Docetaxel Sandoz - instructions for use, dose, 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 phase of mitosis and interfacial processes in tumor cells. Docetaxel long time is stored in cells, where its concentration reaches high values. It is active against some, though not all, cells producing in excess P-glycoprotein, which is encoded by the gene of multiple resistance to chemotherapeutic drugs.

Pharmacokinetics:

The kinetics of docetaxel is dose-dependent and corresponds to a three-phase pharmacokinetic model with a half-life (T_1/2) for about 4 minutes, 36 minutes and 11.1 hours, respectively. Link with blood plasma proteins - more than 95%. After a one-hour infusion of docetaxel at a dose of 100 mg / m² mean values of the maximum concentration of docetaxel in the blood 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%.

Within 7 days docetaxel is excreted by the kidneys and intestines after oxidizing the terbutyl ether group with cytochrome P450 (6% and 75% of the administered dose, respectively). Approximately 80% of the drug produced by the intestine is detected within 48 hours as a basic inactive metabolite and 3 less significant inactive metabolites, and in a very small amount - unchanged.

The pharmacokinetics of docetaxel are independent of age and gender patient.

In patients with signs of negligible violations of liver function (activity of alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) is 1.5 times higher than the upper limit of the norm (VGN) in combination with an increase in the activity of alkaline phosphatase> 2.5 VGN), the overall clearance is reduced by 27% compared with the average.

The clearance of docetaxel does not change in patients with mild or moderate fluid retention; information about the clearance of the drug in patients with severe fluid retention is not present.

Indications:

Breast Cancer (BC)

Adjuvant therapy:

- operable breast cancer (drug Docetaxel Sandoz® in combination with doxorubicin and cyclophosphamide);

- operable breast cancer with regional lymph nodes;

- operable breast cancer without lesions of regional lymph nodes in patients who are shown chemotherapy according to established international screening criteria for primary chemotherapy of early stages of breast cancer (with one or more factors of high risk of recurrence: tumor size more than 2 cm, negative status of estrogen and progesterone receptors, high degree of malignancy of the tumor (degree 2-3), age less than 35 years);

- operable breast cancer with tumor overexpression HER2 (doxorubicin and cyclophosphamide followed by use of the preparation Docetaxel Sandoz^® in combination with trastuzumab (scheme AC-TN));

Neoadjuvant therapy:

- operable and locally advanced breast cancer (doxorubicin and cyclophosphamide with the subsequent application of the drug Docetaxel Sandoz^®).

Metastatic and / or locally advanced breast cancer:

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

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

- locally distributed or metastatic breast cancer with ineffectiveness preceding chemorapwhich included anthracyclines or alkylating agents (Docetaxel Sandoz® in monotherapy);

- locally distributed or metastatic breast cancer with ineffectiveness previous chemotherapy, including anthracyclines (drug Docetaxel Sandoz® in combination with capecitabine);

Non-small cell lung cancer (NSCLC)

- inoperable locally advanced or metastatic NSCLC in combination with cisplatin or carboplatin as 1st line therapy;

- locally distributed or metastatic NSCLC in monotherapy as a therapy of the 2nd line with ineffectiveness of previous chemotherapy;

Ovarian Cancer

- metastatic ovarian cancer as a therapy for the 2nd line with inefficiency previous therapy of the 1 st line.

Head and neck cancer

- inoperable locally advanced squamous cell carcinoma of the head and neck (in combination with cisplatin and fluorouracil) as induction therapy.

Prostate Cancer

- metastatic, hormone-resistant cancer prostate (in combination with prednisolone or prednisone).

Stomach cancer

- metastatic stomach cancer, including adenocarcinoma gastroesophageal joint (in combination with cisplatin and fluorouracil), as a therapy for the 1st line.

Contraindications:

- Increased individual sensitivity to docetaxel or other components of the drug;

- neutropenia (initial number of neutrophils in peripheral blood <1500 / μl);

- severe liver dysfunction;

- pregnancy;

- the period of breastfeeding;

- Children under 18 years.

When using the drug Docetaxel Sandoz® in combination with other drugs should also take into account contraindications to their use.

