Docetaxel - instructions for use, dose, side effects, contraindications

Note. The nominal quantity of substances is indicated. In production, the vials containing the preparation and the solvent are filled with a small excess (0.61 ml (20 mg / 0.5 ml) and 2.36 ml (80 mg / 2 ml) for the preparation and 1.98 ml and 7.33 ml for solvent) to compensate for losses in the syringe and needle during extraction.

Description:

Concentrate: Pa viscous solution from yellow to brownish yellow in color.

Solvent: Pcolorless liquid.

Pharmacotherapeutic group:antitumor agent - alkaloid

ATX: & nbsp

L.01.C.D.02 Docetaxel

Pharmacodynamics:

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, of cells that produce in excess P-glycoprotein (P-gP), encoded by a gene of multiple resistance to chemotherapeutic drugs. In vivo docetaxel has a broad 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 in adults

The pharmacokinetics of docetaxel is dose-dependent and corresponds to a three-phase pharmacokinetic model with a half-life 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 / m² mean values of the maximum concentration of docetaxel in plasma (C_mOh) 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 binds more than 95% to plasma proteins.

Docetaxel after oxidation of the tert-butyl ether group with the P450 isoenzyme system is excreted through the kidneys for 7 days, 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 on the age and sex of the patient.

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

The clearance of docetaxel in combination therapy with cisplatin does not change, but compared with its clearance with monotherapy. The pharmacokinetic profile of cisplatin administered shortly after 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 with docetaxel, cisplatin and fluorouracil does not change their pharmacokinetic parameters.

Pharmacokinetics in 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)

Operational breast cancer (Docetaxel in combination with doxorubicin and cyclophosphamide, adjuvant chemotherapy):

- 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 grade of tumor malignancy (grade 2 - 3), age less than 35 years).

Metastatic and / or locally advanced breast cancer:

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

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

- locally advanced or metastatic breast cancer with ineffectiveness of previous chemotherapy involving anthracyclines or alkylating facilities (Docetaxel in monotherapy) or in the ineffectiveness of previous chemotherapy that included anthracyclines (Docetaxel in combination with capecitabine).

Non-small cell lung cancer

- mCommonly spread or metastatic non-small cell lung cancer with ineffectiveness of previous chemotherapy (Docetaxel in monotherapy);

- Mr.Injectable locally advanced or metastatic non-small cell lung cancer (Docetaxel in combination with cisplatin, first-line therapy).

Ovarian Cancer

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

Prostate Cancer

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

Stomach cancer

- muteratic gastric cancer, including cancer of the esophageal-gastric transition zone (Docetaxel in combination with cisplatin and fluorouracil, 1st line therapy).

Head and neck cancer

- Locally spread squamous cell carcinoma of the head and neck (Docetaxel 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;

- severe liver dysfunction;

- bPregnancy and period of breastfeeding;

- dUp to 18 years of age.

When using the drug Docetaxel In combination with other drugs, contraindications to their use should also be considered.

Carefully:

With the simultaneous use of drugs that induce or inhibit cytochrome P450-3A isoenzymes, or metabolized with isoenzymes

cytochrome P450-3A, such as ciclosporin, terfenadine, antifungal agents from the group of imidazoles (ketoconazole, itraconazole), erythromycin and troleandomycin, protease inhibitors (ritonavir) (see the section "Interaction with other medicinal products").

Dosing and Administration:

Treatment with drug Docetaxel should be carried out 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 the drug Docetaxel (except for patients with prostate cancer, recommendations for premedication for which see below), in the absence of contraindications prior to its administration, a glucocorticosteroid premedication, for example, dexamethasone inside at a dose of 16 mg / day (8 mg twice a day) during 3 days, starting 1 day before drug administration Docetaxel.

In patients with prostate cancer receiving concomitant treatment with prednisone or prednisolone, dexamethasone is premedicated at a dose of 8 mg for 12, 3 and 1 hour before the administration of the drug Docetaxel.

To reduce the risk of development of hematological complications, preventive administration of granulocyte colony-stimulating factor (G-CSF) is recommended.

A drug Docetaxel is administered intravenously drip for 1 hour 1 time per 3 weeks.

