Docetaxel Sandoz, 10 mg/ml 16 ml

Breast cancer

Breast cancer (BC)

Adjuvant therapy:

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

– operable breast cancer with regional lymph node involvement;

– operable breast cancer without involvement of regional lymph nodes in patients eligible for chemotherapy according to the established international selection criteria for primary chemotherapy for early stages of breast cancer (in the presence of one or more high-risk factors for recurrence: tumor size greater than 2 cm, negative estrogen and progesterone receptor status, high grade of tumor malignancy (grade 2-3), age less than 35 years);

– operable breast cancer with tumor overexpression of HER2 (doxorubicin and cyclophosphamide followed by Docetaxel Sandoz® in combination with trastuzumab (AC-TN regimen));

Neoadjuvant therapy:

– operable and locally advanced breast cancer (doxorubicin and cyclophosphamide followed by Docetaxel Sandoz®).

Metastatic and/or locally advanced breast cancer:

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

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

– locally advanced or metastatic breast cancer when previous chemotherapy, including anthracyclines or alkylating agents, has failed (Docetaxel Sandoz® in monotherapy);

– locally advanced or metastatic breast cancer when previous chemotherapy including anthracyclines has failed (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 first-line therapy;

– locally advanced or metastatic NSCLC in monotherapy as 2nd-line therapy if prior chemotherapy is ineffective;

Ovarian cancer

– metastatic ovarian cancer as 2nd-line therapy if prior 1st-line therapy is ineffective.

Head and neck cancer

Inoperable locally advanced squamous cell head and neck cancer (in combination with cisplatin and fluorouracil) as induction therapy.

Prostate cancer

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

Gastric cancer

– Metastatic gastric cancer, including gastroesophageal junction adenocarcinoma (in combination with cisplatin and fluorouracil), as 1st-line therapy.

Active ingredient

Composition

Concentrate for preparation of infusion solution as a clear liquid, colorless to light yellow in color.

1 ml docetaxel (anhydrous)10 mg

Associates:

Polysorbate 80 – 80 mg,

Macrogol 300 – 648 mg,

Interaction

In vitro studies have shown that the biotransformation of the drug may be altered with concomitant use of other drugs that induce, inhibit or are metabolized by CYP3A cytochrome isoenzyme, such as cyclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. In this regard, caution should be exercised when using these drugs concomitantly, given the possibility of significant interaction.

Concomitant use of docetaxel with CYP3A4 isoenzyme inhibitors may increase the risk of adverse reactions. In case of necessity of concomitant use of docetaxel with strong CYP3A4 isoenzyme inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir, nefadozone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) caution should be observed; dose adjustment of docetaxel is required.

Studies conducted in patients receiving docetaxel and ketoconazole concomitantly showed that the clearance of docetaxel was reduced by 49%, apparently due to the fact that the main route of metabolism of docetaxel is its metabolism by CYP3A4 isoenzyme. In this case, even with lower doses of docetaxel, its tolerability may be impaired.

In vitro .Drugs that firmly bind to plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole and valproic acid, had no effect on the binding of docetaxel to plasma proteins. Dexamethasone also has no effect on the degree of binding of docetaxel to plasma proteins. Docetaxel has no effect on the binding to plasma proteins of digitoxin. The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide did not change when used together.

The pharmacokinetics of docetaxel in the presence of prednisone has been studied in patients with metastatic prostate cancer; although docetaxel is metabolized by the CYP3A4 isoenzyme and prednisone is an inducer of the CYP3A4 isoenzyme, no statistically significant effect of prednisone on docetaxel pharmacokinetics was observed.

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

Directions for use

Intravenously by infusion (for 1 hour) once every 3 weeks.

In order to prevent hypersensitivity reactions and to reduce fluid retention, all patients (except for patients with prostate cancer – see below) are given glucocorticoid premedication prior to administration of docetaxel unless contraindicated.

