Docetaxel "ebewe"

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXETAXEL «EBEWE» (DOCETAXEL «EBEWE»)

Composition:

Active substance: docetaxel;

1 ml of concentrate contains 10 mg of docetaxel;

Excipients: citric acid anhydrous, macrogol 300, polysorbate 80, ethanol 96%.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless or pale yellow solution.

Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural agents. Taxanes. ATC code L01CD02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Docetaxel is an antineoplastic agent whose mechanism of action involves promoting the assembly of tubulin into stable microtubules and inhibiting their disassembly, resulting in a significant reduction in free tubulin concentration. When docetaxel binds to microtubules, the number of protofilaments remains unchanged.

It has been established that docetaxel disrupts the microtubular network in vitro in cells, which is essential for vital cellular functions during mitosis and interphase.

Pharmacodynamic effects. Docetaxel exhibits cytotoxic activity in vitro against various human and murine or rat tumor cell lines, as well as in clonogenic assays using freshly excised human tumors. Docetaxel achieves high intracellular concentrations and is retained within cells for prolonged periods. Furthermore, docetaxel is active against some, although not all, cell lines that overexpress P-glycoprotein encoded by the multidrug resistance gene. In vivo, docetaxel demonstrates broad-spectrum antitumor activity against established murine tumors and human tumor xenografts, regardless of the administration schedule.

Pharmacokinetics

Absorption. The pharmacokinetics of docetaxel were studied in cancer patients during phase I trials following doses of 20–115 mg/m². The kinetic profile of docetaxel is dose-independent and fits a three-compartment pharmacokinetic model, with half-lives for the α-, β-, and γ- phases of 4 minutes, 36 minutes, and 11.1–17.5 hours, respectively, based on sampling up to 24 hours. In an additional study evaluating docetaxel pharmacokinetics at similar doses (75–100 mg/m²) in patients over a longer period (over 22 days), a longer mean terminal half-life was observed—91–120 hours. This final phase is partially attributed to relatively slow release of docetaxel from the peripheral compartment.

Distribution. After administration of a 100 mg/m² dose as a 1-hour infusion, the mean peak plasma concentration of docetaxel is 3.7 µg/mL, with an AUC of 4.6 h·µg/mL. Mean values for total clearance and volume of distribution at steady state are 21 L/h/m² and 113 L, respectively. Inter-individual variability in total clearance reaches approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

Elimination. A study using radiolabeled 14C-docetaxel was conducted in three cancer patients. Over 7 days, docetaxel was eliminated in urine and feces following oxidative metabolism of the tert-butyl ether group mediated by cytochrome P450. Excretion in urine and feces accounted for 6% and 75% of the administered radioactive dose, respectively. Approximately 80% of the radioactivity recovered in feces was excreted within the first 48 hours as one major inactive metabolite, three minor inactive metabolites, and unchanged drug in very low amounts.

Special patient populations.

Age and sex. Population pharmacokinetic analysis was performed in 577 patients treated with docetaxel. Pharmacokinetic parameters assessed were very similar to those obtained in phase I studies. The pharmacokinetics of docetaxel were not affected by patient age or sex.

Hepatic impairment. In a small number of patients (n=23) with biochemical indicators of mild or moderate hepatic dysfunction (ALT and AST activity more than 1.5 times the upper limit of normal, and alkaline phosphatase activity more than 2.5 times the upper limit of normal), total clearance was reduced by an average of 27%.

Fluid retention. Docetaxel clearance was not altered in patients with mild or moderate fluid retention. Data in patients with severe fluid retention are lacking.

Combination therapy.

Doxorubicin. When administered in combination, docetaxel does not affect the clearance of doxorubicin or plasma levels of doxorubicinol (a metabolite of doxorubicin). No changes in the pharmacokinetics of docetaxel, doxorubicin, or cyclophosphamide were observed when these agents were administered concomitantly.

Capecitabine. In a phase I study evaluating the effect of capecitabine on docetaxel pharmacokinetics and vice versa, no effect of capecitabine on docetaxel pharmacokinetics (Cmax and AUC) was observed, nor was there any effect of docetaxel on the pharmacokinetics of 5’-DFUR, the relevant metabolite of capecitabine.

Cisplatin. Docetaxel clearance during combination therapy with cisplatin was similar to that observed during monotherapy. When cisplatin was administered shortly after docetaxel infusion, its pharmacokinetic profile was comparable to that seen when cisplatin was administered alone.

