Docetaxel Sandoz conc. 10 mg/ml 8 ml flak.1sht.

antineoplastic agent – an alkaloid

Active substance:
Docetaxel

Manufacturer

Ebewe Pharma, Austria

Composition

The concentrate for solution for infusion into a clear liquid, from colorless to pale yellow.

1 ml docetaxel (anhydrous) 10 mg

Excipients: Polysorbate 80 – 80 mg Macrogol 300 – 648 mg anhydrous citric acid – 4 mg, 96% ethanol – 275.9 mg

.

Indications

Breast cancer (BC)

Adjuvant therapy:

– operable breast cancer (Sandoz® drug docetaxel in combination with doxorubicin and cyclophosphamide);

– operable breast cancer with a lesion of regional lymph nodes;

– operable breast cancer without lymph node metastases in patients who have shown chemotherapy according to established international criteria for selection for primary chemotherapy early stages of breast cancer (in the presence of one or more high-risk relapse factors: a 2 cm tumor size, negative status of estrogen and progesterone receptor, high tumor grade (grade 2-3), age less than 35 years);

– with operable breast cancer tumor overexpressing HER2 (doxorubicin and cyclophosphamide followed by application Sandoz® drug docetaxel in combination with trastuzumab (AU-VT scheme));

Neoadjuvant therapy:

– operable and locally advanced breast cancer (doxorubicin and cyclophosphamide followed by application of the drug docetaxel Sandoz®)

.

Metastatic and / or locally advanced breast cancer:

– locally advanced or metastatic breast cancer (Sandoz® drug docetaxel in combination with doxorubicin therapy 1st line);

– breast cancer with metastatic tumor overexpressing HER2 (Sandoz® drug docetaxel in combination with trastuzumab therapy 1st line);

– locally advanced or metastatic breast cancer after failure of prior chemotherapy that included alkylating agents or anthracyclines (Preparation Sandoz® docetaxel monotherapy);

– locally advanced or metastatic breast cancer after failure of prior chemotherapy that included anthracyclines (Sandoz® drug docetaxel in combination with capecitabine);

Non-small cell lung cancer (NSCLC)

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

– locally advanced or metastatic NSCLC in monotherapy as a treatment 2nd line after failure of prior chemotherapy;

Ovarian Cancer

– metastatic ovarian cancer therapy as 2nd line therapy after failure of prior 1st 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-refractory prostate cancer (in combination with prednisone or prednisolone)

.

Stomach Cancer

– metastatic stomach cancer including adenocarcinoma gastroesophageal compound (in combination with cisplatin and fluorouracil), as a therapy 1st line

.

Contraindications

Increased individual sensitivity to docetaxel or other ingredients;

– neutropenia (baseline neutrophil counts in peripheral blood < 1500 / L);

– The expressed disturbances of liver function;

– pregnancy;

– the period of breast-feeding;

– Children under 18 years old

.

When applied Sandoz® drug docetaxel in combination with other drugs should also consider the contraindications for their use.

Caution:

With simultaneous use of drugs that induce or inhibit cytochrome isoenzymes R450-3A, ilimetaboliziruyuschihsya via cytochrome isoenzymes R450-3A such as cyclosporine, terfenadine, antifungals of the imidazoles group (ketoconazole, itraconazole, voriconazole), erythromycin, troleandomycin, clarithromycin , telithromycin, protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir) and nefadozon.

Side effects

According to the World Health Organization (WHO), undesirable effects are classified according to their rate of development as follows: very common (≥1 / 10), commonly (≥1 / 100,

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

From the blood and lymphatic system

very often: reversible neutropenia after an average of 7 days (in patients previously treated with chemotherapy, this period may be shorter), the average duration of significant neutropenia (less than 500 cells / l) – 7 days; febrile neutropenia, anemia, thrombocytopenia, infection;

often: severe infections, combined with a reduction in the number of neutrophils in the peripheral blood of less than 500 cells / mm; severe infections, including sepsis and pneumonia, including fatal; thrombocytopenia less than 100000 / l, bleeding, thrombocytopenia combined with less than 50,000 / microliter, and anemia (hemoglobin concentration is less than 11 g / dl), including: heavy (hemoglobin concentration is less than 8 g / dl);

rare: severe thrombocytopenia;

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

From the

immune system

Very common: 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 receiving premedication, these cases are fatal rarely)

.