In order to prevent hypersensitivity reactions and to reduce fluid retention, all patients (except prostate cancer patients – see below) are given premedication with glucocorticosteroids (GCS) such as oral dexamethasone at a dose of 16 mg/day (8 mg twice daily) for 3 days, starting one day before the administration of docetaxel if not contraindicated.

In patients with prostate cancer receiving concomitant treatment with prednisone or prednisolone, premedication with dexamethasone at a dose of 8 mg 12, 3, and 1 hour before the start of docetaxel administration.

In order to reduce the risk of hematologic complications, prophylactic administration of granulocyte colony-stimulating factor (G-CSF) is recommended.

Breast cancer (BC)

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

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

The following drug doses are recommended for neoadjuvant therapy in patients with operable and locally advanced breast cancer:

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

– T (cycles 5-8): docetaxel (T) 100 mg/m2 once every 3 weeks, 4 cycles.

The following doses of docetaxel (AC-TN chemotherapy) are recommended for adjuvant therapy of operable breast cancer with HER2 tumor overexpression:

– AC (cycles 1-4): doxorubicin (A) 60 mg/m2 followed by 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) administered weekly according to the following regimen:

three weeks after day 1 of cycle 8: trastuzumab 6 mg/mL every 3 weeks.

Trastuzumab is administered for a total of 1 year.

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

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

Consecutive doses of docetaxel are administered immediately after the end of the trastuzumab infusion (if the preceding trastuzumab dose is well tolerated). For trastuzumab dose and route of administration, see trastuzumab administration instructions.

In combination with capecitabine (1250 mg/m2 orally twice daily for 2 weeks followed by a one-week break), the recommended dose of docetaxel is 75 mg/m2 every 3 weeks.

Non-small cell lung cancer

In patients who have not previously received chemotherapy, the following regimen is recommended: docetaxel 75 mg/m2 , immediately followed by cisplatin (75 mg/m2 for 30-60 minutes) or carboplatin (AUC 6 mg/mL/min for 30-60 minutes).

For treatment after ineffectiveness of platinum-based chemotherapy, docetaxel monotherapy at a dose of 75 mg/m2 is recommended.

Metastatic ovarian cancer

A dose of docetaxel 100 mg/m2 every 3 weeks is recommended for 2nd-line therapy for ovarian cancer.

Prostate cancer

The recommended dose of docetaxel is 75 mg/m2 once every 3 weeks. Prednisone or prednisolone is given long-term at 5 mg orally twice daily.

Gastric cancer, including gastroesophageal junction adenocarcinoma

For gastric cancer, the recommended dose of docetaxel is 75 mg/m2 as a 1-hour infusion followed by cisplatin infusion at a dose of 75 mg/m2 for 1-3 h (both drugs on day 1 only). Upon completion of cisplatin infusion, a 24-hour infusion of fluorouracil 750 mg/m2/day is given for 5 days. Treatment is repeated every 3 weeks. Patients should be premedicated with antiemetics and appropriately hydrated for cisplatin administration. Granulocyte colony-stimulating factor (G-CSF) is indicated for prophylactic purposes to reduce the risk of hematologic toxicity (see dose adjustment).

Head and neck cancer

Induction chemotherapy followed by radiotherapy

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

Induction chemotherapy followed by chemoradiation therapy

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

Patients should be premedicated with antiemetics and receive appropriate hydration (before and after cisplatin administration). The development of neutropenic infections should be prevented with antibiotics.

Dose adjustment

General principles

Docetaxel should be administered when peripheral blood neutrophil counts are ≥1500/μL. In case of febrile neutropenia, decrease of neutrophil count <500/μl lasting more than one week, skin reactions expressed or intensified with repeated administrations, or marked peripheral neuropathy during docetaxel therapy, its dose should be reduced from 100 mg/m2 to 75 mg/m2 and/or from 75 mg/m2 to 60 mg/m2 in subsequent administrations. If similar reactions persist at the 60 mg/m2 dose of docetaxel, treatment should be discontinued.