Carefully:

With the simultaneous use of drugs that induce or inhibit isoenzymes cytochrome P450-3A, or metabolized by cytochrome P450-3A isoenzymes, such as ciclosporin, terfenadine, antifungal agents from the group of imidazoles (ketoconazole, itraconazole, voriconazole), erythromycin, troleandomycin, clarithromycin, telithromycin, protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir), as well as nefadozone.

Pregnancy and lactation:

Data on the use of docetaxel in pregnancy are absent. The use of the drug during pregnancy is contraindicated.

Women with a preserved childbearing potential it is necessary to use reliable measures during treatment contraception, in the case of occurrence at them pregnancy during treatment it is necessary to inform on it immediately to the attending physician.

It is not known whether docetaxel with breast milk. Application of the drug Docetaxel Sandoz^® during the period of breastfeeding is contraindicated. Docetaxel has genotoxic effect and can violate male fertility (the ability to conceive). Men of reproductive age during drug therapy Docetaxel Sandoz^® and at least 6 months after the end of treatment should use reliable methods of contraception, before starting treatment should consider preservation of sperm.

Dosing and Administration:

Intravenous infusion (for 1 hour) 1 time in 3 weeks.

To prevent hypersensitivity reactions and to reduce fluid retention, premedication with glucocorticosteroids (SCS), for example, dexamethasone inside at a dose of 16 mg, is administered to all patients (except for patients with prostate cancer - see below) before docetaxel administration, in the absence of contraindications / day (8 mg twice a day) for 3 days, starting one day before docetaxel administration.

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 h before the onset of docetaxel administration.

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

Breast Cancer (BC)

With adjuvant therapy non-metastatic operative breast cancer with regional lymph node involvement and without regional lymph node involvement, the recommended dose of the drug is 75 mg / m² 1 hour after the administration of doxorubicin (50 mg / m²) and cyclophosphamide (500 mg / m²) every 3 weeks. The course of treatment - 6 cycles.

With locally advanced or metastatic breast cancer as a therapy for the 1st line, the dose of docetaxel is 75 mg / m² (administered in combination with doxorubicin (50 mg / m²)); as a second line therapy, the recommended dose of docetaxel in monotherapy is 100 mg / m².

For neoadjuvant therapy patients with operable and locally advanced breast cancer are recommended the following doses of the drug:

- AC (cycles 1-4): 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.

With adjuvant therapy Operable breast cancer with tumor overexpression HER2 the following doses of docetaxel are recommended (chemotherapy according to the AC-TN scheme):

- 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 1 time in 3 pedals, 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 8-15 - trastuzumab 2 mg / kg;

- Three weeks after the day of cycle 1 8 - trastuzumab 6 mg / mL every 3 weeks.

Trastuzumab is administered for a total of 1 year.

For combination with trastuzumab when treating patients with locally advanced or metastatic breast cancer with tumor overexpression of HER2, the recommended dose of docetaxel is 100 mg / m² every 3 weeks with a weekly administration of trastuzumab.

Initial infusion of docetaxel is carried out on the day after the administration first dose of trastuzumab.

Subsequent doses of docetaxel are administered immediately after the end of the infusion of trastuzumab (with good tolerability previous dose of trastuzumab). For the dose of trastuzumab and the route of administration, instructions for use trastuzumab.

When combined with capecitabine (1250 mg / m² inside 2 times a day for 2 weeks followed by a weekly break) the recommended dose of docetaxel is 75 mg / m² every 3 weeks.

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 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 2 nd line of therapy for ovarian cancer, a dose of docetaxel 100 mg / m² every 3 weeks.

Prostate Cancer

The recommended dose of docetaxel is 75 mg / m² 1 time in 3 weeks. Prednisone or prednisolone appoint a long 5 mg orally 2 times a day.

Stomach cancer, including adenocarcinoma of the gastroesophageal junction

To treat stomach cancer, the recommended dose of docetaxel is 75 mg / m² in the form of a 1-hour infusion followed by cisplatin infusion at a dose of 75 mg / m² for 1-3 h (both drugs only on day 1). 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 hydration for the administration of cisplatin. To reduce the risk of hematological toxicity (see dose adjustment), the introduction of a granulocyte colony-stimulating factor (G-CSF) is indicated for prophylactic purposes.

