80 mg / 2.0 mL) in the form of release in one bottle does not need a preliminary dilution of the solvent and is already ready for addition to the infusion solution.

Each vial of the drug is intended for single use and should be immediately used.

If the drug was stored in a refrigerator, before using it for the preparation of a solution for infusions, the required number of bottles with Novotax® should be kept at room temperature (not above 25 ° C) for 5 minutes.

The required volume of concentrate for the preparation of a solution for Novotax® infusions in accordance with the required dose in aseptic conditions is removed from the vials with a single graduated syringe and injected into an infusion bag or vial containing 250 ml of 0.9% sodium chloride solution or 5% dextrose solution (the introduction of the concentrate is carried out by a single injection into the reservoir with the infusion solution of the entire required dose). If the required dose of docetaxel exceeds 200 mg, a larger volume of infusion fluid should be used, so that the concentration of docetaxel does not exceed 0.74 mg / ml.

The contents of the infusion bag or vial should be mixed by slowly turning them over. Infusion of the solution should be started immediately after its preparation.

Concentrate for the preparation of a solution for Novautax® infusions, 20 mg / 0.5 mL, 40 mg / 1 mL, 80 mg / 2.0 mL, and the infusion solution must be considered before administration. In the presence of sediment and any other inclusions, the solution is not allowed to enter, and it must be destroyed.

Remains of the preparation and all materials used for reconstitution and administration should be disposed of in accordance with standard regulations.

Correction of the dosing regimen

General principles

Novotax® should be administered at a neutrophil count in peripheral blood ≥1500 / μL. In the case of febrile neutropenia, a decrease in the number of neutrophils <500 / μl lasting more than one week, expressed or cumulative (intensifying with repeated administration) skin reactions, or severe peripheral neuropathy against docetaxel therapy, its dose in the following administrations should be reduced from 100 mg /m² up to 75 mg /m² and / or with 75 mg /m² up to 60 mg /m². If such reactions persist and with a dose of docetaxel 60 mg /m², they should stop treatment.

Combination therapy, including Novotax® for the treatment of breast cancer

Adjuvant treatment of breast cancer

Patients with breast cancer, receiving adjuvant therapy with the drug Novotax® in in combination with doxorubicin and cyclophosphamide (TAC regimen), the introduction of G-CSF is recommended for primary prevention. Patients who underwent febrile neutropenia or neutropenic infection in all subsequent cycles should reduce the dose of Novotax® to 60 mg / m². In patients who developed stomatitis 3 or 4 severity, it is necessary to reduce the dose of docetaxel to 60 mg / m².

Novotaks® in the chemotherapeutic regimen ACT

With operable and locally advanced breast cancer after an episode of febrile neutropenia or infection with neoadjuvant therapy according to the ACT scheme, G-CSF should be used prophylactically for all subsequent cycles, and the Novotax® dose should be reduced from 100 mg / m²up to 75 mg / m².

Novotax® in combination with anti-HER2 therapy

In operable breast cancer with tumor overexpression of HER2 after an episode of febrile neutropenia or infection with adjuvant therapy, G-CSF should be used prophylactically for all subsequent cycles, and the dose of docetaxel should be reduced from 100 mg / m² up to 75 mg / m². The risk associated with neutropenia should be considered, guided by generally accepted recommendations, if necessary, to use G-CSF. In the case of advanced stomatitis of 3 or 4 degrees of severity, the dose of docetaxel should be reduced from 100 mg / m² up to 75 mg / m².

Novotax® in combination with capecitabine

To correct the dose of capecitabine in combination with Novotax®, see the instructions for the medical use of capecitabine.

When Novotax® is used in combination with capecitabine for the first appearance of toxicity of 2 degrees of severity, which is maintained at the beginning of the next cycle of Novotax® / capecitabine, the next treatment cycle can be postponed until the toxicity is reduced to 0-1 severity, and during the next cycle 100% of the initial dose is administered.

In patients with repeated development of toxicity of 2 degrees of severity or the first development of toxicity of 3 degrees of severity at any time of the cycle, treatment is postponed until toxicity is reduced to 0-1 severity, then treatment with Novotax® is resumed at a dose of 55 mg / m².

For any subsequent occurrence of toxicity or the appearance of any toxicity of the 4th severity level, Novotax® should be discontinued.

Novotax® in combination with cisplatin or carboplatin

In patients who initially received docetaxel in a dose of 75 mg / m² in combination with cisplatin or carboplatin, and whose platelet count in the previous cycle was reduced to 25000 / l, or in patients who have developed a febrile neutropenia, or upatsientov with severe hematological toxicity, dose of docetaxel in subsequent cycles to be reduced to 65 mg / m².