Adjuvant therapy for breast cancer

Patients with non-metastatic breast cancer receiving adjuvant therapy with docetaxel in combination with doxorubicin and cyclophosphamide are recommended to receive G-CSF. Patients who develop febrile neutropenia or neutropenic infection should have the dose of docetaxel reduced to 60 mg/m2 in all subsequent cycles. In patients who have developed grade 3 or 4 stomatitis, the dose of docetaxel should be reduced to 60 mg/m2.

In operable and locally advanced breast cancer after an episode of febrile neutropenia or infection on neoadjuvant therapy, G-CSF should be used prophylactically for all subsequent cycles, and the docetaxel dose should be reduced from 100 mg/m2 to 75 mg/m2.

In operable breast cancer with tumor HER2 overexpression after an episode of febrile neutropenia or infection on neoadjuvant therapy with an AC TN regimen, G-CSF should be used prophylactically for 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

. In patients who initially received docetaxel at a dose of 75 mg/m2 in combination with cisplatin or carboplatin and whose 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.

In combination with capecitabine

In the first occurrence of grade 2 toxicity that persists by the start of the next cycle of docetaxel/capecitabine, the next treatment cycle may be delayed until toxicity is reduced to grade 0-1, with 100% of the original dose administered during the next treatment cycle. In patients with recurrent development of grade 2 toxicity or the first development of grade 3 toxicity at any time during the cycle, treatment is deferred until toxicity decreases to grade 0-1, then treatment with docetaxel is resumed at a dose of 55 mg/m2.

Any subsequent manifestation of toxicity or the appearance of any grade 4 toxicity, docetaxel should be discontinued.

Recommendations for adjustment of capecitabine doses 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 should receive anti-emetics and adequate hydration according to current accepted guidelines. G-CSF should be used to reduce the risk of complicated neutropenia.

If episodes of febrile neutropenia, prolonged neutropenia, or neutropenic infection occur despite G-CSF administration, the dose of docetaxel is reduced from 75 to 60 mg/m2. In subsequent episodes of complicated neutropenia, the dose of docetaxel is reduced from 60 mg/m2 to 45 mg/m2 . In the development of grade 4 thrombocytopenia, the docetaxel dose is reduced from 75 mg/m2 to 60 mg/m2 . Subsequent cycles with docetaxel are possible at neutrophil >1500/μl and platelet >100000/μl counts. If toxic manifestations persist, treatment should be discontinued.

Patients receiving docetaxel in combination with cisplatin and fluorouracil (FU) should have their doses adjusted if toxicity occurs.

Toxicity

Dose adjustment

Degree 3 diarrhea

First episode: Decrease the dose of FU by 20%

Repeated episode: reduce dose of docetaxel by 20%

Degree 4 diarrhea

First episode: reduce doses of docetaxel and FP by 20%

Repeat episode: discontinue treatment

Grade 3 stomatitis/mucositis

First episode: reduce FU dosage by 20%

Repeat episode: discontinue only FU in all subsequent courses

Third episode: reduce docetaxel dose by 20%

Grade 4 stomatitis/mucositis

First episode: discontinue only FU in all subsequent cycles

Repeat episode: Reduce docetaxel dose by 20%

Special patient groups

Patients with impaired liver function

In patients with plasma hepatic transaminase activity greater than 1.5 times the upper limit of normal (ULN) or alkaline phosphatase activity greater than 2.5 times the ULN, the recommended dose of Docetaxel Sandoz® is 75 mg/m2. In patients with bilirubin concentration and/or “hepatic” transaminases activity increase (>3.5 VGN) in combination with alkaline phosphatase activity increase more than 6 times VGN, Docetaxel Sandoz® is not recommended, except for strict indications.

Patients in the Elderly

There are no specific instructions for the use of docetaxel in elderly patients. When combining with capecitabine in patients over 60 years of age, a reduction in the starting dose of capecitabine is recommended according to the drug’s instructions.