Cisplatin and 5-fluorouracil. In 12 patients with solid tumors receiving a combination of docetaxel, cisplatin, and 5-fluorouracil, no changes in the pharmacokinetics of any individual drug were observed.

Prednisone and prednisolone. The effect of prednisone on docetaxel pharmacokinetics, administered with standard dexamethasone premedication, was evaluated in 42 patients.

Prednisone. No effect of prednisone on docetaxel pharmacokinetics was observed.

Preclinical safety data

The carcinogenic potential of docetaxel has not been studied.

Docetaxel was shown to be genotoxic via an aneugenic mechanism in in vitro micronucleus and chromosomal aberration tests in CHO-K1 cells, and in in vivo micronucleus tests in mice. However, it did not induce mutagenicity in the Ames test or in the CHO/HGPRT gene mutation assay. These findings are consistent with the pharmacological activity of docetaxel.

Adverse effects on the testes observed in rodent toxicity studies indicate that docetaxel may impair male fertility.

Clinical characteristics.

Indications.

Breast cancer.

DOCETAXEL "EBEVE" in combination with doxorubicin and cyclophosphamide is indicated for adjuvant therapy in patients with

• operable breast cancer with lymph node involvement;
• operable breast cancer without lymph node involvement.

Among patients with operable breast cancer without lymph node involvement, adjuvant therapy should be administered only to those patients who are eligible for chemotherapy according to established international criteria for primary treatment of early-stage breast cancer.

DOCETAXEL "EBEVE" in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this disease.

Monotherapy with DOCETAXEL "EBEVE" is indicated for the treatment of patients with locally advanced or metastatic breast cancer in whom cytotoxic therapy has proven ineffective. Prior chemotherapy must have included the use of an anthracycline or an alkylating agent.

DOCETAXEL "EBEVE" in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer exhibiting HER2 protein overexpression by tumor cells and who have not previously received chemotherapy for metastatic disease.

DOCETAXEL "EBEVE" in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior cytotoxic chemotherapy. Previous therapy must have included an anthracycline.

Non-small cell lung cancer.

DOCETAXEL "EBEVE" is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.

DOCETAXEL "EBEVE" in combination with cisplatin is indicated for the treatment of patients with inoperable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this disease.

Prostate cancer.

DOCETAXEL "EBEVE" in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone-refractory metastatic prostate cancer.

Gastric adenocarcinoma.

DOCETAXEL "EBEVE" in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not previously received chemotherapy for metastatic disease.

Head and neck cancer.

DOCETAXEL "EBEVE" in combination with cisplatin and 5-fluorouracil is indicated for induction therapy in patients with locally advanced squamous cell carcinoma of the head and neck.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Baseline neutrophil count < 1500 cells/mm³. Severe hepatic impairment (see sections "Method of administration and dosage" and "Special precautions"). Contraindications to other medicinal products used in combination with docetaxel must also be taken into account.

Special safety precautions.

DOCETAXEL "EBEVE" belongs to antineoplastic agents and, like any other potentially toxic agent, requires adherence to safety measures during handling and preparation of solutions with DOCETAXEL "EBEVE". Use of protective gloves is recommended when handling the product.

If the concentrate of DOCETAXEL "EBEVE" or its infusion solution comes into contact with the skin, it should be immediately and thoroughly washed off with soap and water. If the concentrate of DOCETAXEL "EBEVE" or its infusion solution comes into contact with mucous membranes, they should be immediately and thoroughly rinsed with water.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that the metabolism of docetaxel may be altered when co-administered with drugs that induce, inhibit, or are metabolized by cytochrome P450-3A (resulting in potential competitive enzyme inhibition), such as cyclosporine, terfenadine, troleandomycin, ketoconazole, and erythromycin. Due to the potential for significant drug interactions, these medicinal products should be prescribed with caution as concomitant therapy.

When administering the drug in combination with CYP3A4 inhibitors, the frequency of adverse reactions caused by docetaxel may increase due to reduced metabolism. If concomitant use of potent CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) cannot be avoided, close clinical monitoring of patients should be ensured, and dose adjustment of docetaxel during therapy with a potent CYP3A4 inhibitor may be necessary. A pharmacokinetic study involving 7 patients showed that concomitant administration of docetaxel with the potent CYP3A4 inhibitor ketoconazole resulted in a significant reduction in docetaxel clearance (by 49%).