Breast Cancer (BC)

Adjuvant therapy

With adjuvant therapy of operative breast cancer with regional lymph nodes and operative breast cancer without regional lymph nodes, the recommended dose of the drug Docetaxel is 75 mg / m² 1 hour after the administration of doxorubicin (50 mg / m²) and cyclophosphamide (500 mg / m²) every 3 weeks (TAC scheme). A total of 6 cycles (see also "Dose Correction for Chemotherapy").

With adjuvant therapy of patients with operable breast cancer with tumor overexpression HER2 the following doses of the drug are recommended Docetaxel.

Chemotherapy according to the AC TH

- 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.

- Three weeks after the day of cycle 1 8: trastuzumab 6 mg / kg every 3 weeks. Trastuzumab is introduced for a total of 1 year.

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 the combination drug Docetaxel plus trastuzumab recommended dose of the drug Docetaxel is 100 mg / m² every 3 weeks with a weekly administration of trastuzumab. The initial intravenous infusion of docetaxel is performed the 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 / m² inside 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 for 30-60 min or carboplatin (AUC 6 mg / ml / min) for 30-60 minutes.

For treatment after the ineffectiveness of chemotherapy on the basis of platinum preparations, monotherapy with docetaxel at a dose of 75 mg / m is recommended².

Metastatic ovarian cancer

For the treatment of the second line of ovarian cancer, a dose of docetaxel 100 mg / m²every 3 weeks in monotherapy.

Prostate Cancer

For the treatment of patients with prostate cancer, the recommended dose of the drug Docetaxel is 75 mg / m²1 time in 3 weeks. Prednisone or prednisolone appoint a long 5 mg orally 2 times a day.

Stomach cancer

To treat stomach cancer, the recommended dose of the drug Docetaxel is 75 mg / m² in the form of a one-hour infusion with subsequent infusion of cisplatin 75 mg / m² for 1-3 h (both drugs only on the first day of each cycle of chemotherapy). Upon completion of cisplatin administration, a 24-hour 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 fluid administration (hydration) when cisplatin is administered. To reduce the risk of hematological toxicity (see "Dose Correction for Chemotherapy" below), the introduction of G-CSF is indicated for prophylactic purposes.

Head and neck cancer

Patients should receive premedication with antiemetic medications, they should be given appropriate hydration (before and after cisplatin administration).It is necessary to prevent the development of neutropenic infections. All patients who have had treatment regimens containing the drug Docetaxel, received antibiotics with a preventive purpose.

Induction chemotherapy followed by radiotherapy.

For induction therapy for locally advanced inoperable squamous cell carcinoma of the head and neck, the recommended dose of the drug Docetaxel 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 is carried out 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 a low probability of surgical cure or in organ preservation), the recommended dose of the drug Docetaxel is 75 mg / m² in the form of a one-hour intravenous infusion followed by a 0.5 to 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 undergo chemoradiotherapy. For information on correcting doses of cisplatin and fluorouracil, see instructions for the use of these drugs.

Correction of doses for chemotherapy

General recommendations

A drug Docetaxel should be administered at a neutrophil count in the 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 similar reactions persist and with a dose of docetaxel 60 mg / m², treatment should be discontinued.

Combination therapy, including the drug Docetaxel for the treatment of breast cancer

Adjuvant treatment of breast cancer

Patients with breast cancer receiving adjuvant therapy with the drug Docetaxel in combination with doxorubicin and cyclophosphamide (TAC regimen), the introduction of G-CSF is recommended for primary prevention. Patients who suffered febrile neutropenia or neutropenic infection in all subsequent cycles should reduce the dose of the drug Docetaxel up 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.

A drug Docetaxel in the chemotherapeutic scheme AS TH

With operable breast cancer with tumor overexpression HER2 after an episode of febrile neutropenia or infection in the background of adjuvant therapy according to the AC VT scheme, it is necessary to use G-CSF for prophylactic purposes on all subsequent cycles, and the dose of the drug Docetaxel in the AC circuit, the TH should be reduced from 100 mg / m² up to 75 mg / m².

Since in clinical practice the development of neutropenia was observed on the first cycle of chemotherapy,neutropenic risk and current recommendations should be considered and, if necessary, G-CSF should be used.

In case of development of stomatitis of 3 or 4 degree of severity, the dose of the drug Docetaxel in the AC circuit TH should be reduced from 100 mg / m² up to 75 mg / m².

To adjust the dose of trastuzumab, see the information in the instructions for use of trastuzumab.