If docetaxel is combined with other anticancer drugs, the dose (including dose adjustments) and route of administration should be adjusted according to the instructions for medical use of these drugs.

Preparing the infusion solution

Docetaxel Sandoz®, concentrate for preparation of the infusion solution, does not require pre-dilution with a solvent and is ready to be added to the infusion solution.

If vials are stored in refrigerator, the required number of packs of the drug with concentrate for preparation of solution for infusion should be kept at room temperature (not exceeding 25 °C) for 5 min before using it for preparation of infusion solution.

. The required volume of docetaxel concentrate to prepare the infusion solution, 10 mg/ml, according to the required dose under aseptic conditions is extracted from the vials using a single graduated syringe connected to a needle, and injected into an infusion bag or vial with 5% dextrose solution or 0.9% sodium chloride solution until the concentration of docetaxel does not exceed 0.74 mg/ml (injection is performed by injecting the entire required dose into the infusion container once). The resulting infusion solution should be stirred by slowly turning the infusion bag or bottle. The resulting solution should be used within 4 h (including a 1-hour infusion) at room temperature and under normal light conditions.

The infusion solution should be inspected prior to administration; if sediment is present, the solution should be destroyed.

Special Instructions

Treatment with Docetaxel Sandoz® should only be performed under the supervision of a physician experienced in the use of antitumor drugs in a specialized hospital setting.

Neutropenia

General blood counts should be monitored periodically. In case of pronounced neutropenia (neutrophil count less than 500/μL for 7 days or more) during the course of therapy with Docetaxel Sandoz® it is recommended to decrease the drug dose (see Dosage and Administration) in subsequent courses or use adequate symptomatic measures. Continuation of therapy with Docetaxel Sandoz® is possible after restoration of neutrophil count to 1500/μL.

In case of G-CSF patients receiving docetaxel in combination with cisplatin and fluorouracil, febrile neutropenia and/or neutropenic infections develop less frequently. Therefore, when using this combination, G-CSF should be administered prophylactically to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, neutropenic infection). The condition and laboratory values of patients receiving this chemotherapy regimen should be closely monitored.

Hypersensitivity reactions

In order to detect hypersensitivity reactions, patients should be closely monitored, especially during the first and second infusions. The development of hypersensitivity reactions is possible in the very first minutes of infusions of the drug. Manifestations of hypersensitivity, such as facial redness or localized skin reactions, do not require interruption of the drug administration. Severe hypersensitivity reactions (decreased blood pressure, bronchospasm or generalized rash/erythema) require immediate withdrawal of Docetaxel Sandoz® and appropriate treatment measures. Reuse of Docetaxel Sandoz® in such patients is not permitted.

Patients with hepatic impairment

. In patients receiving docetaxel monotherapy at a dose of 100 mg/m2 and with high “hepatic” transaminase activity of more than 1.5 times IGN, combined with elevated alkaline phosphatase activity of more than 2,5 times the ULN, there is an extremely high risk of severe side effects such as sepsis, gastrointestinal bleeding, 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®. In patients with elevated bilirubin concentration and/or “hepatic” transaminase activity (>3.5 VGN) in combination with increased alkaline phosphatase activity more than 6 times VGN, Docetaxel Sandoz® is not recommended.

There are currently no data regarding the use of docetaxel in combination with other drugs in patients with hepatic impairment.

Fluid retention

Due to the possibility of fluid retention, close monitoring of patients with pleural effusion, pericardium, or ascites is necessary. If edema occurs, saline and fluid restriction and administration of diuretics are necessary.

Respiratory system damage

. Cases of acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis, and respiratory failure, including fatalities, have been reported. Cases of radiation pneumonitis have also been reported with concomitant radiation therapy.