The pharmacokinetics of docetaxel when co-administered with prednisone were studied in patients with metastatic prostate cancer. Docetaxel is metabolized by CYP3A4, and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.

Docetaxel is highly bound to plasma proteins (> 95%). Although potential in vivo interactions between docetaxel and concomitant medications have not been formally studied, in vitro studies of interactions with drugs highly bound to plasma proteins, such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate, did not impair the binding of docetaxel to plasma proteins. Furthermore, dexamethasone does not impair the binding of docetaxel to plasma proteins. Docetaxel does not affect the plasma protein binding of digoxin.

The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide were not altered when these agents were administered concomitantly. Limited data from a single uncontrolled study suggest a possible interaction between docetaxel and carboplatin. When used in combination with docetaxel, the clearance of carboplatin was nearly 50% higher than previously observed during carboplatin monotherapy.

Special precautions for use.

When treating breast cancer and non-small cell lung cancer, premedication with an oral corticosteroid such as dexamethasone 16 mg daily (8 mg twice daily) for 3 days, starting 1 day before docetaxel administration, may reduce the frequency and severity of fluid retention and hypersensitivity reactions. For the treatment of prostate cancer, premedication consists of oral dexamethasone 8 mg administered 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion.

Hematological changes during treatment with the drug. The most common adverse reaction during docetaxel therapy is neutropenia. The lowest neutrophil counts were observed on average on day 7 of treatment; however, the time to reach the nadir of neutropenia may be shorter in patients who previously underwent multiple courses of anticancer therapy. All patients receiving docetaxel should undergo careful monitoring of complete blood counts. Subsequent treatment cycles with docetaxel should be administered only after neutrophil counts have recovered to ≥1500 cells/mm³ following the previous cycle.

If severe neutropenia (<500 cells/mm³ for 7 days or longer) develops during docetaxel therapy, the dose of the drug should be reduced in subsequent treatment cycles or appropriate symptomatic treatment initiated.

In patients receiving docetaxel in combination with cisplatin and 5-fluorouracil (TCF), a lower incidence of febrile neutropenia and neutropenic infections has been observed when patients received prophylactic G-CSF. Patients receiving TCF therapy should receive prophylactic G-CSF to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, or neutropenic infections). Careful monitoring of patients receiving G-CSF is required.

In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred less frequently when primary prophylaxis with G-CSF was used. In patients receiving adjuvant TAC therapy for breast cancer, primary prophylaxis with G-CSF should be considered to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, or neutropenic infection). Patients receiving TAC therapy should be closely monitored (see sections “Dosage and administration” and “Adverse reactions”).

Gastrointestinal reactions. Caution is advised when administering the drug to patients with neutropenia, especially those at increased risk of gastrointestinal complications. Although most cases occurred during the first or second cycle of chemotherapy with docetaxel, enterocolitis may develop at any time and can be fatal as early as the first day after onset. Patients should be carefully monitored for early signs of serious gastrointestinal toxicities (see sections “Special precautions for use,” “Dosage and administration,” and “Adverse reactions”).

Hypersensitivity reactions. Patients should be carefully monitored for possible hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within minutes after the start of docetaxel infusion; therefore, appropriate measures for treating hypotension and bronchospasm should be readily available. Mild hypersensitivity reactions, such as flushing or localized skin reactions, do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm, or generalized rash/erythema, require immediate discontinuation of docetaxel infusion and initiation of appropriate treatment. Re-administration of docetaxel is contraindicated in patients who have experienced a severe hypersensitivity reaction.

Patients with a history of hypersensitivity reactions to paclitaxel have an increased risk of hypersensitivity reactions to docetaxel, including more severe forms. Such patients should be closely monitored from the beginning of docetaxel therapy.

Skin reactions. Cases of localized erythema of the skin of the extremities (on palms and soles), accompanied by edema and subsequent desquamation of the epithelium, have been reported. Cases of severe symptoms such as skin rash with subsequent desquamation of the epithelium, necessitating interruption or complete discontinuation of docetaxel therapy, have also been reported.

Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, have been reported during docetaxel therapy. Patients should be informed about signs and symptoms of serious skin reactions and monitored closely. If signs or symptoms suggestive of these reactions occur, discontinuation of docetaxel should be considered.

Fluid retention. Patients with severe fluid retention, including pleural effusion, pericardial effusion, and ascites, should be closely monitored.