Head and neck cancer

Induction chemotherapy followed by radiotherapy

For induction therapy for locally advanced inoperable squamous cell carcinoma of the head and neck, the recommended dose of docetaxel is 75 mg / m² in the form of a 1-hour infusion with subsequent administration also as a 1-hour infusion of cisplatin (75 mg / m²) on day 1 and subsequent 24-hour continuous infusion of fluorouracil (750 mg / m² ) for 5 days. This pattern is repeated every 3 weeks for 4 cycles. After chemotherapy, patients should receive radiation therapy.

Induction chemotherapy followed by chemoradiotherapy

For induction therapy of locally advanced squamous unresectable head and neck cancer (with a low probability of surgical cure or with organ preservation), the recommended dose of docetaxel is 75 mg / m² in the form of a 1-hour intravenous infusion on the 1st day followed by a 0.5-3 hour infusion of cisplatin (100 mg / m²) and subsequent continuous infusion of fluorouracil (1000 mg / m²) from 1 to 4 days. This treatment regimen is repeated every 3 weeks, the course of treatment - 3 cycles. After chemotherapy, patients should receive chemoradiotherapy.

Patients should receive premedication with antiemetics, they should be given appropriate hydration (before and after cisplatin administration). It is necessary to prevent the development of neutropenic infections with antibiotics.

Correction of dose

General principles

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 worsening with repeated administration of skin reactions, or severe peripheral neuropathy with docetaxel therapy, its dose in the following administrations should be reduced from 100 mg / m² up to 75 mg / m²and / 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.

Adjuvant treatment of breast cancer

Patients with nonmetastatic breast cancer receiving adjuvant therapy with docetaxel in combination with doxorubicin and cyclophosphamide are recommended to administer G-CSF. Patients who developed febrile neutropenia or neutropenic infection in all subsequent cycles should reduce the dose of docetaxel to 60 mg / m². In patients who developed stomatitis 3 or 4 degrees, it is necessary to reduce the dose of docetaxel to 60 mg / m².

With operable and locally advanced breast cancer after an episode of febrile neutropenia or infection with neoadjuvant therapy, the preventive goal is to use G-CSF on all subsequent cycles, and the dose of docetaxel should be reduced from 100 mg / m²up to 75 mg / m².

With operative breast cancer with tumor overexpression HER2 after an episode of febrile neutropenia or infection with neoadjuvant therapy according to the AC VT scheme, 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.

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.

In combination with capecitabine

At the first appearance of grade 2 toxicity, which persists at the beginning of the next docetaxel / capecitabine cycle, the next treatment cycle can be delayed until toxicity is reduced to 0-1 degree, with 100% of the initial dose being injected during the next treatment cycle. In patients with repeated development of grade 2 toxicity or the first development of grade 3 toxicity at any time of the cycle, treatment is delayed until toxicity is reduced to 0-1 degree, then treatment with docetaxel is resumed at a dose of 55 mg / m².

For any subsequent manifestations of toxicity or the appearance of any type of toxicity, grade 4, docetaxel administration should be discontinued.

Recommendations for the correction of doses of capecitabine are given in the instructions for use of the drug.

Docetaxel in combination with cisplatin and fluorouracil

Patients receiving docetaxel 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, episodes of febrile neutropenia, prolonged neutropenia, or neutropenic infection, the dose of docetaxel is reduced from 75 to 60 mg / m². With the subsequent development of episodes of complicated neutropenia, the dose of docetaxel is reduced from 60 mg / m² up to 45 mg / m² . With the development of thrombocytopenia of the 4th degree, the dose of docetaxel is 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. If the toxic effects persist, treatment should be discontinued.