If new respiratory symptoms occur or existing symptoms worsen, patients should be closely monitored by a physician and symptomatic therapy is indicated. Treatment with docetaxel should be suspended until the diagnosis is clarified. Resumption of docetaxel treatment should be decided based on a careful assessment of the benefit of such treatment.

Leukemia

. When combining Docetaxel Sandoz® with doxorubicin and cyclophosphamide for non-metastatic operable breast cancer, the risk of delayed myelodysplasia and/or myeloid leukemia requires hematologic monitoring of patients.

Heart failure

The symptoms of chronic heart failure (CHF) should be monitored during and after treatment with docetaxel. Patients with breast cancer with lymph node involvement who receive TAC chemotherapy have a higher risk of developing CHF in the first year after completion of treatment.

In patients receiving Docetaxel Sandoz® in combination with trastuzumab for metastatic breast cancer with tumorigenic HER2 hyperexpression, especially after anthracycline-containing chemotherapy (doxorubicin or epirubicin), heart failure may develop and may be moderate to severe, leading to death. When a patient is indicated for treatment with Docetaxel Sandoz® in combination with trastuzumab, she should have an initial cardiac evaluation. Cardiac function should be monitored every three months to identify patients who may develop heart failure.

Visual disturbances

The development of macular edema has been reported in patients taking docetaxel. Patients should undergo a complete ophthalmologic examination if visual impairment occurs. If macular edema is diagnosed, the drug should be discontinued.

The need for contraception

. Because preclinical studies have shown that docetaxel has genotoxic effects and may impair male fertility (ability to conceive), men treated with docetaxel are advised to refrain from conceiving during treatment and for at least 6 months after the end of chemotherapy and are advised to perform sperm preservation before treatment.

Women should tell their doctor immediately if they become pregnant during treatment.

Patients of both sexes should use reliable contraception during and for at least 6 months after discontinuation of therapy.

Neurotoxicity

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

Elderly patients

. Compared with patients younger than 60 years of age, patients 60 years of age and older receiving docetaxel+capecitabine combination chemotherapy had an increased incidence of treatment-related adverse events of severity 3 and 4, treatment-related serious adverse reactions (SARs) and early treatment withdrawal due to the development of SARs.

There are limited data on the use of the combination of docetaxel with doxorubicin and cyclophosphamide in patients over age 70.

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

When using the combination of docetaxel with cisplatin and fluorouracil, the following adverse reactions (all degrees of severity) were observed: lethargy (drowsiness, lethargy, stupor), stomatitis, neutropenic infection, were ≥10% more common in patients over 65 years old than in younger patients. Therefore, patients over 65 years of age receiving this combination require close monitoring.

Ethanol content

Docetaxel Sandoz® contains ethanol at a concentration of 27 vol% (10 mg/ml contains 0.28 g ethanol in terms of the main 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).

Handling and precautions for handling the drug

Care must be taken when using and preparing solutions of Docetaxel Sandoz®. The use of gloves is recommended. If the concentrate or solution for infusion comes in contact with the skin, it should be immediately washed thoroughly with soap and water. If contact is made with mucous membranes, they should be rinsed immediately and thoroughly with water.

Special precautions when disposing of unused medication

Drug residues, all instruments and materials that have been used to prepare solutions for intravascular and intravesical administration of Docetaxel Sandoz® must be destroyed in accordance with standard hospital procedures for the disposal of cytotoxic waste, subject to applicable hazardous waste disposal regulations.

The effect on driving ability: The drug is used in a hospital setting. No special studies have been performed. However, the development of adverse reactions on the nervous system and organs of vision, as well as the presence of ethanol in the drug may lead to the decrease in the rate of psychomotor reactions and attention. That is why during the treatment by Docetaxel Sandoz® it is not recommended to drive a vehicle and engage in other potentially dangerous activities.

Contraindications

Individual hypersensitivity to docetaxel or other drug components;

– neutropenia (baseline peripheral blood neutrophil count < 1500/μl);

– marked impairment of liver function;

– pregnancy;

– period of breastfeeding;

– children under 18 years of age.