Respiratory disorders. Cases of acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis, and respiratory failure, which may be fatal, have been reported. Cases of radiation pneumonitis have been observed in patients receiving concomitant radiotherapy.

In the event of new or worsening pulmonary symptoms, careful monitoring, urgent evaluation, and appropriate treatment are required. Docetaxel therapy should be discontinued until a diagnosis is established. Early symptomatic treatment may improve patient outcomes. The benefit-risk ratio of resuming docetaxel therapy should be carefully evaluated.

Patients with hepatic impairment. Patients receiving monotherapy with docetaxel at a dose of 100 mg/m² who have serum transaminase levels (ALT and/or AST) more than 1.5 times the upper limit of normal (ULN) and alkaline phosphatase levels more than 2.5 times ULN are at higher risk of severe adverse reactions, including fatal outcomes due to drug toxicity (including sepsis and gastrointestinal bleeding), febrile neutropenia, infections, thrombocytopenia, stomatitis, and asthenia. Therefore, the recommended dose of docetaxel in patients with elevated liver function tests is 75 mg/m². Liver function tests should be performed before treatment initiation and prior to each new chemotherapy cycle.

For patients with serum bilirubin levels above ULN and/or ALT and AST levels exceeding 3.5 times ULN, accompanied by alkaline phosphatase levels more than 6 times ULN, no dose reduction is recommended; the drug should not be used unless absolutely necessary.

In clinical trials of docetaxel in combination with cisplatin and 5-fluorouracil for the treatment of gastric adenocarcinoma, patients with ALT and/or AST levels exceeding 1.5 times ULN in combination with elevated alkaline phosphatase (more than 2.5 times ULN) and bilirubin were excluded from the pivotal study. Therefore, dose reduction of docetaxel cannot be recommended for such patients, and the drug should not be used in this patient population unless absolutely necessary. Data on the use of docetaxel in combination therapy for other indications in patients with hepatic impairment are lacking.

Patients with renal impairment. Data on the use of docetaxel in patients with severe renal impairment are lacking.

Nervous system. The development of severe peripheral neurotoxic effects requires dose reduction of the drug (see section “Dosage and administration”).

Cardiotoxic effects. Cases of heart failure have been observed in patients receiving docetaxel in combination with trastuzumab, particularly if previous chemotherapy included anthracyclines (doxorubicin or epirubicin). This heart failure may be moderate or severe and is associated with a high risk of fatal outcome.

If docetaxel is to be used in combination with trastuzumab, the patient’s cardiovascular status should be evaluated before initiating therapy. Cardiac function should be monitored regularly during treatment (e.g., every 3 months) to identify patients who may develop cardiac dysfunction. More detailed information is provided in the trastuzumab product information.

Ventricular arrhythmias, including ventricular tachycardia (sometimes fatal), have been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil, and/or cyclophosphamide. Evaluation of cardiovascular status before initiating therapy is recommended.

Ocular disorders. Cases of cystoid macular edema (CME) have been reported in patients receiving docetaxel. Patients experiencing visual disturbances should undergo urgent and complete ophthalmological examination. If CME is diagnosed, docetaxel should be discontinued and appropriate treatment initiated (see section “Adverse reactions”).

Recurrence of primary malignant tumors.

Recurrences of primary malignant tumors have been reported during docetaxel therapy in combination with other chemotherapeutic agents and/or radiotherapy, associated with the primary malignancies. Recurrent primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma) may occur several months or years after docetaxel treatment. Patients should be monitored for recurrence of primary malignant tumors (see section “Adverse reactions”).

Tumor lysis syndrome. Tumor lysis syndrome has been reported with docetaxel use after the first or second treatment cycle (see section “Adverse reactions”). Patients at risk of tumor lysis syndrome (e.g., patients with renal dysfunction, hyperuricemia, bulky tumors, rapid progression) should be closely monitored. Correction of dehydration and treatment of elevated uric acid levels are recommended before initiating therapy.

Other warnings.

Women of childbearing potential must use contraception during treatment and for two months after discontinuation of docetaxel therapy. Men should use contraception during treatment and for four months after discontinuation of docetaxel therapy (see section “Use during pregnancy or breastfeeding”).

Concomitant use of docetaxel with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole should be avoided (see section “Interaction with other medicinal products and other forms of interaction”).