Recommendations for dose adjustment in the development of toxicity in patients receiving docetaxel in combination with cisplatin and fluorouracil (FU)

Toxicity	Correction of the dosing regimen
Diarrhea 3 degrees	The first episode: reduce the dose of FU by 20% Secondary episode: reduce the dose of docetaxel by 20%
Diarrhea 4 degrees	The first episode: reduce doses of docetaxel and FU by 20% Repeat episode: stop treatment
Stomatitis / mucositis 3 degrees	The first episode: reduce the dose of FU by 20% Repeat episode: stop only taking FU in all subsequent courses The third episode: reduce the dose of docetaxel by 20%
Stomatitis / mucositis 4 degrees	The first episode: stop receiving only FU for subsequent cycles Secondary episode: reduce the dose of docetaxel by 20%

Special patient groups

Patients with impaired hepatic function

With the activity of "hepatic" transaminases in the blood plasma, which exceeds the upper limit of the norm (VGN) or alkaline phosphatase exceeding more than 2.5 times the VGN by more than 1.5 times, the recommended dose of the drug Docetaxel Sandoz® is 75 mg / m². In patients with an increase in the concentration of bilirubin and / or activity of "hepatic" transaminases (> 3.5 VGN) in combination with an increase in activity of alkaline phosphatase more than 6 times that of UGN, Docetaxel Sandoz® is not recommended, except for strict indications.

Elderly patients

Special instructions for the use of docetaxel in elderly patients are absent. When combined with capecitabine in patients older than 60 years, a reduction in the starting dose of capecitabine is recommended in accordance with the instruction for the drug.

When combining docetaxel with other antitumor drugs dose (including dose adjustment), the method of application should be selected according to the instructions for the medical use of these drugs.

Preparation of a solution for infusions

Docetaxel Sandoz®,concentrate for the preparation of a solution for infusions, does not require preliminary dilution with a solvent and is already ready for addition to the infusion solution.

If the vials are stored in the refrigerator, the required number of packs of the preparation with concentrate for the preparation of the infusion solution should be kept at room temperature (not higher than 25 ° C) for 5 minutes before use for the preparation of the infusion solution.

The required volume of docetaxel concentrate for the preparation of the infusion solution, 10 mg / ml, is extracted from the vials according to the required dose in aseptic conditions using a single graduated syringe connected to the needle and inserted into an infusion bag or a 5% dextrose solution bottle or 0 , 9% solution of sodium chloride to a docetaxel concentration of not more than 0.74 mg / ml (the administration is carried out by a single injection into the infusion container of the entire required dose). The resulting infusion solution should be mixed by slowly turning the infusion bag or vial. The resulting solution should be used for 4 hours (including a 1-hour infusion) at room temperature and normal light conditions.

The infusion solution must be inspected before administration; In the presence of sediment, the solution should be destroyed.

Side effects:

According to the World Health Organization (WHO), undesirable effects are classified according to their frequency of development as follows: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, < 1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown (the frequency of occurrence of phenomena can not be determined on the basis of available data).

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

On the part of the blood and lymphatic system

Often: reversible neutropenia on average after 7 days (in patients who received previous chemotherapy, this period may be shorter), the average duration of severe neutropenia (less than 500 cells / μl) is 7 days; febrile neutropenia, anemia, thrombocytopenia, infections;

often: severe infections, combined with a decrease in the number of neutrophils in peripheral blood less than 500 / μL; Serious infections, including sepsis and pneumonia, incl. with lethal outcome; Thrombocytopenia less than 100,000 / μL, bleeding combined with thrombocytopenia of less than 50,000 / μL and anemia (hemoglobin concentration less than 11 g / dL), incl. severe (hemoglobin concentration less than 8 g / dL);

infrequently: severe thrombocytopenia;

frequency is unknown: oppression of bone marrow hematopoiesis and other hematological adverse reactions; the development of disseminated intravascular coagulation (DIC), often in association with sepsis and multiorgan failure.

From the immune system

Often: Allergic reactions usually occur within a few minutes after the start of infusion ( "tides" of blood to the face, rash combined with itching and without it, the feeling of chest tightness, 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;

frequency is unknown: anaphylactic shock, sometimes fatal (in patients who received premedication, these cases ended in a lethal outcome very rarely).

From the skin and subcutaneous tissue

Often: reversible skin reactions are usually mild or moderately expressed: a localized rash, mainly on the hands and feet, as well as on the face and chest, which are often accompanied by itching,rashes usually occurred within one week after docetaxel infusion; disorders from the nails are characterized by hypo- and hyperpigmentation, pain and onycholysis; alopecia;

often: severe skin reactions, incl. a rash followed by desquamation, including severe palpitation and stop syndrome, which may require interruption or discontinuation of docetaxel treatment;

infrequently: severe alopecia;

rarely: cutaneous lupus erythematosus, bullous rash, 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), scleroderma-like changes , which is preceded by lymphangiectatic edema.