For correcting the dose of cisplatin or carboplatin, see instructions for the use of these drugs.

Combination therapy, including Novotax® with non-small cell lung cancer

Novotax® in combination with cisplatin or carboplatin

In patients who initially received docetaxel in a dose of 75 mg / m² in combination with cisplatin or carboplatin and in which the number of platelets in the previous cycle decreased to 25,000 / μL, or in patients who developed febrile neutropenia, or in patients with severe non-hematologic toxicity, the dose of docetaxel in subsequent cycles should be reduced to 65 mg / m².

To correct the dose of cisplatin or carboplatin,instructions for the use of these drugs.

Novotax® in combination with cisplatin and fluorouracil for stomach cancer or head and neck cancer

Patients receiving Novotax® in combination with cisplatin and fluorouracil, in accordance with existing generally accepted recommendations, should receive antiemetic drugs and sufficient hydration. To reduce the risk of complicated neutropenia, G-CSF should be used.

If, despite the use of G-CSF, febrile neutropenia, prolonged neutropenia, or neutropenia-induced infection, the dose of Novotax® should be reduced from 75 to 60 mg / m². With the subsequent development of episodes of complicated neutropenia, it is recommended to reduce the dose of Novotax® with 60 mg / m² up to 45 mg / m². With the development of thrombocytopenia of the 4th degree of severity, the dose of Novotax® should be reduced from 75 mg / m² up to 60 mg / m². Subsequent cycles using docetaxel are possible with neutrophil counts> 1500 / μL and platelets> 100,000 / μL. With persistent retention of these toxic manifestations, treatment should be discontinued.

The recommended dose adjustment for toxicity development in patients receiving Novotax® in combination with cisplatin and fluorouracil (FU)

Toxicity	Correction of the dosing regimen
Diarrhea 3 degrees of severity	The first episode: reduce the dose of FU by 20% Secondary episode: reduce the dose of Novotax® by 20%.
Diarrhea 4 degrees of severity	The first episode: reduce the dose of Novotax® and FU by 20% Repeat episode: stop treatment.
Stomatitis / mucositis 3 degrees of severity	The first episode: reduce the dose of FU by 20% Repeat episode: stop receiving only FU in all subsequent cycles. The third episode: reduce the dose of Novotax® by 20%
Stomatitis / mucositis 4 degrees of severity	The first episode: stop only accepting FU in all subsequent cycles Secondary episode: reduce the dose of Novotax® by 20%,

For recommendations on correcting doses of cisplatin and fluorouracil, see instructions for their use.

In patients with squamous cell carcinoma of the head and neck who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia or infection), the use of G-CSF is recommended for all subsequent cycles (for example, from 1 to 15 days of the chemotherapy cycle).

Use in special patient groups

Children

Safety and efficacy of docetaxel in children have not been studied.There is limited experience with docetaxel in children. So far, the effectiveness and safety of docetaxel in nasopharyngeal cancer in children and adolescents from 1 month to 18 years has not been established. Docetaxel was not used in children according to indications: breast cancer, non-small cell lung cancer, prostate cancer, stomach cancer and head and neck cancer, except for malodifferentiated nasopharyngeal cancer (type I and II).

Elderly patients

Based on the data of population pharmacokinetic analysis, there are no specific indications for the use of docetaxel in elderly patients.

In patients 60 years of age and older with the combination of docetaxel with capecitabine, a 25% reduction in the dose of capecitabine is recommended (see the instructions for capecitabine).

Patients with hepatic insufficiency

Based on the pharmacokinetic data obtained for docetaxel in monotherapy at a dose of 100 mg / m², in patients with ALT activity and / orACT> 1.5 VGN or alkaline phosphatase activity> 2.5 VGN, the recommended dose of Novotax® is 75 mg / m². In patients with an increase in the concentration of bilirubin in the blood (> 1 VGN) and / or with increased activity of ALT and ACT (> 3.5 BHN) in combination with an increase in the activity of alkaline phosphatase (> 6 VGN)can not be recommended to reduce the dose and should not be without strict indications to apply docetaxel.

The combination of docetaxel with cisplatin and fluorouracil in the treatment of patients with gastric cancer was not used in patients with increased ALT and / or ACT activity (> 1.5 HNV) in combination with an increase in the activity of alkaline phosphatase (> 2.5 UGN) and an increase in the concentration of bilirubin in the blood (> 1 UGN); In such patients, dose reduction may not be recommended and should not be used without strict indications docetaxel.