Skin and subcutaneous tissue

very often: reversible skin reactions are usually mild or moderate: a localized rash, mainly on the hands and feet, as well as on the face and chest, often accompanied by itching, rash usually occurred within one week after the infusion of docetaxel; disorders of the nail characterized by hypo- and hyperpigmentation, pain and onycholysis; alopecia;

often: severe skin reactions, including rash with subsequent desquamation, including heavy defeats syndrome the palms and soles, which may require interruption or discontinuation of docetaxel treatment;

rare: severe alopecia;

very rare: cutaneous lupus erythematosus, bullous eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (in some cases, to the development of these states contributed by several factors, such as opportunistic infections, at the same time to take other drugs and related disease), scleroderma such changes preceded limfangiektatichesky swelling.

From the water-electrolyte metabolism

very often: fluid retention;

often: severe fluid retention. Reported on the development of peripheral edema and less frequently on pleural and pericardial effusion, ascites and weight gain. The frequency and severity of water retention increase with repeated administration of docetaxel;

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

.

On the part of the gastrointestinal tract

Very common: nausea, vomiting, diarrhea, anorexia, stomatitis, taste disturbance;

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

rare: severe gastrointestinal bleeding, constipation and severe esophagitis, expressed taste disturbances;

Rare: 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

.

On the part of the liver and biliary tract

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

very rare: hepatitis (fatal outcome was observed in patients with a history of liver disease)

.

From the

Nervous System

Very common: mild to moderate neurosensory response: paresthesia, dysesthesia, pain including burning sensation; and neuromotor response is mainly manifested by muscle weakness; common: severe neurosensory and neuromotor response reaction; rare: seizures, transient loss of consciousness, sometimes develops during infusion dosing

.

From the cardiovascular system

common: arrhythmias, increased or decreased blood pressure; bleeding;

Uncommon: heart failure;

rarely rarely been cases of venous thromboembolism and myocardial infarction

.

From a sight organ

rarely tearing combined with conjunctivitis (or without it), transient visual disturbances (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, which usually disappear after discontinuation of the infusion < / p>

very rare: lacrimal occlusion, resulting in excessive tearing

.

On the part of the organ of hearing and labyrinth disorders

rare: ototoxic effects of the drug, impaired hearing and / or hearing loss

.

The respiratory system, thorax and mediastinum

very common: shortness of breath;

often: severe shortness of breath;

rarely, acute respiratory distress syndrome, interstitial pneumonia / pneumonitis, interstitial lung disease, respiratory distress, which may lead to death; while conducting irradiation are rare cases of radiation pneumonitis; pulmonary fibrosis, pulmonary edema;

From the

Musculoskeletal System

Very common: myalgia;

common: arthralgia

.

General disorders and reactions at the injection site

very common: asthenia, including heavy; generalized and localized pain, including chest pain noncardia origin;

often: reaction injection site, usually mild: hyperpigmentation, inflammation, redness and dryness, phlebitis, hemorrhage from the punctured vein or vein swelling; pronounced generalized and localized pain, including chest pain noncardia genesis.

Other

very rarely, acute myeloid leukemia and myelodysplastic syndrome, macular edema, local phenomenon of return radiation reaction in previously irradiated area, deteriorating renal function, renal failure, in most cases associated with concurrent use of nephrotoxic drugs

.

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

When applied Sandoz® drug docetaxel in combination with doxorubicin as compared to a monotherapy drug docetaxel Sandoz® observed high frequency of neutropenia, including severe neutropenia; febrile neutropenia; Thrombocytopenia, including severe thrombocytopenia; anemia; infections, including serious 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; nail infections, including severe; fluid retention, including the heavy; anorexia, neurosensory and neuromotor reactions, including severe forms; hypotension; arrhythmias; increase in liver transaminases, alkaline phosphatase, bilirubin in the blood; myalgia; asthenia.