Additional warnings for use in adjuvant therapy of breast cancer.

Complicated neutropenia. For patients experiencing complicated neutropenia (prolonged neutropenia, febrile neutropenia, or infections), the use of G-CSF and dose reduction of docetaxel should be considered.

Gastrointestinal reactions. Early symptoms such as abdominal pain, tenderness, or abdominal pain on palpation, fever, and diarrhea (with or without neutropenia) may be the first signs of serious gastrointestinal toxicity and require immediate evaluation and treatment.

Heart failure (HF). Patients should be monitored for possible symptoms of heart failure during and after treatment. An increased risk of developing HF has been demonstrated in patients receiving TAC therapy for lymph node metastatic breast cancer during the first year after treatment (see sections “Adverse reactions” and “Pharmacodynamic properties”).

Leukemia. The risk of delayed onset myelodysplasia or myeloid leukemia in patients treated with the combination of docetaxel, doxorubicin, and cyclophosphamide (TAC) necessitates hematological monitoring during follow-up.

Patients with ≥4 metastatic lymph nodes. Since the benefits observed in patients with metastases in ≥4 lymph nodes were not statistically significant for disease-free survival (DFS) and overall survival (OS), the positive benefit-risk ratio of TAC therapy in these patients was not fully demonstrated in the final analysis (see section “Pharmacodynamic properties”).

Elderly patients

Safety data analysis in patients aged 60 years and older receiving the combination of docetaxel + capecitabine showed an increased incidence of treatment-related adverse reactions of grade 3–4 severity, serious treatment-related adverse reactions, and early discontinuation due to adverse reactions compared to patients under 60 years of age.

Warnings for use in adjuvant therapy of breast cancer

Data on the use of docetaxel in combination with doxorubicin and cyclophosphamide in patients aged 70 years and older are lacking.

Warnings for use in castration-resistant prostate cancer

Of the 333 patients who received docetaxel every three weeks in the prostate cancer study (TAX327), 209 were aged 65 years or older, and 68 were aged 75 years or older. When docetaxel was administered every three weeks, treatment-related nail changes in patients aged ≥65 years were reported ≥10% more frequently than in younger patients. Treatment-related increases in body temperature, diarrhea, loss of appetite, and peripheral edema occurred ≥10% more frequently in patients aged ≥75 years compared to those under 65 years.

Warnings for use in hormone-sensitive prostate cancer

Of the 545 patients who received docetaxel every three weeks in the hormone-sensitive prostate cancer study (STAMPEDE [Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluating the Use of New Agents]), 296 were aged 65 years or older, and 48 were aged 75 years or older. In most patients aged ≥65 years in the docetaxel group, hypersensitivity reactions, neutropenia, anemia, fluid retention, dyspnea, and nail changes were reported more frequently compared to patients under 65 years. None of these increases reached a 10% difference compared to the control group. In patients aged ≥75 years compared to younger patients, neutropenia, anemia, diarrhea, dyspnea, and upper respiratory tract infections were reported more frequently (at least 10% more).

Warnings for use in gastric adenocarcinoma

Of the 300 patients (221 patients in the phase III part and 79 patients in the phase II part of the clinical study) who received docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were aged ≥65 years and 4 were aged ≥75 years. The frequency of serious adverse reactions was higher in elderly patients compared to younger patients. In patients aged ≥65 years, lethargy, stomatitis, and neutropenic infection occurred ≥10% more frequently than in younger patients (all grades of severity).

Careful monitoring of elderly patients is required when using the TCF combination.

Excipients. This medicinal product contains 27% (by mass) ethanol (alcohol), meaning that 160 mg (average dose) contains 4100 mg of alcohol, equivalent to less than 100 ml of beer. The alcohol content should be considered when prescribing the drug to pregnant women, breastfeeding women, children, and patients in high-risk groups, such as patients with liver disease or epilepsy.

The product is harmful to patients suffering from alcoholism.

The potential impact of the drug on the central nervous system (CNS) should be considered.

The alcohol contained in this medicinal product may alter the effects of other medicinal products.

The alcohol contained in this medicinal product may negatively affect patients' ability to drive or operate machinery.

Shelf life after opening the vial. 28 days at 2–8°C and at room temperature, with or without protection from light.

Shelf life after dilution. The docetaxel infusion solution is supersaturated and may crystallize/precipitate over time. The infusion solution should be visually inspected carefully for precipitate before administration. If the infusion solution becomes cloudy or precipitate appears, the solution must be discarded.