At the moment, there is no data on the use of docetaxel in combination with other drugs in patients with impaired liver function.

Patients with impaired renal function

There are no data on the use of docetaxel in patients with impaired renal function of severe severity.

Side effects:

To indicate the incidence of unwanted adverse reactions (CPD), the World Health Organization's NCD classification is used: very often ≥ 10%; often ≥ 1% and <10%; infrequently ≥0.1% and <1%; rarely ≥ 0.01% and <0.1%; very rarely <0.01%; an unknown frequency (it is not possible to determine the frequency of occurrence of NDP by available data).

Monotherapy with docetaxel (75 mg / m² and 100 mg / m²)

Violations of the blood and lymphatic system

Often

Reversible and non-cumulative (not increasing with repeated injections) neutropenia, observed in 96.6% of patients who did not receive G-CSF. The number of neutrophils is reduced to the minimum values on average after 7 days (in patients with intensive prior chemotherapy this period may be shorter), the average duration of severe neutropenia (<500 cells / μl) is also 7 days. Febrile neutropenia, infection.

Often

Severe infections, combined with a decrease in the number of neutrophils in peripheral blood <500 / μL; severe infections, including sepsis and pneumonia, including fatalities; thrombocytopenia <100000 / μL; bleeding, combined with thrombocytopenia <50000 / μL and anemia (hemoglobin <11 g / dl), including with severe anemia (hemoglobin <8 g / dL).

Infrequently

Severe thrombocytopenia.

Immune system disorders

Often

Allergic reactions that usually occur within a few minutes after the onset of intravenous infusion of docetaxel are easily or mildly expressed (hyperemia of the skin, a rash in combination with itching and without it, a feeling of tightness in the chest, back pain, dyspnea, drug fever, or chills ).

Often

Severe allergic reactions, characterized by a decrease in blood pressure and / or bronchospasm or generalized rash / erythema, disappeared after discontinuation of intravenous infusion and appropriate therapy.

Disturbances from the skin and subcutaneous tissues

In some cases, the combination of several factors, such as concomitant infections, concomitant therapy, and underlying disease, had an additional effect on the onset of these reactions.

Often

Reversible skin reactions, usually mild or moderately expressed: localized rashes, mainly on the hands and feet, as well as on the face and chest, which are often accompanied by itching. Eruptions usually occurred within one week after intravenous infusion of docetaxel.

Violations from the nails are characterized by hypo- and hyperpigmentation, pain and onycholysis (loss of nails from the free edge of the nail).

Alopecia.

Often

Severe skin reactions, such as rashes followed by desquamation, including severe palmar-plantar syndrome, which may require interruption or discontinuation of docetaxel treatment.

Infrequently

Severe alopecia.

Disorders from the gastrointestinal tract

Often

Nausea, vomiting, diarrhea, anorexia, stomatitis.

Partially

Severe nausea; severe vomiting; severe diarrhea; constipation; severe stomatitis, esophagitis; pain in the epigastrium, including the strong; gastrointestinal bleeding.

Infrequently

Severe gastrointestinal bleeding, severe constipation, severe esophagitis.

Disturbances from the liver and bile ducts

Often

Increase in serum activity of ACT, ALT, alkaline phosphatase and bilirubin concentration in the blood, more than 2.5 times higher than UGN.

Disturbances from the nervous system

Often

Light or mild neurosensory reactions: paresthesia, dysesthesia, pain, including burning sensation; neuromotor reactions, mainly manifested by muscle weakness; a violation of taste sensations.

Often

Heavy neurosensory and neuromotor reactions (3-4 degrees of severity).

Infrequently

Severe disturbance of gustatory sensations.

When these neurologic symptoms occur, the dosage regimen should be corrected.

If the symptoms of neuropathy persist, then treatment should be discontinued.The mean time to spontaneous resolution of neurotoxic reactions was 81 days from their onset (from 0 to 741 days).

Heart Disease

Often

Heart rhythm disturbances.

Infrequently

Heart failure.

Vascular disorders

Often

Increase or decrease in blood pressure, bleeding.

Disturbances from the respiratory system, chest and mediastinal organs

Often

Dyspnea.

Often

Severe shortness of breath.

Disturbances from musculoskeletal and connective tissue

Often

Myalgia

Often

Arthralgia.

General disorders and disorders at the site of administration

Often

Asthenia, including severe asthenia; generalized and localized pain syndrome, including pain in the chest of non-cardial genesis.