From the side of water-electrolyte exchange

Often: fluid retention;

often: severe fluid retention. It was reported on the development of peripheral edema and less often about pleural and pericardial efflux, ascites and weight gain.The frequency and severity of fluid retention increases with repeated administration of docetaxel;

frequency is unknown: reported cases of development of hyponatremia, mainly in combination with dehydration, vomiting and pneumonia.

From the gastrointestinal tract

Often: nausea, vomiting, diarrhea, anorexia, stomatitis, impaired taste;

often: severe nausea and vomiting, severe diarrhea, constipation, severe stomatitis, esophagitis, epigastric pain (including pronounced), gastrointestinal bleeding;

infrequently: severe gastrointestinal bleeding, severe constipation and esophagitis, marked taste disorders;

rarely: dehydration as a consequence of reactions from the gastrointestinal tract, perforation of the stomach or bowel, colitis, including ischemic, neutropenic enterocolitis, ileus (intestinal obstruction), intestinal obstruction.

From the liver and biliary tract

often: increased serum activity ACT, ALT, alkaline phosphatase and bilirubin concentration in the blood (more than 2.5 times higher than UGN);

rarely: hepatitis (death was observed in patients with a history of liver disease).

From the nervous system

Often: mild to moderate neurosensory reactions: paresthesia, dysesthesia, pain, including burning sensation; and neuromotor reactions, mainly manifested by muscle weakness; often: severe neurosensory reactions and neuromotor reactions; rarely: convulsions, transient loss of consciousness, sometimes developing during the infusion of the drug.

From the side of the cardiovascular system

often: arrhythmia, increase or decrease in blood pressure; bleeding;

infrequently: heart failure;

rarely: there were rarely cases of venous thromboembolism and myocardial infarction.

From the side of the organ of vision

rarely: lacrimation in conjunction with conjunctivitis (or without it), transient visual disorders (flashes of light in the eyes, the appearance of cattle), usually occurring during the administration of the drug and combined with the development of hypersensitivity reactions that usually disappear after cessation of infusion;

rarely: occlusion of the lacrimal canal, leading to excessive lacrimation.

From the side of the hearing organ and labyrinthine disorders

rarely: ototoxic effect of the drug, hearing impairment and / or hearing loss.

On the part of the respiratory system, the organs of the thorax and the mediastinum

Often: dyspnea;

often: severe shortness of breath;

rarely: acute respiratory distress syndrome, interstitial pneumonia / pneumonitis, interstitial lung disease, respiratory failure, which could be fatal; at a simultaneous carrying out of irradiation there were rare cases of radiation pulmonitis; pulmonary fibrosis, pulmonary edema;

From the musculoskeletal system

Often: myalgia;

often: arthralgia.

General disorders and reactions at the site of administration

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

often: reactions at the injection site, usually mild: hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, bleeding from the punctured vein or vein edema; sharply expressed generalized and localized pain syndrome, including pain in the chest of non-cardial genesis.

Other

rarely: acute myeloid leukemia and myelodysplastic syndrome, macular edema, the phenomenon of local radiation reaction return in the previously irradiated area, impaired renal function, development of renal failure, in most cases associated with concomitant use of nephrotoxic drugs.

Docetaxel Sandoz® in combination with other drugs Docetaxel Sandoz® in combination with doxorubicin

When using the drug Docetaxel Sandoz® in combination with doxorubicin compared with monotherapy with the drug Docetaxel Sandoz® showed a high incidence of neutropenia, including severe neutropenia; 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 hepatic transaminases, alkaline phosphatase, bilirubin in the blood; myalgia; asthenia.

Sandoz® docetaxel in combination with doxorubicin and cyclophosphamide (TAC circuit)

When this chemotherapeutic regimen is used in comparison with monotherapy with the drug Docetaxel Sandoz® observed 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 disturbance, constipation, fatigue, arthralgia, alopecia, colitis, enterocolitis, myelodysplastic syndrome.