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

When applying this scheme chemotherapy compared to a monotherapy 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 observed a higher rate of non-severe anemia, thrombocytopenia, nausea, vomiting, stomatitis, taste disturbance, constipation, fatigue, arthralgia, alopecia, colitis, enterocolitis, myelodysplastic syndrome.

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

doxorubicin and cyclophosphamide) followed by application Sandoz® drug docetaxel in combination with trastuzumab (AU-VT scheme)

When using these regimens, compared to a monotherapy drug docetaxel Sandoz® often arose alopecia; anemia, including anemia Grade 3-4; thrombocytopenia including thrombocytopenia Grade 3-4; nausea, including nausea Grade 3-4; stomatitis; vomiting; diarrhea; constipation; anorexia; stomach ache; increasing the activity of ACT, ALT, and alkaline phosphatase; myalgia; nail infections; arthralgia; Grade 3-4 infections; heart failure.

There was no increase in febrile neutropenia.

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

In addition, registered insomnia, elevated serum creatinine concentration in the blood.

Sandoz® Docetaxel in combination with capecitabine

When using the drug docetaxel Sandoz® in combination with capecitabine, there is a more frequent development of adverse effects on the gastrointestinal tract (stomatitis, diarrhea, vomiting, constipation, abdominal pain, taste dysfunction); arthralgia; severe thrombocytopenia, and anemia; hyperbilirubinemia; hand-foot syndrome (dermahemia limbs (hands and feet), followed by edema and desquamation); but more rare development of severe neutropenia; alopecia; violations of the nail polish color change, including onycholysis, dyspnea, paresthesia, dehydration, watery eyes; asthenia; myalgia; loss of appetite and anorexia.

Additionally observed dyspepsia, dry mouth, sore throat, oral candidiasis, dermatitis, erythematous rash, pyrexia, pain in extremity, back pain, lethargy (sleepiness, lethargy, stupor), cough, nosebleeds, dizziness, headache, peripheral neuropathy, decrease in body weight.

As compared with patients younger patients 60 years and older who received a combination of the drug docetaxel with capecitabine Sandoz®, often marked the development of Grade 3-4 toxicity.

Sandoz® Docetaxel in combination with trastuzumab

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

As compared with docetaxel was observed increase in the incidence of severe adverse reactions.

The combination of the drug docetaxel Sandoz® with cisplatin or carboplatin

When using these regimens, compared to a monotherapy drug docetaxel Sandoz® often arose thrombocytopenia, including Grade 3-4 thrombocytopenia; anemia, including anemia Grade 3-4; nausea, including nausea Grade 3-4; Grade 3-4 diarrhea; anorexia, including diarrhea Grade 3-4; reactions at the injection site. However, less neutropenia were observed, including neutropenia Grade 3-4; infection; febrile neutropenia; allergic reactions; skin reactions; nail infections; fluid retention, fluid retention including Grade 3-4; disease, neurosensory, and neuromotor less neuropathy; alopecia; asthenia, and myalgia.

In addition, observed: Fever in the absence of infection, including Grade 3-4; the pain.

The combination of the drug docetaxel Sandoz® with prednisolone or prednisone

When applied Sandoz® drug docetaxel in combination with prednisone or prednisolone versus monotherapy with a drug Sandoz® docetaxel significantly reduced the incidence of side effects: anemia, including Grade 3-4; infections; neutropenia, including Grade 3-4; thrombocytopenia; febrile neutropenia; weakness; allergic reactions; neurosensory, and neuromotor responses; alopecia; rash; desquamation; nausea; diarrhea; stomatitis; vomiting; anorexia; myalgia; arthralgia; fluid retention; but more common taste disturbance and heart failure.

In addition, observed: nosebleeds, cough, weakness, tearing

.

The combination of the drug docetaxel Sandoz® with cisplatin and fluorouracil

When using this combination compared to monotherapy with the drug docetaxel Sandoz® often observed anemia, including Grade 3-4; thrombocytopenia, including Grade 3-4; febrile neutropenia; neutropenic infection (even when using G-CSF); nausea; vomiting; anorexia; stomatitis; diarrhea; esophagitis / dysphagia / pain when swallowing; but less frequently observed infections; allergic reactions; fluid retention; neurosensory, and neuromotor responses; myalgia; alopecia; rash; itching; nail infections; skin desquamation; rhythm disorders.