When using Docetaxel Sandoz® in combination with other drugs, the contraindications for their use should also be considered.

With caution:

. When concomitant use of drugs that induce or inhibit cytochrome P450-3A isoenzymes or metabolize with cytochrome P450-3A isoenzymes, such as cyclosporine, terfenadine, imidazole antifungal agents (ketoconazole, itraconazole, voriconazole), erythromycin, troleandomycin, clarithromycin, telithromycin, protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir), and nefadozone.

Side effects

According to the World Health Organization (WHO), adverse effects are classified according to their frequency of development as follows: Very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), and very rare (< 1/10000); frequency unknown (frequency of events cannot be determined from available data).

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

Blood and lymphatic system disorders

very common: Reversible neutropenia after an average of 7 days (this period may be shorter in patients who have received prior chemotherapy); 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 peripheral blood neutrophil count of less than 500/μL; severe infections, including sepsis and pneumonia including.severe infections including sepsis and pneumonia, including lethal; thrombocytopenia less than 100,000/μL, bleeding combined with thrombocytopenia less than 50,000/μL and anemia (hemoglobin concentration less than 11 g/dL), including severe (hemoglobin concentration less than 8 g/dL);

infrequent: severe thrombocytopenia;

frequency unknown: Inhibition of medullary hematopoiesis and other hematologic adverse reactions; development of disseminated intravascular coagulation syndrome (DICS), often in combination with sepsis and multi-organ failure.

Immune system disorders

very often: Allergic reactions, usually occurring within minutes of starting the infusion (“flushes” of blood to the face, rash with or without itching, feeling of tightness in the chest, back pain, shortness of breath, drug-induced fever or chills);

often: Severe allergic reactions characterized by decreased blood pressure and/or bronchospasm or generalized rash/erythema;

incidence unknown: anaphylactic shock, sometimes fatal (in patients who received premedication, these cases were very rarely fatal).

Skin and subcutaneous tissue disorders

very common: reversible skin reactions usually mild to moderate in severity: Localized rash, mainly on the arms and legs and on the face and chest, often accompanied by itching, rashes usually occurred within one week of docetaxel infusion; nail disorders characterized by hypo- and hyperpigmentation, pain and onycholysis; alopecia;

often: severe skin reactions, incl.ч. rash followed by desquamation, including severe palm and foot lesion syndrome, which may require interruption or discontinuation of treatment with docetaxel;

infrequently: severe alopecia;

very 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 co-infections, other medications taken simultaneously, and comorbidities), scleroderma-like changes preceded by lymphangiectatic edema.

Aqueous-electrolyte metabolism disorders

very common: fluid retention;

frequent: marked fluid retention. The development of peripheral edema has been reported and, less frequently, pleural and pericardial effusion, ascites, and weight gain. The frequency and severity of fluid retention increases with repeated administration of docetaxel;

frequency unknown: cases of hyponatremia have been reported, mostly in combination with dehydration, vomiting, and pneumonia.

Gastrointestinal tract disorders

very common: nausea, vomiting, diarrhea, anorexia, stomatitis, taste disorder;

often: severe nausea and vomiting, severe diarrhea, constipation, severe stomatitis, esophagitis, epigastric pain (incl.ч. severe), gastrointestinal bleeding;

infrequent: severe gastrointestinal bleeding, severe constipation and esophagitis, severe taste disorders;

rarely: Dehydration as a consequence of developing GI reactions, gastric or intestinal perforation, colitis including ischemic, neutropenic enterocolitis, ileus (intestinal obstruction), intestinal obstruction.

Hepatic and biliary tract disorders

often: increased serum ACT, ALT, alkaline phosphatase and bilirubin concentrations in blood (more than 2.5 times higher than VGN);

very rarely: Hepatitis (lethal outcome observed in patients with a history of liver disease).

Nervous system disorders

very common: 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: seizures, transient loss of consciousness, sometimes developing during infusion of the drug.