Chemical and physical in-use stability has been demonstrated for 4 hours when stored at 2–8°C protected from light or at temperatures below 25°C without light protection, when diluted in 5% glucose solution or 0.9% sodium chloride solution (0.3 mg/mL and 0.74 mg/mL).

From a microbiological standpoint, the product should be used immediately. If not used immediately, the user is responsible for the duration and conditions of storage prior to use.

Use during pregnancy or breastfeeding.

Pregnancy.

Women of childbearing potential and men taking docetaxel should be advised to avoid pregnancy, women should not give birth, and must inform their physician immediately if pregnancy occurs.

Due to genotoxic risk (see section “Preclinical safety data”), women of childbearing potential must use effective contraception during treatment and for two months after discontinuation of docetaxel therapy. Men must use effective contraception during treatment and for four months after discontinuation of docetaxel therapy.

There are no data on the use of docetaxel in pregnant women. In animal studies, docetaxel showed embryotoxic and fetotoxic effects. Like other cytotoxic medicinal products, docetaxel may harm the fetus if used during pregnancy. Therefore, docetaxel should not be administered during pregnancy except in cases of absolute necessity.

Breastfeeding. Docetaxel is a lipophilic substance, but it is unknown whether it passes into breast milk.

Therefore, due to the potential for adverse effects in breastfed infants, breastfeeding must be discontinued during docetaxel therapy.

Fertility.

Animal studies have shown that docetaxel may affect male fertility (see section “Preclinical safety data”). Therefore, men receiving docetaxel should seek advice regarding sperm cryopreservation before starting treatment.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of docetaxel on the ability to drive or operate machinery have not been conducted.

The alcohol content of this medicinal product and the adverse effects of this drug may impair the ability to drive or operate machinery (see sections “Special precautions for use” and “Adverse reactions”). Therefore, patients should be warned about the potential impact of this drug on their ability to drive or operate machinery and advised not to engage in such activities if they experience the mentioned adverse effects during treatment.

Method of Administration and Dosage

Docetaxel should only be administered in departments specialized in cytotoxic chemotherapy. Docetaxel must be administered under the supervision of a physician experienced in anticancer chemotherapy.

Recommended Doses
For the treatment of breast cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer, premedication may be administered in the absence of contraindications. This premedication consists of oral corticosteroids such as dexamethasone 16 mg per day (8 mg twice daily) for 3 days, starting 1 day before docetaxel administration. Prophylactic use of granulocyte colony-stimulating factor (G-CSF) may be considered to reduce the risk of hematological toxicity.

For the treatment of metastatic castration-resistant prostate cancer, the recommended premedication regimen with oral dexamethasone, considering concomitant use of prednisone or prednisolone, includes administration of 8 mg of the drug 12 hours, 3 hours, and 1 hour before the first docetaxel infusion (see section "Special Instructions").

For the treatment of metastatic hormone-sensitive prostate cancer, the recommended premedication regimen with oral dexamethasone, regardless of concomitant use of prednisone or prednisolone, includes administration of 8 mg of the drug 12 hours, 3 hours, and 1 hour before docetaxel infusion (see section "Special Instructions").

To reduce the risk of hematological toxicity of docetaxel, prophylactic use of granulocyte colony-stimulating factor (G-CSF) may be considered. Docetaxel is administered as a 1-hour intravenous infusion every 3 weeks.

Breast Cancer
In adjuvant therapy of operable breast cancer with or without lymph node involvement, the recommended dose of docetaxel is 75 mg/m², administered as a 1-hour infusion given 1 hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for 6 cycles (TAC regimen) (see also section "Dose Adjustments During Treatment").

For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dose of docetaxel is 100 mg/m² as monotherapy. For first-line therapy, docetaxel 75 mg/m² should be administered in combination with doxorubicin (50 mg/m²).

The recommended dose of docetaxel in combination with trastuzumab is 100 mg/m² every 3 weeks, with trastuzumab administered weekly. In the pivotal study, the initial docetaxel infusion was administered the day after the patient received the first dose of trastuzumab. Subsequent doses of docetaxel were administered immediately after completion of trastuzumab infusion, provided the patient tolerated the previous trastuzumab dose well. Dosing and administration instructions for trastuzumab are described in the "Summary of Product Characteristics" for trastuzumab.