In addition, fever were observed in the absence of infection; lethargy (drowsiness, lethargy, stupor); changes in hearing; dizziness; watery eyes; dry skin; heartburn; myocardial ischemia; underlined venous pattern; cancer pain; weight loss. Prophylactic G-CSF reduces the incidence of febrile neutropenia and / or neutropenic infection.

How to accept, acceptance rate and dosage

Intravenous infusion (within 1 hr) 1 every 3 weeks.

To prevent hypersensitivity reactions as well as to reduce fluid retention, all patients (with the exception of patients with prostate cancer – see below.) Prior to administration of the docetaxel in the absence of contraindications carried premedication glucocorticosteroids (GCS), e.g., dexamethasone inwardly dose of 16 mg / day (8 mg 2 times a day) for 3 days starting one day prior to docetaxel administration.

in patients with prostate cancer receiving concomitant treatment with prednisone or prednisolone, dexamethasone premedication is conducted at a dose of 8 mg in 12, 3 and 1 hour prior to docetaxel administration.

recommended prophylactic administration of granulocyte colony-stimulating factor to reduce the risk of hematological complications (G-CSF).

Breast cancer (BC)

When adjuvant therapy of operable breast cancer, non-metastatic lesion with and without lymph node metastases in regional lymph nodes lesion recommended dose of 75 mg / m2 after 1 h after the administration of Doxorubicin (50 mg / m2) and cyclophosphamide (500 mg / m 2) every 3 weeks. The course of treatment – 6 cycles

.

In locally advanced or metastatic breast cancer as a therapy 1st line docetaxel dose – 75 mg / m2 (administered in combination with doxorubicin (50 mg / m2)); as therapy 2nd line recommended dose of docetaxel monotherapy – 100 mg / m2

.

To neoadjuvant therapy in patients with resectable and locally advanced breast cancer are recommended the following doses:

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

– T (cycles 5-8): docetaxel (T) 100 mg / m2 1 every 3 weeks for 4 cycles

.

When adjuvant therapy of operable breast cancer with a tumor overexpressing HER2 below recommended doses of docetaxel (chemotherapy according to the scheme SS-VT):

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

– VT (cycles 5-8): docetaxel (T) 100 mg / m2 once every one pedal action 3, 4 cycle and trastuzumab (H) administered weekly in accordance with the following scheme:

• 5 cycle (starting 3 weeks after the last cycle AC): 1 day – 4 mg trastuzumab / kg (loading dose); Day 2 docetaxel 100 mg / m2; 8 and day 15: Trastuzumab 2 mg / kg;
• Cycles 6-8: Day 1 – 100 mg docetaxel / m2 Trastuzumab 2 mg / kg; Day 8-15 – trastuzumab 2 mg / kg;

– three weeks after Day 1 of cycle 8 – trastuzumab 6 mg / mL every 3 weeks
.
 

Trastuzumab is administered in a total of over 1 year.

For combination with trastuzumab in the treatment of patients with locally advanced or metastatic breast cancer with a tumor overexpressing HER2 recommended dose of docetaxel – 100 mg / m2 every 3 weeks with weekly trastuzumab

.

The initial infusion of docetaxel is held the day after the first dose of trastuzumab.

Subsequent doses are administered immediately after the docetaxel infusion trastuzumab closure (trastuzumab perenosimostipredshestvuyuschey with good dose). With regard to trastuzumab dose and route of administration – see primeneniyutrastuzumaba instructions

..

In combination with capecitabine (1250 mg / m2 orally 2 times daily for 2 weeks followed by one week apart), the recommended dose of docetaxel – 75 mg / m2 every 3 weeks

.

Non-small cell lung cancer

In patients not previously treated with chemotherapy, the recommended regimen: docetaxel 75 mg / m2, immediately after the administration of cisplatin (75 mg / m2 for 30-60 min) or carboplatin (AUC 6 mg / ml / min 30-60 minutes).