A drug Docetaxel in combination with capecitabine

To correct the dose of capecitabine in combination with the drug Docetaxel see the instructions for the medical use of capecitabine.

When using the drug Docetaxel 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, the next treatment cycle can be delayed until the toxicity is reduced to 0-1 grade, and 100% of the initial dose is administered during the next treatment cycle. 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 degree of severity, then treatment with the drug Docetaxel resumed at a dose of 55 mg / m².

For any subsequent occurrence of toxicity or the appearance of any toxicity of 4 degrees of severity, the administration of the drug Docetaxel must be terminated.

Combination therapy, including the drug Docetaxel, with non-small cell lung cancer drug Docetaxel in combination with cisplatin or carboplatin

In patients who initially received docetaxel in a dose of 75 mg / m in combination with cisplatin or carboplatin and in which the platelet count 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, see the instructions for use of cisplatin.

A drug Docetaxel in combination with cisplatin and fluorouracil for stomach cancer and head and neck cancer

Patients receiving the drug Docetaxel in combination with cisplatin and fluorouracil, in accordance with existing generally accepted recommendations, antiemetic preparations and sufficient additional fluid administration (hydration) should be obtained.To reduce the risk of complicated neutropenia, G-CSF should be used.

If despite the reception of G-CSF there are episodes of febrile neutropenia, prolonged neutropenia or neutropenic infection, the dose of the drug Docetaxel reduced from 75 to 60 mg / m². With the subsequent development of episodes of complicated neutropenia, it is recommended to reduce the dose of the drug Docetaxel with 60 mg / m² up to 45 mg / m². With the development of thrombocytopenia of the 4th degree of severity, the dose of the drug Docetaxel it is recommended to reduce 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 in the development of toxicity in patients receiving the drug Docetaxel 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%. Repeat episode: reduce the dose of the drug Docetaxel on 20%.
Diarrhea 4 degrees of severity	First episode: reduce the dose of the drug Docetaxel 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 the drug Docetaxel on 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 cycle).

Special patient groups

Children

Safety and efficacy of the drug Docetaxel in children not studied. There is limited experience with docetaxel in children. While the effectiveness and safety of the drug have not been established Docetaxel at a cancer of a nasopharynx at children and teenagers from 1 mes to 18 years. 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 special instructions for the use of the drug Docetaxel in the elderly. Patients aged 60 years and older with a combination of the drug Docetaxel with capecitabine, a reduction in the dose of capecitabine by 25% (see instructions for the use of 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 / or ACT > 1.5 VGN or alkaline phosphatase activity> 2.5 VGN, the recommended dose of the drug Docetaxel 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 VGN) in combination with an increase in the activity of alkaline phosphatase (> 6 UGN), dose reduction can not be recommended and should not be used without strict indications docetaxel. Combination of the drug Docetaxel with cisplatin and fluorouracil in the treatment of patients with gastric cancer was not used in patients with increased ALT activity and / or ACT (> 1.5 VGN) in combination with an increase in the activity of alkaline phosphatase (> 2.5 VGN) and an increase in the concentration of bilirubin in the blood (> 1 VGN).

Such patients can not be recommended to reduce the dose and should not be without strict indication to apply docetaxel.

At the moment there are no data on the use of the drug 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 severe renal dysfunction.

Preparation of the infusion solution

Concentrate solution preparation time for infusion of 20 mg / 0.5 ml: the actual content in the vial is 24.4 mg / 0.61 ml, which allows you to compensate for the loss of fluid when preparing a premixed solution, due to foaming, adhesion to the walls of the bottle and the presence of "dead space". Thus, the excess drug in vial ensures that after dilution of the contents enclosed minimum volume of solvent dialed premixed solution is 2 ml, containing 10 mg / ml docetaxel, corresponding to 20 mg (dose indicated on the label).

Concentrate for the preparation of solution for infusions 80 mg / 2 ml: the actual content in the vial is 94.4 mg / 2.36 ml, which makes it possible to compensate for fluid loss during the preparation of the premixed solution, due to foaming, adhesion to the walls of the vial and the presence of "dead space". Thus, the excess of the drug in the vial ensures that after diluting its contents with the applied solvent, the minimum volume of the previously mixed solution is 8 ml containing 10 mg / ml of docetaxel, which corresponds to 80 mg (the catch shown on the vial label),

a) Preparation of the premixed solution of the preparation Docetaxel (with the concentration of docetaxel 10 mg / ml)

Concentrate for the preparation of a solution for drug infusions Docetaxel must be previously diluted in the attached solvent. If the vials with the preparation and the solvent were stored in the refrigerator, then, before dilution, they must be kept at room temperature (below 25 ° C) for 5 minutes. All contents of the vial with a solvent in aseptic conditions are typed with a needle into the syringe (the vial is placed slightly at an angle) and injected into the vial with the drug Docetaxel.