Further observed: perforation of the colon without deaths, acute myeloid leukemia, acute leukemia. Prophylactic G-CSF reduced incidence of neutropenia (60%) and neutropenic infections 3-4 degrees.

Doxorubicin and cyclophosphamide) with the subsequent application of the drug Docetaxel Sandoz® in combination with trastuzumab (scheme AC-TN)

When these chemotherapy regimens are used in comparison with monotherapy with the drug Docetaxel Sandoz® more often there was an alopecia; Anemia, including anemia of 3-4 degrees of severity; thrombocytopenia, including thrombocytopenia 3-4 degrees of severity; nausea, including nausea 3-4 degrees of severity; stomatitis; vomiting; diarrhea; constipation; anorexia; stomach ache; increased activity ACT, ALT and alkaline phosphatase; myalgia; defeat of nails; arthralgia; infections of 3-4 degrees of severity; heart failure.

There was no increase in febrile neutropenia.

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

Insomnia, increased concentration of creatinine in the blood.

Docetaxel Sandoz® in combination with capecitabine

When using the drug Docetaxel Sandoz ® in combination with capecitabine, there is a more frequent development of adverse events from the gastrointestinal tract (stomatitis, diarrhea, vomiting, constipation, abdominal pain, taste disorders); arthralgia; heavythrombocytopenia 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, changes in the color of the nails, including onycholysis, dyspnea, paresthesia, dehydration, lacrimation; asthenia; myalgia; decreased appetite and anorexia.

In addition, dyspepsia, dry mouth, sore throat, oral candidiasis, dermatitis, erythematous rash, pyrexia, pain in the extremities, back pain, lethargy (drowsiness, inhibition, stupor), cough, nosebleeds, dizziness, headache, peripheral neuropathy, weight loss.

Compared with younger patients, patients 60 years of age or older who received a combination of the drug Docetaxel Sandoz® with capecitabine, the development of toxicity of 3-4 degrees of severity is more often noted.

Docetaxel Sandoz® in combination with trastuzumab

Patients receiving a combination of the drug Docetaxel Sandoz^®with trastuzumab (in comparison with monotherapy with drug Docetaxel Sandoz®), 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, especially in patients previously treated with anthracyclines as adjuvant therapy, but less often observed neutropenia 3-4 degrees of severity, asthenia, weakness, alopecia, nail damage, skin rashes, vomiting, stomatitis and myalgia. Additionally observed: lacrimation, conjunctivitis, pain, dyspnea, paresthesia, inflammation of the mucous membranes, nasopharyngitis, pain in the pharynx and larynx, epistaxis, rhinorrhea, influenza-like diseases, cough, pyrexia, chills, chest pain, pain in the extremities, pain in the back, bone pain, lethargy (drowsiness, inhibition, stupor), insomnia, erythema, indigestion, headache, hypoesthesia.

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

Combination of the drug Docetaxel Sandoz® with cisplatin or carboplatin

When these chemotherapy regimens are used in comparison with monotherapy with the drug Docetaxel Sandoz® often caused thrombocytopenia, including thrombocytopenia 3-4 degrees of severity; 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 diarrhea 3-4 degrees of severity; reaction at the site of administration. However, less frequent neutropenia, including neutropenia of 3-4 degrees of severity; infection; febrile neutropenia; allergic reactions; skin reactions; defeat of nails; fluid retention, including fluid retention of 3-4 degrees of severity; 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 of the drug Docetaxel Sandoz® with prednisolone or prednisone

When using the drug Docetaxel Sandoz® in combination with prednisolone or prednisone in comparison with monotherapy with drug Docetaxel Sandoz® significantly reduced the incidence of side effects: anemia, including 3-4 degrees of severity; infections; neutropenia, including 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 was a taste disorder and heart failure.

Additionally observed: epistaxis, cough, weakness, lacrimation.

Combination of the drug Docetaxel Sandoz® with cisplatin and fluorouracil

When this combination is used in comparison with monotherapy with the drug Docetaxel Sandoz® was more likely to have anemia, 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; rhythm disturbances.

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; decrease in body weight.The prophylactic use of G-CSF reduces the incidence of febrile neutropenia and / or neutropenic infectious complications.