When docetaxel is used in combination with capecitabine, the recommended dose of docetaxel is 75 mg/m² every 3 weeks, and capecitabine 1250 mg/m² twice daily (within 30 minutes after meals) for 2 weeks followed by a 1-week rest period. Specific dosing recommendations for capecitabine based on body surface area are described in the "Summary of Product Characteristics" for capecitabine.

Non-Small Cell Lung Cancer
In patients who have not previously received chemotherapy and are being treated for non-small cell lung cancer, the recommended dosing regimen is docetaxel 75 mg/m² followed immediately by cisplatin 75 mg/m² administered as a 30–60 minute infusion. For treatment after prior platinum-based chemotherapy has failed, the recommended dose is 75 mg/m² as monotherapy.

Prostate Cancer

Metastatic Castration-Resistant Prostate Cancer
The recommended dose of docetaxel is 75 mg/m². Prednisone or prednisolone 5 mg orally twice daily should be administered continuously (see section "Pharmacodynamics").

Metastatic Hormone-Sensitive Prostate Cancer
The recommended dose of docetaxel is 75 mg/m² every 3 weeks for 6 cycles. Prednisone or prednisolone may be administered continuously at 5 mg orally twice daily.

Gastric Adenocarcinoma
The recommended dose of docetaxel is 75 mg/m² administered as a 1-hour infusion, followed by cisplatin 75 mg/m² as a 1–3 hour infusion (both drugs administered only on day 1 of the cycle). Immediately after completion of cisplatin infusion, 5-fluorouracil 750 mg/m²/day is administered as a continuous 24-hour infusion for 5 days. This treatment cycle should be repeated every 3 weeks. Patients should receive antiemetic premedication and adequate hydration prior to cisplatin administration. Prophylactic use of G-CSF is recommended to reduce the risk of hematological toxicity (see also section "Dose Adjustments During Treatment").

Head and Neck Cancer
Patients should receive antiemetic premedication and adequate hydration (before and after cisplatin administration). Prophylactic use of G-CSF may be considered to reduce the risk of hematological toxicity. In studies TAX 323 and TAX 324, all patients in the docetaxel group received prophylactic antibiotics.

• Induction chemotherapy followed by radiotherapy (TAX 323)
  For induction chemotherapy of unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN), docetaxel 75 mg/m² should be administered as a 1-hour infusion, immediately followed on day 1 of the cycle by cisplatin 75 mg/m² as a 1–3 hour infusion. Immediately after completion of cisplatin infusion, 5-fluorouracil 750 mg/m²/day is administered as a continuous infusion for 5 days. This regimen should be repeated every 3 weeks for a total of 4 cycles. After chemotherapy, patients should receive radiotherapy.

• Induction chemotherapy followed by chemoradiotherapy (TAX 324)
  For induction therapy in patients with locally advanced SCCHN (technically unresectable, with low probability of surgical resection or requiring an organ-preserving approach), the recommended dose of docetaxel is 75 mg/m² administered as a 1-hour intravenous infusion, immediately followed on day 1 of the cycle by cisplatin 100 mg/m² as an infusion lasting from 30 minutes to 3 hours. Immediately after completion of cisplatin infusion, 5-fluorouracil 1000 mg/m²/day is administered as a continuous infusion for 4 days.

This regimen should be administered every 3 weeks for 3 cycles. After chemotherapy, patients should receive chemoradiotherapy.

Dose adjustment recommendations for cisplatin and 5-fluorouracil are described in the respective "Summary of Product Characteristics" for these medicinal products.

Dose Adjustments During Treatment

General Principles
Docetaxel should be administered only if the neutrophil count is ≥ 1500 cells/mm³.

If febrile neutropenia develops during docetaxel therapy, or if the neutrophil count is < 500 cells/mm³ for more than 1 week, or if severe acute or cumulative skin reactions or severe peripheral neuropathy occur during treatment, the dose of docetaxel should be reduced from 100 mg/m² to 75 mg/m² and/or from 75 mg/m² to 60 mg/m². If such reactions occur at the 60 mg/m² dose level, treatment should be discontinued.

Adjuvant Therapy for Breast Cancer
In patients receiving adjuvant therapy with docetaxel, doxorubicin, and cyclophosphamide (TAC regimen) for breast cancer, primary prophylaxis with G-CSF should be considered. The dose of docetaxel should be reduced to 60 mg/m² in all subsequent cycles in patients who experience febrile neutropenia and/or neutropenic infection. Patients who develop grade III or IV stomatitis should have the dose reduced to 60 mg/m².