Fluid retention; reported on the development of peripheral edema and increased body weight and less often - the appearance of effusions in the pleural and pericardial cavity, ascites. Peripheral edema usually began with the lower limbs and could pass into generalized, with an increase in body weight of 3 kg or more. The fluid retention is cumulative (increases with repeated administration of the drug).

The fluid retention was not accompanied by acute episodes of oliguria or lowering blood pressure.

Often

Reactions at the site of administration, usually mild and manifested as hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, haemorrhages from the punctured vein or edema of the vein.

Sharply expressed generalized and localized pain syndrome, including pain in the chest of non-cardial genesis.

Severe forms of fluid retention.

In patients treated with docetaxel in monotherapy at a dose of 100 mg / m², the median of the total dose before the end of treatment due to fluid retention was more than 1000 mg / m², and the median time to reverse development of fluid retention is 16.4 weeks (0 to 42 weeks). In patients undergoing premedication, there was a delay in the onset of a moderate or severe fluid retention (the average total docetaxel dose at which fluid retention was observed was 818.9 mg / m3 during premedication², and without premedication - 489.7 mg / m²), but in some cases, fluid retention developed during the first courses of therapy.

Docetaxel in combination with other drugs

Docetaxel in combination with doxorubicin

When docetaxel was used in combination with doxorubicin compared with monotherapy with docetaxel, a greater incidence of neutropenia, including severe neutropenia, was observed; febrile neutropenia; thrombocytopenia, including severe thrombocytopenia; anemia; infections, including severe infections; nausea; vomiting; diarrhea, including severe diarrhea; constipation; stomatitis, including severe stomatitis; heart failure; alopecia; but a lower frequency of allergic reactions; skin reactions, including severe ones; lesions of nails, including heavy; fluid retention, including severe; anorexia, neurosensory and neuromotor reactions, including severe forms; arterial hypotension; rhythm disturbances; increased activity of hepatic transaminases, alkaline phosphatase, bilirubin concentration in the blood; myalgia; asthenia.

Docetaxel in combination with doxorubicin and cyclophosphamide (TAC regimen)

When this chemotherapeutic regimen is used in comparison with monotherapy with the drug Docetaxel there was a lower incidence of neutropenia, severe anemia, febrile neutropenia, infections, allergic reactions, peripheral edema,neurosensory, and neuromotor responses, nail infections, diarrhea, arrhythmia, but there was a large incidence of non-severe anemia, thrombocytopenia, nausea, vomiting, stomatitis, taste disturbances, constipation, fatigue, arthralgia, alopecia.

Additionally observed: colitis, enterocolitis, large intestine perforation without lethal outcomes (2 of 4 patients required discontinuation of treatment), acute myeloid leukemia, acute leukemia, myelodysplastic syndrome.

Prophylactic G-CSF reduced incidence of neutropenia (60%) and neutropenic infections 3-4 degrees.

Docetaxel in combination with capecitabine

When docetaxel is used in combination with capecitabine, there is a more frequent development of adverse events on the part of the gastrointestinal tract (stomatitis, diarrhea, vomiting, constipation, abdominal pain, impaired taste perception); arthralgia; severe thrombocytopenia and anemia; hyperbilirubinemia; palmar-plantar syndrome (hyperemia of the skin of the limbs (palms and feet), followed by swelling and desquamation); but a more rare development of severe neutropenia; alopecia; violations of the nails, including onycholysis, asthenia; myalgia; decreased appetite and anorexia.

In addition, there was dyspepsia, dry mouth, sore throat, candidiasis of the mouth, dermatitis, erythematous rash, discoloration of the nails, pyrexia, pain in the extremities, pain, back pain, lethargy (drowsiness, inhibition, stupor), dyspnea, nosebleeds, paresthesia, dizziness, headache, peripheral neuropathy, dehydration, lacrimation, weight loss.

Compared with patients younger patients 60 years and older who received a combination of docetaxel with capecitabine, most marked development of Grade 3-4 toxicity.

Docetaxel in combination with trastuzumab

Nausea, diarrhea, constipation, abdominal pain, taste disorders, febrile neutropenia, arthralgia, anorexia, toxic effects of 4 degrees of severity, and cases of heart failure were more common in patients who received the combination of docetaxel with trastuzumab (in comparison with monotherapy with docetaxel), especially in patients who pre-commissioned anthracyclines as adjuvant therapy, but less frequent neutropenia 3-4 degrees of severity, asthenia, weakness, alopecia, nail damage, skin rashes, vomiting, stomatitis and myalgus and I.