After removing the needle, the contents of the vial with the resulting mixture are mixed by turning the bottle upside down for 45 seconds (do not shake!) And left for 5 minutes at room temperature, after which the solution is checked for homogeneity and transparency (the presence of foam even after 5 minutes is the norm from for the content of polysorbate 80 in the formulation). Pre-mixed contains docetaxel in a concentration of 10 mg / ml and should be used immediately to prepare a solution for infusion.

b) Preparation of a solution for infusion. The required volume of the premixed solution in accordance with the required dose is introduced into the infusion bag or vial containing 250 ml of a 5% solution of dextrose or 0.9% solution of sodium chloride. If the required dose of docetaxel exceeds 200 mg, then it should be diluted in a larger volume of the infusion solution, so that the concentration of docetaxel is not above 0.74 mg / ml. The contents of the infusion bag or vial should be mixed with rotational movements. Infusion of the resulting solution should be carried out no later than 4 hours after preparation (including 1 hour of administration) when stored at room temperature (below 25 ° C) and under normal light conditions. Pre-mixed solution of the drug Docetaxel and the infusion solution, like any other preparation for parenteral use, should be inspected before administration; In the presence of sediment, the solution should be destroyed.

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

Side effects:

To indicate the frequency of unwanted adverse reactions (NDP), the World Health Organization's CPD classification is used: Often ≥ 10%; often ≥ 1% and <10%; infrequently ≥0.1% and <1%; rarely ≥ 0.01% and <0.1%; rarely < 0,01%, frequency unknown (according to available data it is not possible to estimate the frequency of development of NDP).

Monotherapy with the drug 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 the drug Docetaxel and are easily or moderately expressed (hyperemia of the skin, 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.

Often

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

Increased activity ACT, ALT, alkaline phosphatase and a concentration of bilirubin 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; and 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 average time to spontaneous resolution of neurotoxic reactions was 81 days from the beginning (from 1 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: it was reported on the development of peripheral edema and increase in body weight and less often about the appearance of effusion 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 / m, and the median time to reverse development of fluid retention was 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 incidence 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; hypotension; rhythm disturbances; increased activity of "liver" transaminases, alkaline phosphatase, bilirubin concentration in the blood; myalgia; asthenia.

Docetaxel in combination with doxorubicin and cyclophosphamide (TAC scheme)

When this chemotherapeutic regimen was used in comparison with monotherapy with docetaxel, a lower incidence of neutropenia, severe anemia, febrile neutropenia, infections, allergic reactions, peripheral edema, neurosensory and neuromotor reactions, nail damage, diarrhea, arrhythmia was observed, but a high incidence of mild anemia, thrombocytopenia, nausea, vomiting, stomatitis, impaired taste, constipation, asthenia, arthralgia, alopecia. Additionally observed: colitis, enterocolitis, large intestine perforation without lethal outcomes (2 of 4 patients required discontinuation of treatment), acute myeloid 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; disorders 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, nail color change, pyrexia, pain in the extremities, pain, back pain, lethargy (drowsiness, inhibition, stupor), dyspnea, cough, 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

Patients treated with the combination of docetaxel with trastuzumab (compared to docetaxel) detected more frequently nausea, diarrhea, constipation, abdominal pain, taste disturbances, febrile neutropenia, arthralgia, anorexia, toxic effects 4 severity, cases of heart failure, especially in patients previously treated with anthracyclines as adjuvant therapy, but rarely observed Grade 3-4 neutropenia, asthenia, fatigue, alopecia, nail infections, skin rash, vomiting, stomatitis and myalgias and I. Further observed: lacrimation, conjunctivitis, inflammation of the mucous membranes, nasopharyngitis, pain in the throat and larynx, nasal bleeding, runny nose, flu-like illness, cough, pyrexia, chills, pain, chest pain, pain in extremity, back pain, pain in the bones, lethargy (sleepiness, lethargy, stupor), insomnia, dyspnea, erythema, neuralgia, paresthesia, headache, hypoesthesia.