For the treatment ineffective after platinum-based chemotherapy, docetaxel monotherapy recommended dose of 75 mg / m2.

Metastatic ovarian cancer

In the 2nd line therapy of ovarian cancer is recommended docetaxel dose is 100 mg / m2 every 3 weeks.

Prostate cancer

The recommended dose of docetaxel -75 mg / 1 m2 every 3 weeks. Prednisone or prednisolone administered long by 5 mg orally two times a day.

Gastric cancer, including

adenocarcinoma of the gastroesophageal connection

For the treatment of gastric cancer the recommended dose of docetaxel – 75 mg / m2 as a 1-hour infusion, followed by infusion of cisplatin at a dose of 75 mg / m2 (only 1 day both drugs) for 1-3 hours. Upon completion of cisplatin carried out 24-hour infusion of fluorouracil 750 mg / m2 / day for 5 days. Treatment is repeated every 3 weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration. To reduce the risk of hematological toxicities (see. The dose correction) shown prophylactic administration of granulocyte colony stimulating factor (G-CSF).

Head and Neck Cancer

Induction chemotherapy followed by radiotherapy

For induction therapy in locally advanced unresectable squamous head and neck cancer the recommended dose of docetaxel – 75 mg / m2 as a 1-hour infusion, followed by administration as a 1 hour infusion of cisplatin (75 mg / m2) in 1- day and subsequent 24-hour continuous infusion of fluorouracil (750 mg / m2) for 5 days. This pattern is repeated every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.

Induction chemotherapy followed by chemoradiotherapy

For induction therapy for locally advanced squamous unresectable cancer, head and neck (with low probability of surgical cure or at solving the conservation body) the recommended dose of docetaxel – 75 mg / m2 as a 1-hour intravenous infusion on day 1, followed by 0.5-3-hour infusion of cisplatin (100mg / m2) and followed by a continuous infusion of fluorouracil (1000 mg / m2) from 1 to 4 minutes per day. This treatment schedule is repeated every 3 weeks for a course of treatment – 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.

Patients should receive premedication with antiemetic agents, they should carry out appropriate hydration (prior to and after cisplatin administration). It is necessary to carry out prevention of neutropenic infections with antibiotics.

No dose adjustment

General principles

Docetaxel should be administered when the number of neutrophils in the peripheral blood ≥1500 / l. In the case of febrile neutropenia, reduced neutrophil count

The adjuvant breast cancer therapy

Patients with non-metastatic breast cancer patients receiving adjuvant therapy with docetaxel in combination with doxorubicin and cyclophosphamide, recommended administration of G-CSF. Patients who developed a febrile neutropenia, neutropenic infection and in all subsequent cycles necessary to reduce the dose of docetaxel and 60 mg / m2. Patients who develop stomatitis grade 3 or 4, it is necessary to decrease the dose of docetaxel 60 mg / m2.

When operable and locally advanced breast cancer after an episode of febrile neutropenia or infection on the background of neoadjuvant therapy requires prophylactic use of G-CSF in all subsequent cycles and the dose of docetaxel should be reduced from 100 mg / m2 to 75 mg / m2.

When operable breast cancer with a tumor overexpressing HER2 after an episode of febrile neutropenia or infection on the background of neoadjuvant therapy scheme AU VT must prophylactic use of G-CSF in all subsequent cycles and the dose of docetaxel should be reduced from 100 mg / m2 to 75 mg / m2.

in combination with cisplatin or carboplatin

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

In combination with capecitabine

The first appearance of toxicity of 2 degrees, which is retained by the next cycle docetaxel / capecitabine next treatment cycle may be postponed to reduce toxicity to 0-1 degrees, wherein during the next cycle of treatment is administered 100% of the original dose. Patients with repeated development toxicity grade 2 toxicity or the first development cycle of 3 degrees at any time, the treatment is delayed up to reduce toxicity to 0-1 degrees, then resumes docetaxel treatment at a dose of 55 mg / m2.

or appearance of toxicity of any grade 4 toxicities administering docetaxel should be discontinued any subsequent manifestations.