Additionally observed: lacrimation, conjunctivitis, inflammation of the mucous membranes, nasopharyngitis, pain in the pharynx and larynx, epistaxis, rhinorrhea, influenza-like diseases, cough, pyrexia, chills, pain, chest pain, pain in the extremities, back pain, pain in the bones, lethargy (drowsiness, inhibition, stupor), insomnia, dyspnea, erythema, dyspepsia, paresthesia, headache, hypoesthesia.

Compared with monotherapy with docetaxel, there was an increase in the incidence of serious adverse reactions.

Docetaxel in the scheme AC-TH (doxorubicin and cyclophosphamide followed by docetaxel with trastuzumab)

The use of such combinations compared with monotherapy with docetaxel was accompanied by an increase in the incidence of many side effects: more common were alopecia, anemia, including anemia of 3-4 degrees of severity, thrombocytopenia, including 3-4 degrees of severity, nausea, including 3-4 degrees of severity, stomatitis, vomiting, diarrhea, constipation, anorexia, abdominal pain, increased activityACT, ALT and alkaline phosphatase, myalgia, nail damage, arthralgia, 3-4 grade infections, heart failure.

There was no increase in febrile neutropenia.

Less commonly met neutropenia 3-4 degrees of severity, fluid retention, neurosensory and neuromotor reactions, rash and desquamation, allergic reactions.

Additionally recorded: insomnia, increased concentration of creatinine in the blood.

Combinations of docetaxel with cisplatin or carboplatin

When this scheme of chemotherapy was used in comparison with monotherapy with docetaxel, thrombocytopenia appeared more often, including thrombocytopenia of 3-4 degrees of severity (mostly with carboplatin); Anemia, including anemia of 3-4 degrees of severity; nausea, including nausea 3-4 degrees of severity; diarrhea 3-4 degrees of severity; anorexia, including anorexia 3-4 degrees of severity (mostly with cisplatin); reaction at the site of administration.

However, less frequent neutropenia, including neutropenia of 3-4 degrees of severity; anemia, including anemia of 3-4 degrees of severity, infections; febrile neutropenia; allergic reactions; skin reactions; defeat of nails; fluid retention, including fluid retention of 3-4 degrees of severity (mostly with carboplatin); stomatitis, neurosensory and, to a lesser extent, neuromotor neuropathy; alopecia; asthenia and myalgia.

Additionally observed: fever in the absence of infection, including 3-4 degrees of severity; pain.

Combination docetaxel with prednisolone or prednisone

When docetaxel was used in combination with prednisolone or prednisone, compared with monotherapy with docetaxel, the incidence of side effects such as anemia, including 3-4 degrees of severity, was significantly reduced; infection; neutropenia, including 3-4 degrees of severity; thrombocytopenia; febrile neutropenia; weakness; allergic reactions; neurosensory and neuromotor reactions; alopecia; rash: desquamation; nausea; diarrhea; stomatitis; vomiting; anorexia; myalgia; arthralgia; fluid retention; but more often there were taste disorders and heart failure.

Additionally observed: nasal bleeding, cough, shortness of breath, weakness, lacrimation.

Combination of docetaxel with cisplatin and fluorouracil

When this combination was used, compared with monotherapy with docetaxel, anemia was more frequent, including 3-4 degrees of severity; thrombocytopenia, including 3-4 degrees of severity; febrile neutropenia; neutropenic infections (even with the use of G-CSF);nausea; vomiting; anorexia; stomatitis; diarrhea; esophagitis / dysphagia / pain when swallowing; but there were fewer infections; allergic reactions; fluid retention; neurosensory and neuromotor reactions; myalgia; alopecia; rash; itching; defeat of nails; skin desquamation; disturbance of the rhythm of the heart.

Additionally observed: fever in the absence of infection; lethargy (drowsiness, confusion, numbness); changes in hearing; dizziness; lacrimation; dry skin; heartburn; myocardial ischemia; underlined venous pattern; cancer pain; conjunctivitis; decrease in body weight.

Prophylactic use of G-CSF reduces the incidence of febrile neutropenia and / or neutropenic infections.

Data obtained by post-marketing use of docetaxel preparations

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Rarely

Acute myeloid leukemia and myelodysplastic syndrome associated with docetaxel when applied in combination with other chemotherapeutic agents and / or irradiation.

Violations of the blood and lymphatic system

It was reported that oppression of bone marrow hematopoiesis and other hematological adverse reactions.

It reported on the development of disseminated intravascular coagulation (DIC), often in association with sepsis or multiple organ failure.

Immune system disorders

Rarely

Anaphylactic shock, sometimes fatal. In patients who received premedication, these cases ended in a lethal outcome very rarely.