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

Docetaxel in the scheme AC-TN (see section "Method of administration and dose")

The use of this scheme compared with monotherapy with docetaxel was accompanied by an increase in the incidence of many side effects: alopecia, anemia, including anemia of 3-4 degrees of severity, thrombocytopenia, including thrombocytopenia of 3-4 degrees of severity, nausea including nausea of 3-4 degrees of severity, stomatitis, vomiting, diarrhea, constipation, anorexia, abdominal pain, increased activity ACT, ALT and alkaline phosphatase, myalgia, nail damage, arthralgia, infections of 3-4 degrees of severity, 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.

In addition, insomnia is registered, an increase in the concentration of creatinine in the blood.

Combination of docetaxel with cisplatin or carboplatin

When these chemotherapy regimens were used in comparison with monotherapy with docetaxel,thrombocytopenia, including thrombocytopenia 3-4 degrees of severity (mostly with carboplatin); nausea, including nausea 3-4 degrees of severity; diarrhea 3-4 degrees of severity; anorexia (mostly with cisplatin), including anorexia 3-4 degrees of severity; 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.

In addition, there was fever in the absence of infection, including 3-4 degrees of severity; pain.

Combination of 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 was significantly reduced: anemia, including 3-4 degrees of severity; infections; neutropenia,including those of 3-4 degrees of severity; thrombocytopenia; febrile neutropenia; weakness; allergic reactions; neurosensory and neuromotor reactions; alopecia; rashes; 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 is used in comparison with monotherapy 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; Infection was less common; 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, fever was observed 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 with the use of the drug after its registration

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.

The development of the syndrome of disseminated intravascular coagulation (DVS-syndrome), often in combination with sepsis or multiorgan insufficiency, has been reported.

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 developing during intravenous infusion of the drug.

Disturbances on the part of the organ of sight

Rarely:

Lachrymation combined with conjunctivitis (or without it) and in very rare cases with obstruction of the tear duct, leading to its rupture; cases of transient visual disorders ( "flash of light" 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:

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

Violations from the heart and blood vessels

Rarely:

Venous thromboembolic complications and myocardial infarction.

Disturbances from the respiratory system, chest and mediastinal organs

Rarely:

Acute respiratory distress syndrome, interstitial pneumonia, interstitial lung disease, pulmonary fibrosis, respiratory failure, which could lead to death. 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:

Hepatitis, sometimes fatal, mainly in patients with concomitant liver disease.

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.

The development of similar scleroderma changes was reported, which was usually preceded by peripheral lymphangiectatic edema.In some cases, several factors contributed to the development of these conditions, such as concomitant infections, concomitant medications and concomitant diseases.

General disorders and disorders at the site of administration

Rarely:

The phenomenon of return of local radiation reaction in the previously irradiated area, pulmonary edema.

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.

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 drug can change with the simultaneous use of substances inducing or inhibiting cytochrome P450-3A isoenzymes, or metabolized (competitive inhibition) with cytochrome P450-3A isoenzymes such as ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, care must be taken with the simultaneous administration of such drugs, given the possibility of pronounced interaction.

With the simultaneous use of docetaxel with inhibitors CYP3A4, such as antifungal agents from the group of imidazoles (ketoconazole, itraconazole) 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 way of metabolizing docetaxel is its metabolism with the help of the CYP3A4 isoenzyme. In this case, even with lower doses of docetaxel, its tolerability may be worsened.The pharmacokinetics of docetaxel in the presence of prednisolone has been studied in patients with metastatic prostate cancer. Although docetaxel metabolized by the CYP3A4 isoenzyme, and prednisolone is an inducer of the isoenzyme 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 sodium valproate, do not interfere with the binding of docetaxel with 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

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

In the case of G-CSF administration, patients receiving the drug Docetaxel in combination with cisplatin and fluorouracil, febrile neutropenia and / or neutropenic infections develop less frequently. Therefore, the use of this combination requires the introduction of G-CSF for prophylactic purposes to reduce the risk of complications of 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 the drug Docetaxel 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 TAS 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 the infusion of the drug Docetaxel, therefore at its introduction 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, patients experienced severe hypersensitivity reactions,such as severe lowering of blood pressure, bronchospasm or generalized rash / erythema, and very rarely fatal anaphylactic reactions. The appearance of hypersensitivity reactions requires the immediate cessation of the administration of the drug Docetaxel and appropriate therapy. Patients who have undergone severe hypersensitivity reactions should not resume treatment with the drug Docetaxel.