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

docetaxel in combination with cisplatin and fluorouracil

Patients receiving docetaxel in combination with cisplatin and fluorouracil, in accordance with the existing generally accepted guidelines should receive antiemetics and adequate hydration. To reduce the risk of complicated neutropenia should be used with G-CSF.

If, despite receiving G-CSF, the episodes occur febrile neutropenia, prolonged neutropenia or neutropenic infection, the dose of docetaxel reduced from 75 to 60 mg / m2. Upon subsequent development episodes neutropenia complicated docetaxel dose reduced to 60 mg / m2 to 45 mg / m2. With the development of grade 4 thrombocytopenia docetaxel dose reduced to 75 mg / m2 to 60 mg / m2. Subsequent cycles are possible using docetaxel with neutrophil count > 1500 / L and platelets > 100,000 / L. When you save a persistent toxic manifestations, treatment should cease.

Guidelines for dose adjustments during the development of toxicity in patients treated with docetaxel in combination with cisplatin and fluorouracil (FU)

Toxicity

The correction dosing regimen

Diarrhea grade 3

The first episode: reduce FU dose by 20%

Repeat episode: reduce docetaxel dose by 20%

Diarrhea grade 4

The first episode: reduce docetaxel dose and FU 20%

Repeat episode: discontinue treatment

Stomatitis / mucositis grade 3

The first episode: reduce FU dose by 20%

Repeat episode: stop only receiving FU in all subsequent courses

The third episode: reduce docetaxel dose by 20%

Stomatitis / mucositis grade 4

The first episode: stop taking FU only during subsequent cycles

Repeat episode: reduce docetaxel dose by 20%

Special groups of patients

Patients with hepatic impairment

When the activity of “liver” transaminases in blood plasma, greater than more than 1.5 times the upper limit of normal (ULN), or alkaline phosphatase, exceeding more than 2.5 times the ULN, the recommended docetaxel dose is 75 Sandoz® mg / m2. Patients with increasing bilirubin concentration and / or activity “liver” transaminases (> 3,5 ULN) in combination with increased alkaline phosphatase activity in more than 6 times the ULN, docetaxel Sandoz® use is not recommended, except strict indications.

Elderly

Specific instructions for the use of docetaxel in elderly patients are missing. When combined with capecitabine in patients older than 60 years recommended starting dose reduction of capecitabine in accordance with the instructions to the drug.

docetaxel When combined with other anticancer drugs dose (including correction of doses), the method of application must be chosen according to the instruction on the medical application of these drugs.

solution for infusion

Docetaxel Sandoz®, concentrate for solution for infusion, does not require pre-dilution solvent and is ready to add to the infusion solution.

If the vials are stored in refrigerator, the required number of packages of the preparation of the concentrate for solution for infusion should be kept at room temperature (no higher than 25 ° C) for 5 minutes prior to its use for the preparation of infusion solution.

The required amount of concentrate of docetaxel for the preparation of an infusion solution, 10 mg / ml, in accordance with a desired dose aseptically removed from the flasks using a graduated syringe connected to a needle, and injected into the bag for infusion or bottle with a 5% solution dextrose or 0.9% sodium chloride solution to a concentration of docetaxel is not more than 0.74 mg / ml (injection is carried out by a single injection into the infusion container with all necessary dose). The resulting infusion solution should be mixed by slowly inverting the infusion bag or bottle. The resulting solution should be used within 4 hours (including 1-hour infusion) at room temperature and normal lighting conditions.

The solution for infusion should be inspected prior to administration; if there is to be destroyed residue solution.

Active substance

Docetaxel

Interaction

in vitro studies showed that the drug biotransformation can be varied while the use of other drugs inducing, inhibiting or metabolized by cytochrome isoenzyme CYP3A, such as cyclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, care should be taken while the use of such medicaments, considering the possibility of interaction expressed.

With the simultaneous use of docetaxel with inhibitors of CYP3A4 may increase the risk of its side effects. If necessary, the simultaneous use of docetaxel with potent inhibitors isoenzyme CYP3A4 (ketoconazole, itraconazole, clarithromycin, indinavir, nefadozon, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) caution is required dose correction docetaxel.