Cardiovascular system disorders

often: arrhythmia, increased or decreased blood pressure; bleeding;

infrequently: Heart failure;

rarely: cases of venous thromboembolism and myocardial infarction have rarely been reported.

A visual organ side

seldom: Lacrimation in association with (or without) conjunctivitis, transient visual disturbances (flashes of light in the eyes, appearance of scotomas), usually occurring during administration and combined with the development of hypersensitivity reactions, which usually disappear after stopping the infusion;

very rare: Lacrimal duct occlusion leading to excessive lacrimation.

Hearing and labyrinth disorders

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

Respiratory, thoracic and mediastinal disorders

very common: dyspnea;

frequently: severe dyspnea;

rarely: acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, respiratory failure, which could be fatal; rare cases of radiation pulmonitis occurred with concurrent radiation; pulmonary fibrosis, pulmonary edema;

musculoskeletal system disorders

very often: Myalgia;

often: arthralgia.

General disorders and injection site reactions

very common: asthenia, including severe; generalized and localized pain syndrome, including noncardiac chest pain;

often: injection site reactions, usually mild: hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, hemorrhage from a punctured vein or vein edema; severe generalized and localized pain syndrome, including noncardiac chest pain.

Other

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

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

A higher incidence of neutropenia, including severe neutropenia, was observed with Docetaxel Sandoz® in combination with doxorubicin compared to Docetaxel Sandoz® monotherapy; 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; nail lesions, including severe fluid retention, including severe; anorexia, neurosensory and neuromotor reactions, including severe; hypotension; rhythm disturbances; increased activity of liver transaminases, alkaline phosphatase, blood bilirubin; myalgia; asthenia.

Docetaxel Sandoz® in combination with doxorubicin and cyclophosphamide (TAC regimen)

. Compared with Docetaxel Sandoz® monotherapy, this chemotherapy regimen resulted in lower rates of neutropenia, severe anemia, febrile neutropenia, infections, allergic reactions, and peripheral edema, neurosensory and neuromotor reactions, nail damage, diarrhea, arrhythmia, but a higher incidence of non-serious anemia, thrombocytopenia, nausea, vomiting, stomatitis, taste disorders, constipation, asthenia, arthralgia, alopecia, colitis, enterocolitis, myelodysplatic syndrome.

In addition, non-fatal perforation of the large intestine, acute myeloid leukemia, and acute leukemia have been observed. Prophylactic use of G-CSF reduced the incidence of neutropenia (by 60%) and neutropenic infections of 3-4 severity.

Doxorubicin and cyclophosphamide) followed by Docetaxel Sandoz® in combination with trastuzumab (AC-TN regimen)

. Alopecia; anemia, including anemia of grade 3 to 4 severity, were more common with these chemotherapy regimens compared with Docetaxel Sandoz® monotherapy; thrombocytopenia, including 3-4 grade thrombocytopenia; nausea, including 3-4 grade nausea; stomatitis; vomiting; diarrhea; constipation; anorexia; abdominal pain; increased ACT, ALT and alkaline phosphatase activity; myalgia; nail lesions; arthralgia; 3-4 grade infections; heart failure.

No increase in febrile neutropenia has been observed.

Rareer cases included grade 3-4 neutropenia, fluid retention, neurosensory and neuromotor reactions, rash and desquamation, and allergic reactions.

In addition, insomnia and increased blood creatinine concentration have been reported.

Docetaxel Sandoz® in combination with capecitabine

When using Docetaxel Sandoz® in combination with capecitabine, a higher incidence of gastrointestinal adverse events (stomatitis, diarrhea, vomiting, constipation, abdominal pain, taste disorders); arthralgia; severe thrombocytopenia and anemia hyperbilirubinemia; palm-tolabial syndrome (hyperemia of the skin of the extremities (palms and feet) with subsequent edema and desquamation); but more rare development of severe neutropenia; alopecia; nail disorders, nail color changes, including onycholisis, shortness of breath, paresthesias, dehydration, lacrimation; asthenia; myalgia; decreased appetite and anorexia.