Disturbances from the nervous system

Rarely

Convulsions or transient loss of consciousness, sometimes developed during intravenous infusion of the drug.

Disturbances on the part of the organ of sight

Rarely

Lachrymation combined with conjunctivitis (or without it)

Rarely

Cases of obstruction of the tear duct, leading to its rupture.

Rarely

Transient visual disorder (light flash in the eyes, the appearance of cattle) normally encountered during intravenous infusion administration and combined with the development of hypersensitivity reactions, which usually disappear after cessation of intravenous infusion.

Patients treated with docetaxel, as well as other taxanes, reported cases of cystic edema in the macular area.

Hearing disorders and labyrinthine disorders

Rarely

Ototoxic effect of the drug, hearing impairment and / or hearing loss, including cases associated with other ototoxic drugs.

Violations from the heart and blood vessels

Rarely

Cases of venous thromboembolic complications and myocardial infarction.

Disturbances from the respiratory system, chest and mediastinal organs

Rarely

Acute respiratory distress syndrome, interstitial pneumonia / pneumonitis, interstitial lung disease, pulmonary fibrosis, respiratory failure, which could be fatal.

With the simultaneous carrying out of irradiation, rare cases of radiation pneumonia.

Disorders from the gastrointestinal tract

Rarely

Dehydration as a consequence of the development of reactions from the gastrointestinal tract; perforation of the stomach or intestines; colitis, including ischemic; neutropenic enterocolitis; rare cases of ileus (intestinal obstruction) and intestinal obstruction.

Disturbances from the liver and bile ducts

Rarely

Cases of hepatitis, sometimes fatal, mainly in patients with concomitant liver disease.

Disorders from the kidneys and urinary tract

Reported deterioration of kidney function and the development of renal failure, in most cases associated with the simultaneous use of nephrotoxic drugs.

Disturbances from the skin and subcutaneous tissues

Rarely

Cases of cutaneous lupus erythematosus, bullous rash, as well as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. In some cases, several factors contributed to the development of these conditions, such as concomitant infections, concomitant medications and concomitant diseases.

The development of similar scleroderma changes was reported, which was usually preceded by peripheral lymphangiectatic edema.

Common disorders and disorders together

Rarely

The phenomenon of the return of the local radiation reaction in the previously irradiated region; pulmonary edema.

Disorders from the metabolism and nutrition

There have been reports of the development of cases of hyponatremia, mainly in combination with dehydration, vomiting and pneumonia.

Overdose:

Symptoms

There are few reports of overdose. The main manifestations of the overdose were suppression of bone marrow function, peripheral neurotoxicity and mucositis (inflammation of the mucous membranes).

Treatment

Currently, the antidote to docetaxel is not known. In case of an overdose, the patient should be hospitalized in a specialized department and carefully monitor the function of vital organs. Patients should, as soon as possible, appoint G-CSF. If necessary, symptomatic therapy.

Interaction:

Research in vitro showed that the biotransformation of the preparation can change with simultaneous application of substances inducing or inhibiting cytochrome P4503A isoenzymes, or metabolized (competitive inhibition) with cytochrome P4503A isoenzymes such as ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, care must be taken with the simultaneous administration of such drugs,taking into account the possibility of pronounced interaction.

With the simultaneous use of docetaxel with inhibitors CYP3A4, such as antifungal agents from the group of imidazoles (ketoconazole, intraconazole) and protease inhibitors (ritonavir), you should be careful.

Studies conducted in patients who simultaneously received docetaxel and ketoconazole, showed that the clearance of docetaxel was reduced by 50%, apparently due to the fact that the main pathway of docetaxel metabolism is its metabolism by isoenzyme CYP3A4. In this case, even with lower doses of docetaxel, its tolerability may be worsened.

The pharmacokinetics of docetaxel in the presence of prednisolone was studied in patients with metastatic prostate cancer. Although docetaxel is metabolized by isoenzyme CYP3A4, a prednisolone is an isoenzyme inducer CYP3A4, there was no statistically significant effect of prednisolone on the pharmacokinetics of docetaxel.

Docetaxel has a high association with plasma proteins (> 95%). In vitro medications that bind firmly to blood plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates,sulfamethoxazole and valproic acid, do not interfere with the binding of docetaxel to plasma proteins.

Dexamethasone also does not affect the degree of binding of docetaxel to plasma proteins. Docetaxel does not affect the binding of digitoxin to plasma proteins.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide did not change with their combined use.