Studies in patients concurrently treated with docetaxel and ketoconazole, has shown that while the clearance of docetaxel was reduced by 49%, apparently due to the fact that the main route of metabolism of docetaxel is its metabolism using isoenzyme CYP3A4. In this case, even when using lower doses of docetaxel may degrade its portability.

In vitro drugs strongly bound to plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole and valproic acid did not affect the binding of docetaxel plasma proteins. Dexamethasone does not affect the degree of binding of docetaxel to plasma proteins. Docetaxel has no effect on protein binding of digitoxin plasma. The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not affected by their joint application.

The pharmacokinetics of docetaxel in the presence of prednisone was studied in patients with metastatic prostate cancer, despite the fact that Docetaxel is metabolized by the isoenzyme of CYP3A4, and prednisone is an inducer izofermentaCYP3A4, there were no statistically significant effect of prednisone on the pharmacokinetics of docetaxel.

There is information about the interaction of docetaxel and carboplatin. When applying the combination of carboplatin and docetaxel carboplatin clearance is increased by 50% compared with carboplatin monotherapy.

Special conditions

Treatment with docetaxel Sandoz® carried out only under the supervision of a physician who is experienced in the use of anticancer drugs to a specialized hospital.

Neutropenia

It is necessary to carry out periodic monitoring of the blood count. If severe neutropenia (neutrophil count below 500 / ml for 7 days or more) during the course of drug therapy to reduce Docetaxel Sandoz® recommended dose (see. Dosing and dose) for subsequent courses or use adequate symptomatic measure. Continue treatment with Docetaxel Sandoz® optionally after recovery of neutrophils to 1500 / l.

In the case of G-CSF patients receiving docetaxel in combination with cisplatin and fluorouracil, febrile neutropenia and / or neutropenic infection occurs less frequently. Therefore, when using this combination must prophylactic designation G-CSF to reduce the risk of complications of neutropenia (febrile neutropenia, prolonged neutropenia, neutropenic infection). You should carefully monitor the status and laboratory parameters of the patients receiving the chemotherapeutic regimens.

Hypersensitivity reactions

In order to identify hypersensitivity reactions, patients should be carefully monitored, especially during the first and second infusions. Development of hypersensitivity reactions are possible on the very first minute infusions. The manifestations of hypersensitivity, such as facial flushing or localized cutaneous reactions do not require interruption of drug administration. Severe hypersensitivity reactions (reduction of blood pressure, bronchospasm, or generalized rash / erythema) require immediate cancellation of administration Sandoz® docetaxel and appropriate therapeutic measures. Repeated use of the drug docetaxel Sandoz® in these patients is not allowed.

Patients with hepatic insufficiency

Patients receiving docetaxel monotherapy at a dose of 100 mg / m2 and at a high activity “liver” transaminase more than 1.5 times the ULN, coupled with an increase in alkaline phosphatase activity more than 2.5 times the ULN extremely high risk of severe side effects, such as sepsis, gastrointestinal hemorrhage, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. In this regard, liver function tests should be determined before the start of therapy and before each subsequent cycle of therapy with docetaxel Sandoz®. Patients with elevated bilirubin concentration and / or activity “liver” transaminases (> 3,5 ULN) in combination with increased alkaline phosphatase activity in more than 6 times the ULN, the drug docetaxel Sandoz® not recommended

.

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

Fluid retention

In connection with the possibility of delay fluid requires careful monitoring of patients with pleural effusion, pericardial or having ascites. When the swelling is necessary to limit the salt and fluid intake and diuretics.

The defeat of the respiratory system

reported cases of acute respiratory distress syndrome, interstitial pneumonia / pneumonitis, interstitial lung disease, lung fibrosis and respiratory failure, including fatal. Prisoputstvuyuschey radiation therapy have also been reported cases of radiation pneumonitis.

When new or worsening of pre-existing symptoms of the respiratory system, patients should be under close medical supervision, is a symptomatic therapy. docetaxel treatment should be suspended pending clarification of the diagnosis. The issue of resumption docetaxel treatment should be decided on the basis of a careful assessment of the benefit of such treatment.