Overdose:

Symptoms: oppression of bone marrow functions, peripheral neuropathy and inflammation of the mucous membranes.

Treatment: hospitalization of the patient, careful monitoring of the functions of vital organs, preventive use of G-CSF, symptomatic therapy. The antidote to docetaxel is currently unknown.

Interaction:

Research in vitro showed that the biotransformation of the drug can change with the simultaneous use of other drugs that induce, inhibit or metabolize the cytochrome isoenzyme CYP3A, such as ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, care must be taken when using such drugs at the same time, given the possibility of pronounced interaction.

With simultaneous application docetaxel with isozyme inhibitors CYP3A4 may increase the risk of developing it adverse reactions. When Mr.the need for simultaneous use of docetaxel with strong inhibitors of isoenzyme CYP3A4 (ketoconazole, itraconazole, clarithromycin, indinavir, nefadozone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), care should be taken, correction of docetaxel dose is required.

Studies conducted in patients who simultaneously received docetaxel and ketoconazole, showed that the clearance of docetaxel decreased by 49%, apparently due to the fact that the main pathway of docetaxel metabolism is its isoenzyme metabolism CYP3A4. In this case, even with lower doses of docetaxel, its tolerability may be worsened.

In vitro drugs that bind strongly to plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole and valproic acid, did not affect 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 relationship with plasma proteins digitoxin. The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide did not change with their combined use.

The pharmacokinetics of docetaxel in the presence of prednisone has been studied in patients with metastatic prostate cancer, despite the fact that docetaxel is metabolized by isoenzyme CYP3A4, a prednisone is an isoenzyme inducer CYP3A4, there was no statistically significant effect of prednisone on the pharmacokinetics of docetaxel.

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:

Treatment with drug Docetaxel Sandoz® is performed only under the supervision of a doctor who has experience in the use of antitumor drugs in a specialized hospital.

Neutropenia

Periodic monitoring of the general blood test should be carried out. With the development of severe neutropenia (the number of neutrophils less than 500 / μL for 7 days or more) during the course of therapy with the drug Docetaxel Sandoz® is recommended to reduce the dose of the drug (see Dosage and Administration) in subsequent courses or use adequate symptomatic measures.Continue drug treatment Docetaxel Sandoz® is possible after restoring the number of neutrophils to 1500 / μL.

In the case of G-CSF production, patients receiving docetaxel in combination with cisplatin and fluorouracil, febrile neutropenia and / or neutropenic infections develop less frequently. Therefore, when this combination is used, the use of G-CSF should be prophylactically used 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.

Hypersensitivity reactions

In order 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 minutes of the drug infusion. Hypersensitivity manifestations, such as facial flushing or localized skin reactions, do not require an interruption in the administration of the drug. Severe hypersensitivity reactions (lowering blood pressure,bronchospasm or generalized rash / erythema) require immediate withdrawal of the drug Docetaxel Sandoz® and the adoption of appropriate treatment activities. Repeated use of the drug Docetaxel Sandoz® in these patients is not allowed.

Patients with hepatic insufficiency

In patients receiving monotherapy with docetaxel at a dose of 100 mg / m² and with a high activity of "hepatic" transaminases more than 1.5 times that of HHV, in combination with an increase in activity of alkaline phosphatase more than 2.5 times higher than UGN, there is an extremely high risk of developing serious side effects such as sepsis, intestinal bleeding, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. In this regard, functional tests of the liver should be determined before the start of therapy and before each subsequent cycle of therapy with the drug Docetaxel Sandoz®. In patients with elevated bilirubin concentration and / or hepatic transaminase activity (> 3.5 VGN) in combination with an increase in alkaline phosphatase activity more than 6 times that of UHN, the drug Docetaxel Sandoz® is not recommended.

There is currently no data on the use of docetaxel in combination with other drugs in patients with impaired hepatic function.

Fluid retention

In connection with the possibility of fluid retention, careful monitoring of patients with effusion to the pleural cavity, pericardium or having ascites is necessary. When swelling appears, the salt and drinking regimen should be limited and diuretics should be prescribed.

Defeat of the respiratory system

There have been reports of cases of development of acute respiratory distress syndrome, interstitial pneumonia / pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure, including fatal. When concomitant radiotherapy also reported cases of radiation radiation pneumonitis.