There is information on the interaction of docetaxel and carboplatin. When using a combination of carboplatin and docetaxel, carboplatin clearance is increased by 50% compared to carboplatin monotherapy.

Special instructions:

Neutropenia

Careful monitoring of the clinical blood test should be carried out in patients receiving Novotax® therapy. With the development of severe neutropenia (<500 / μL for 7 days) during the course of therapy with Novotax^® it is recommended to reduce the dose of the drug on subsequent cycles or to apply adequate symptomatic measures. Continue treatment with Novotax^®it is possible after the restoration of the number of neutrophils to 1500 / μl.

In the case of G-CSF administration, patients receiving Novotax® in combination with cisplatin and fluorouracil, febrile neutropenia and / or neutropenic infections develop less frequently.Therefore, when using this combination, the introduction of G-CSF is necessary for the prevention of the development of complicated neutropenia (febrile neutropenia, prolonged neutropenia, neutropenic infection). Care should be taken to monitor the condition and laboratory performance of patients receiving this chemotherapy regimen.

If patients receive primary G-CSF prophylaxis (from the first cycle) with Novotax^® in combination with doxorubicin and cyclophosphamide (TAC chemotherapy regimen), febrile neutropenia and / or neutropenic infection develop less frequently. Therefore, with the adjuvant chemotherapy of breast cancer according to the TAC scheme, the issue of the preventive administration of G-CSF from the first cycle should be considered to reduce the risk of development of complicated neutropenia (febrile neutropenia, prolonged neutropenia, neutropenic infection). Care should be taken to monitor the condition of patients receiving the TAC chemotherapy regimen.

Hypersensitivity reactions

To detect reactions of hypersensitivity, patients should be carefully monitored, especially during the first and second infusions.The development of hypersensitivity reactions is possible at the very first minute of infusion of docetaxel, therefore, when it is administered, it is necessary to have medicines and equipment for the treatment of arterial hypotension and bronchospasm.

Light manifestations of hypersensitivity (redness of the face or localized skin reactions) do not require an interruption in the administration of the drug.

Despite premedication, severe hypersensitivity reactions were observed in patients, such as a marked decrease in blood pressure, bronchospasm or generalized rash / erythema, and very rarely fatal anaphylactic reactions.

The appearance of hypersensitivity reactions requires the immediate cessation of Novotax^® and appropriate therapy. Patients with severe hypersensitivity reactions should not resume treatment with Novotax^®.

Patients with hepatic insufficiency

In patients receiving monotherapy with docetaxel at a dose of 100 mg / m²and having an increased activity of "hepatic" transaminases (ALT and / or ACT), more than 1.5 times that of HHV,in combination with an increase in serum alkaline phosphatase activity more than 2.5 times higher than UGN, there is an extremely high risk of developing serious side effects such as sepsis, gastrointestinal bleeding, febrile neutropenia, infections, thrombocytopenia, severe skin toxic effects up to lethal outcome, as well as stomatitis and asthenia. In this regard, in such patients with elevated parameters of functional liver samples, the recommended dose of Novotax^® is 75 mg / m².

Functional liver samples should be performed prior to treatment and before each subsequent cycle of therapy with Novotax^®. In patients with elevated concentrations of bilirubin and / or increased activity of ALT and ACT (> 3.5 VGN) in combination with an increase in activity of alkaline phosphatase> 6 VGN, Novotax^® is not recommended.

At the moment, there are no data on the use of docetaxel in combination with other drugs in patients with impaired hepatic function.

Fluid retention

Careful observation of patients with severe fluid retention is necessary: with effusion into the pleural cavity, pericardium, or with ascites.With the appearance of edema - the restriction of salt and drinking regimen and the use of diuretics.

Leukemia

When using a combination of docetaxel with doxorubicin and cyclophosphamide for operative breast cancer, the risk of developing delayed myelodysplasia and / or myeloid leukemia requires hematological monitoring of patients.

Heart failure

In patients who received docetaxel in combination with anti-HER2 therapy, especially after anthracycline-containing chemotherapy (doxorubicin or epirubicin), it is possible to develop heart failure, which can be of medium severity or severe and lead to death.

When a patient is treated with docetaxel in a combination of anti-HER2 therapy, she must undergo a cardiac examination before starting therapy; every three months, heart function should be monitored, which allows to identify patients who may develop heart failure.

For more details, see the instructions for the use of appropriate anti-HER2 drugs.

Disturbances on the part of the organ of sight

In patients treated with docetaxel, as well as other taxanes,reported on the development of cystic edema of the macular area. Patients who have visual impairment, urgently need to undergo a complete ophthalmological examination. In the case of diagnosing cystic edema of the macular area, docetaxel should be discontinued and the patient should be treated accordingly.