Leukemia

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

Heart failure

During treatment with docetaxel and following it up period is necessary to monitor the incidence of symptoms of chronic heart failure (CHF). Higher risk of developing heart failure in patients with breast cancer with lymph node receiving chemotherapy scheme TAS, observed in the first year after completion of treatment.

Patients who received docetaxel Sandoz® in combination with trastuzumab for breast cancer with metastatic tumor overexpressing HER2, especially after chemotherapy containing anthracyclines (doxorubicin or epirubicin) may develop heart failure, it may be moderate to severe and result in death . When the patient is shown Sandoz® treatment with docetaxel in combination with trastuzumab, it must pass the initial cardiac examination. Every three months should be monitored cardiac function, which allows to identify patients who have heart failure may develop.

Violations of the organ of vision

It has been reported about the development of macular edema in patients treated with docetaxel. If you experience blurred vision, patients should undergo a complete eye examination. In the case of diagnosis of macular edema, the drug should be discontinued.

The need for contraception

Since the pre-clinical studies have shown that docetaxel has genotoxic effects and may interfere with male fertility (ability to conceive), men receiving treatment with docetaxel, it is recommended to refrain from conceiving a child during treatment and for at least 6 months after the end chemotherapy treatment and advice to produce sperm preservation.

Women in the event of their pregnancy during treatment should immediately notify your doctor.

At the time and for at least 6 months after discontinuation of therapy in patients of both sexes must use reliable methods of contraception.

neurotoxicity

The development of severe sensory neuropathy requires dose reduction Sandoz® docetaxel formulation.

Elderly

As compared with patients younger than 60 years in patients aged 60 years or older receiving combination chemotherapy with docetaxel + capecitabine, there was an increase in the frequency of treatment-related adverse events grade 3 and 4 severity of treatment-related serious adverse side effects (NDP) and early discontinuation of treatment due to the development of CPD.

There are limited data on the use of docetaxel combination with doxorubicin and cyclophosphamide in patients older than 70 years.

In patients 65 years or older treated with the drug every 3 weeks for prostate cancer, the frequency of changes in the nails was ≥ 10% higher than in younger patients, in patients 75 years and older the frequency of fever, diarrhea, anorexia and peripheral edema was ≥ 10% higher than in younger patients.

When using docetaxel combination with cisplatin and fluorouracil were observed following adverse reactions (all severities): lethargy (drowsiness, lethargy, stupor), stomatitis, neutropenic infection, in patients older than 65 years met at ≥10% more frequently than patients younger. Therefore, patients older than 65 years receiving this combination, require careful observation.

The ethanol content

The preparation of Docetaxel Sandoz® contains ethanol at a concentration of 27 vol% (10 mg / ml containing 0.28 g of ethanol based on the basic substance). This should be taken into account when using the drug in patients with alcoholism and risk patients (patients with liver disease or epilepsy).

Handling and Precautions Regarding a preparation

When applying and preparing solutions the drug docetaxel Sandoz® be careful. It is recommended to use these gloves. If concentrate or infusion solution gets on your skin, it should immediately be washed thoroughly with soap and water. In case of contact with mucous membranes, they should be immediately and thoroughly rinse with water.

Special precautions for the destruction of unused drugs

Residues preparation, all instruments and materials used for the preparation of solutions for intravascular and intravesical docetaxel Sandoz®, must be disposed of in accordance with standard hospital waste disposal procedure cytotoxic substances with regard to the existing regulations destruction of hazardous waste.

The effect on the ability to drive transp. Wed. and fur:. The drug is used in a hospital environment. Special studies have been conducted. However, the development of adverse reactions in the nervous system and organ of vision, as well as the presence may lead to a reduction of psychomotor reaction speed and attention as part of the preparation of ethanol. In this regard, it is not recommended during treatment with docetaxel Sandoz® to drive and engage in other potentially hazardous activities.

Overdose

Symptoms: inhibition of bone marrow, peripheral neuropathy and mucositis

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Treatment: the patient’s hospitalization, careful control of the functions of vital organs, the prophylactic use of G-CSF, symptomatic therapy. Antidote to docetaxel is currently unknown.

Weight	0.045 kg
Dosage form	Infusion solution