Additionally, dyspepsia, dry mouth, sore throat, oral candidiasis, dermatitis, erythematous rash, pyrexia, limb pain, back pain, lethargy (drowsiness, lethargy, stupor), cough, nosebleed, dizziness, headache, peripheral neuropathy, weight loss have been observed.

In comparison with younger patients, patients 60 years of age and older who received the combination of Docetaxel Sandoz® with capecitabine were more likely to develop grade 3 to 4 toxicity.

Docetaxel Sandoz® in combination with trastuzumab

Patients treated with a combination of Docetaxel Sandoz® and trastuzumab Nausea, diarrhea, constipation, abdominal pain, taste disorders, febrile neutropenia, arthralgia, anorexia, and grade 4 toxicities were more frequently reported in patients who received a combination of Docetaxel Sandoz® with trastuzumab (compared to Docetaxel Sandoz® monotherapy), cases of heart failure, especially in patients previously treated with anthracyclines as adjuvant therapy, but less commonly observed were grade 3-4 neutropenia, asthenia, weakness, alopecia, nail lesions, skin rashes, vomiting, stomatitis, and myalgia. Additionally observed were: lacrimation, conjunctivitis, pain, shortness of breath, paresthesias, mucous membrane inflammation, nasopharyngitis, sore throat and pharynx, nasal bleeding, rhinorrhea, flu-like illness, cough, pyrexia, chills, chest pain, limb pain, back pain, bone pain, lethargy (drowsiness, lethargy, stupor), insomnia, erythema, dyspepsia, headache, hypoesthesia.

In comparison with docetaxel monotherapy, there was an increase in the incidence of severe adverse reactions.

Combination of Docetaxel Sandoz® with cisplatin or carboplatin

The incidence of thrombocytopenia, including thrombocytopenia of grade 3-4, was higher with these chemotherapy regimens compared to Docetaxel Sandoz® monotherapy; anemia, including anemia of 3-4 severity; nausea, including nausea of 3-4 severity; diarrhea of 3-4 severity; anorexia, including diarrhea of 3-4 severity; and injection site reactions. However, less commonly observed were neutropenia, including neutropenia of 3-4 severity; infections; febrile neutropenia; allergic reactions; skin reactions; nail lesions; fluid retention, including fluid retention of 3-4 severity; stomatitis, neurosensory and, to a lesser extent, neuromotor neuropathy; alopecia; asthenia and myalgia.

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

Combination of Docetaxel Sandoz® with prednisolone or prednisone

The incidence of side effects was significantly reduced when Docetaxel Sandoz® was used in combination with prednisolone or prednisone compared with Docetaxel Sandoz® monotherapy: Anemia, including grade 3-4 severity; infections; neutropenia, including grade 3-4 severity; thrombocytopenia; febrile neutropenia; weakness; allergic reactions; neurosensory and neuromotor reactions; alopecia; rash; desquamation; nausea; diarrhea; stomatitis; vomiting; anorexia; myalgia; arthralgia; fluid retention; but taste disorders and heart failure were observed more frequently.

Additionally, nasal bleeding, coughing, weakness, and lacrimation were observed.

The combination of Docetaxel Sandoz® with cisplatin and fluorouracil

The use of this combination compared to monotherapy with Docetaxel Sandoz® more frequently observed anemia, including grade 3-4 severe; thrombocytopenia, including grade 3-4 severe; febrile neutropenia neutropenic infections (even with G-CSF); nausea; vomiting; anorexia; stomatitis; diarrhea; esophagitis/dysphagia/swallowing pain; but less commonly observed infections; allergic reactions; fluid retention; neurosensory and neuromotor reactions; myalgia; alopecia; rash; itching; nail lesions; skin desquamation; rhythm disturbances.

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