Elderly patients

In comparison with patients younger than 60 years in patients aged 60 years and over who receive combined chemotherapy docetaxel + capecitabine, there was an increase in the incidence of treatment-related adverse events 3 and 4 severity associated with the treatment of serious CPD and early withdrawal of treatment due to the development of NDP. There are limited data on the use of a combination of docetaxel with doxorubicin and cyclophosphamide in patients older than 70 years.

In patients 65 years and older who received docetaxel treatment every 3 weeks for prostate cancer, the incidence of nail changes was> 10% higher than in younger patients, and in patients 75 years of age and older the incidence of fever, diarrhea, anorexia and peripheral edema was> 10% higher than in younger patients.

Using the combination of docetaxel with cisplatin and fluorouracil, the following adverse reactions (of all degrees of severity): lethargy (drowsiness, inhibition, stupor), stomatitis, neutropenic infection, in patients older than 65 years were> 10% more common than in younger patients. Therefore, patients over 65 years of age who receive this combination need careful monitoring.

The need for contraception

Men and women of childbearing age during treatment with docetaxel should use reliable methods of contraception. Since in pre-clinical studies it was shown that docetaxel has a genotoxic effect and can disrupt male fertility (the ability to conceive), men receiving docetaxel treatment are advised to abstain from conception of the child during treatment with docetaxel and for at least 6 months after the end of chemotherapy and advise before the treatment to preserve the sperm.

Women in case of occurrence of pregnancy during their treatment should immediately inform their doctor about this.

Neurotoxicity

The development of severe sensory neuropathy requires a reduction in Novotax® dose.

Ethanol content

In Novotax® in a vial with 20 mg /0,5 ml of the concentrate contains ethanol of anhydrous 0.198 g, in a vial of 40 mg / 1.0 ml concentrate - 0.395 g, in a vial of 80 mg / 2.0 ml concentrate - 0.790 g. This should be taken into account when using the drug in patients with alcoholism and patients at risk (patients with liver diseases and epilepsy).

Precautions for use

Novotax® is an antitumor drug; as in the case of other potentially toxic substances, care must be taken when using it and preparing solutions. It is recommended to use gloves. If Novotax® solution or Novotax® infusion solution is on the skin, then immediately wash it thoroughly with soap and water. If a concentrate or infusion solution of Novotax® enters the mucous membranes, immediately rinse thoroughly with water.

Neoadjuvant therapy for breast cancer

When complete or partial morphological regression of the tumor is achieved on neoadjuvant chemotherapy, surgical removal of the tumor and, if possible, axillary lymphadenectomy are performed.Conducting additional adjuvant chemotherapy after achieving complete or partial morphological regression does not improve the survival of patients. Therefore, adjuvant chemotherapy is not justified for patients who have achieved complete or partial morphological regression of the tumor after neoadjuvant chemotherapy.

If the answer is minimal after several cycles of neoadjuvant chemotherapy, or the disease progresses at any time, you need to consider an alternative regimen of chemotherapy and / or preoperative radiotherapy followed by surgery, in the form of a mastectomy with axillary lymphodissection. Postoperative adjuvant therapy for these patients consists of the completion of planned chemotherapy if it was not completed before surgery, followed by hormone therapy in women with a positive status of estrogen and / or progesterone receptors.

In patients with breast cancer with tumor overexpression, HER2 is assigned trastuzumab up to one year.

Effect on the ability to drive transp. cf. and fur:Special studies were not conducted.However, the development of adverse reactions from the nervous system, the organ of vision, the gastrointestinal tract, etc., and the presence of ethanol in the formulation may lead to a decrease in the speed of psychomotor reactions and attention. Therefore, it is not recommended to drive vehicles and engage in other potentially hazardous activities during Novotax® treatment.

Form release / dosage:

Concentrate for the preparation of a solution for infusions, 40 mg / ml.

Packaging:

0.5 ml, 1.0 ml, 2.0 ml Novotaks^® in bottles of colorless neutral glass, ukuporennye rubber stoppers with obakkoy caps aluminum.

1 vial is placed in a contour cell pack of film PBX.

1 contour pack with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of 2 to 25 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

Terms of leave from pharmacies:On prescription

Registration number:LP-002269

Date of registration:04.10.2013 / 13.07.2015

Date of cancellation:2018-10-04

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp23.01.2016

Illustrated instructions

Instructions

Novotax® (Novotax®)