Patients with hepatic insufficiency

In patients receiving monotherapy with docetaxel at a dose of 100 mg / m² and having an increased activity of "hepatic" transaminases (ALT and / or ACT), more than 1.5 times higher than IGN, in combination with an increase in alkaline phosphatase activity more than 2.5 times higher than IGN, the risk of serious adverse effects such as sepsis, gastrointestinal bleeding, febrile neutropenia, infection is extremely high , thrombocytopenia, severe toxic skin lesions up to a lethal outcome, as well as stomatitis and asthenia. In this regard, in such patients with elevated indicators of functional liver samples, the recommended dose of the drug Docetaxel is 75 mg / m².

Functional liver samples should be performed prior to treatment and before each subsequent cycle of drug therapy Docetaxel.

In patients with elevated bilirubin concentrations and / or increased ALT activity and ACT (> 3.5 UGN) in combination with an increase in the activity of alkaline phosphatase> 6 UGN, dose reduction can not be recommended and should not be used without strict indications docetaxel.

At the moment there are no data on the use of the drug Docetaxel in combination with other drugs in patients with impaired liver 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 the drug Docetaxel with doxorubicin and cyclophosphamide for operable breast cancer, the risk of developing delayed myelodysplasia and / or myeloid leukemia requires hematological monitoring of patients.

Heart failure

Patients who received the drug Docetaxel in combination with trastuzumab for metastatic breast cancer with tumor overexpression HER2, 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 shown treatment with a drug Docetaxel in combination with trastuzumab, she must undergo a cardiac examination before starting therapy. Every three months, heart function should be monitored, which can identify patients who may develop heart failure. For more details, see the instructions for use of trastuzumab.

Disturbances on the part of the organ of sight

Patients treated with docetaxel, as well as other taxanes, reported the development of cystic edema of the macular area. Patients who have visual impairment should undergo urgent and 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 (see "Side effect" section).

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 of age and older who received docetaxel 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.

When using a combination of docetaxel with cisplatin and fluorouracil, the following adverse reactions (all degrees of severity): lethargy (drowsiness, confusion, stupor), stomatitis, neutropenic infection, in patients older than 65 years were ≥10% more likely 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 drug treatment Docetaxel It is necessary to apply reliable methods of contraception. Since in pre-clinical studies it was shown that docetaxel has genotoxic effect and can violate 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 pregnancy during treatment with docetaxel should immediately inform their doctor about this.

Neurotoxicity

The development of severe sensory neuropathy requires a reduction in the dose of the drug Docetaxel.

Ethanol content

In the preparation Docetaxel is contained ethanol. This should be taken into account when using the drug in patients with alcoholism and patients at risk (patients with liver disease and epilepsy).

Treatment and precautions for handling docetaxel

A drug Docetaxel 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 the drug solution Docetaxel or an infusion solution of the drug Docetaxel gets on the skin, it should be washed immediately with water and soap. If a concentrate or infusion solution of the drug is ingested Docetaxel On mucous membranes they should immediately be thoroughly rinsed with water.

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. In this regard, it is not recommended during treatment with the drug Docetaxel drive and engage in other potentially hazardous activities.

Form release / dosage:

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

Packaging:

0.5 ml (20 mg / 0.5 ml) or 2.0 ml (80 mg / 2 ml) of the drug in clear glass bottles (type I, F. USA), closed with stoppers with a butyl rubber septum, sealed with a snap cover.

1.5 ml (for 20 mg / 0.5 ml) or 6.0 ml (for 80 mg / 2 ml) of the solvent for docetaxel in clear glass bottles (type I.F. USA), closed with butyl rubber stoppers, sealed with a snap-in lid.

1 vial with the drug and 1 bottle with the appropriate solvent is placed in a contour mesh package made of PVC. Contour mesh packaging with instructions for use in cardboard pack.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C.

Keep out of the reach of children.

Shelf life:

Concentrate - 2 years, solvent - 3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002710

Date of registration:13.11.2014 / 14.09.2015

Date of cancellation:2019-11-13

The owner of the registration certificate:Rowecq LimitedRowecq Limited United Kingdom

Manufacturer: & nbsp