When new or worsening of existing symptoms on the part of the respiratory system patients should be under the careful supervision of a physician, symptomatic therapy is indicated. Treatment with docetaxel should be suspended until the diagnosis is clarified. The question of the resumption of treatment with docetaxel should be resolved, based on a thorough evaluation of the benefits of such treatment.

Leukemia

When using a combination of the drug Docetaxel Sandoz® with doxorubicin and cyclophosphamide for non-metastatic surgical breast cancer, the risk of developing delayed myelodysplasia and / or myeloid leukemia requires hematological monitoring of patients.

Heart failure

During treatment with docetaxel and the follow-up period of observation, it is necessary to monitor the manifestations of symptoms chronic heart insufficiency (CHF). A higher risk of CHF in patients with breast cancer with lymph node involvement, receiving chemotherapy under the TAC scheme, is observed in the first year after completion of treatment.

In patients who received Docetaxel Sandoz® 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, it can be of medium severity or severe and lead to death. When a patient is shown treatment with a drug Docetaxel Sandoz® in combination with trastuzumab, it must undergo an initial cardiac examination.Every three months, heart function should be monitored, which can identify patients who may develop heart failure.

Disturbances on the part of the organ of sight

The development of macular edema in patients taking docetaxel. If a visual impairment occurs, patients should undergo a complete ophthalmological examination. In case of diagnosis of macular edema, the drug should be discontinued.

The need for contraception

Since in pre-clinical studies it was shown that docetaxel has genotoxic effect and can violate male fertility (the ability to conceive), men who are treated with docetaxel, it is recommended to refrain from conception of the child during treatment 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 their pregnancy during treatment should immediately inform their doctor about this.

During and for at least 6 months after discontinuing therapy for patients of both sexes, reliable methods of contraception should be used.

Neurotoxicity

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

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 unwanted adverse reactions (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 or older who received treatment every 3 weeks for prostate cancer, the incidence of nail changes was ≥10% higher than in younger patients, in patients 75 years of age and older, the incidence of fever, diarrhea, anorexia and peripheral edema was ≥ 10% higher than in younger patients.

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

Ethanol content

In the preparation Docetaxel Sandoz® is contained ethanol in a concentration of 27 volume% (10 mg / ml contains 0.28 g of ethanol in terms of the basic substance). This should be taken into account when using the drug in patients with alcoholism and patients at risk (patients with liver disease and epilepsy).

Appeal and measures precautions when handling the drug

When using and preparing solutions of the drug Docetaxel Sandoz® should be used with caution. It is recommended to use gloves. If the concentrate or infusion solution hits the skin, then immediately wash it thoroughly with soap and water. If ingested, mucous membranes should be rinsed immediately with water.

Special precautions for the destruction of unused medications

Remains of the preparation, all instruments and materials used to prepare solutions for intravascular and intravesical administration Docetaxel Sandoz®, must be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulations on the destruction of hazardous waste.

Effect on the ability to drive transp. cf. and fur:The drug is used in a hospital. Special studies were not conducted. However, the development of adverse reactions from the nervous system and the organ of vision, as well as the presence of ethanol in the formulation may lead to a decrease in the rate of psychomotor reactions and attention. In this regard, it is not recommended during treatment with the drug Docetaxel Sandoz® to drive a car and engage in other potentially hazardous activities.

Form release / dosage:

Concentrate for solution for infusion, 10 mg / ml.

Packaging:

By 2 ml, 8 ml or 16 ml in a bottle of colorless glass type I (Hept. F.), sealed with a rubber stopper, crimped aluminum cover with a plastic hinged cap.

For 1, 5 or 10 bottles of 2 ml, 1, 5 or 10 bottles of 8 ml, 1, 5 or 10 bottles of 16 ml, along with instructions for medical use, are placed in a cardboard pack.

A bottle with a solvent is not included in the package.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002825

Date of registration:15.01.2015

Date of cancellation:2020-01-15

The owner of the registration certificate:Sandoz S.A.Sandoz S.A. Argentina

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp23.01.2016

Illustrated instructions

Instructions

Docetaxel Sandoz® (Docetaxel Sandoz®)