In Combination with Cisplatin
For patients who, during the previous cycle of treatment with docetaxel 75 mg/m² in combination with cisplatin, had a nadir platelet count < 25,000 cells/mm³, or who developed febrile neutropenia or severe non-hematological toxicities during docetaxel therapy, the dose of docetaxel in subsequent cycles should be reduced to 65 mg/m². Dose adjustment recommendations for cisplatin are described in the respective product information.

In Combination with Capecitabine

• Dose adjustment recommendations for capecitabine are described in the respective product information for capecitabine.
• For patients who experience grade II toxicity that persists at the time of the next scheduled docetaxel/capecitabine treatment, treatment should be delayed until toxicity resolves to grade 0–I, after which treatment should be resumed at 100% of the initial dose.
• For patients who experience a second occurrence of grade II toxicity at any time during the treatment cycle, or a first occurrence of grade III toxicity at any time during treatment, therapy should be interrupted until toxicity resolves to grade 0–I, after which docetaxel should be resumed at a dose of 55 mg/m².
• If further toxicity occurs or grade IV toxicity develops, docetaxel therapy should be discontinued.

Dose adjustment recommendations for trastuzumab are described in the respective product information for trastuzumab.

In Combination with Cisplatin and 5-Fluorouracil
If a patient develops an episode of febrile neutropenia, prolonged neutropenia, or infection during neutropenia despite G-CSF administration, the administered dose of docetaxel should be reduced from 75 mg/m² to 60 mg/m². If further episodes of complicated neutropenia occur, the dose of docetaxel should be reduced from 60 mg/m² to 45 mg/m². In case of grade IV thrombocytopenia, the dose of docetaxel should be reduced from 75 mg/m² to 60 mg/m². Patients may receive subsequent treatment cycles with docetaxel only after recovery of neutrophil counts to > 1500 cells/mm³ and platelet counts to > 100,000 cells/mm³. If the aforementioned toxicities do not resolve, docetaxel treatment should be discontinued (see section "Special Instructions").

Recommended measures for dose adjustment of chemotherapy agents in patients receiving the combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU):

Specific dose adjustments for cisplatin and 5-fluorouracil are described in the respective instructions for medical use of these medicinal products.

In the course of baseline studies in patients with SCCHN who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infectious diseases), prophylactic use of G-CSF (e.g., from day 6 to day 15 of the cycle) is recommended in all subsequent chemotherapy cycles.

Special patient groups.

Patients with hepatic impairment. Based on pharmacokinetic data from monotherapy studies with docetaxel 100 mg/m², in patients with transaminase levels (ALT and/or AST) exceeding the upper limit of normal (ULN) by 1.5 times and alkaline phosphatase levels exceeding ULN by 2.5 times, a docetaxel dose of 75 mg/m² is recommended. In patients with elevated serum bilirubin and/or ALT and AST levels > 3.5 times above normal in combination with alkaline phosphatase levels increased more than 6 times above ULN, no dose reduction recommendations are provided, and docetaxel therapy should not be administered except under compelling clinical indications.

When the drug was used in combination with cisplatin and 5-fluorouracil for the treatment of gastric adenocarcinoma, patients with ALT and/or AST levels exceeding ULN by 1.5 times in combination with elevated alkaline phosphatase (exceeding ULN by 2.5 times) and bilirubin were excluded from the pivotal clinical trial; for such patients, no dose reduction recommendations are available, and docetaxel therapy should not be administered except under compelling clinical indications. Data on the use of docetaxel combination therapy in patients with hepatic impairment for other indications are lacking.

Patients with renal impairment.

Data on the use of docetaxel in patients with renal impairment are lacking.

Elderly patients. According to population pharmacokinetic analysis, there are no specific recommendations for dose adjustment in elderly patients.

When used in combination with capecitabine, the initial dose of capecitabine should be reduced to 75% in patients aged 60 years and older (see General characteristics of the medicinal product capecitabine).

Children. Docetaxel is not recommended for use in children due to limited evidence on safety and/or efficacy in this patient population.

Results from studies on the efficacy and safety of docetaxel for the treatment of children have not been obtained.

The safety and efficacy of docetaxel for the treatment of nasopharyngeal carcinoma in children aged 1 month and older have not yet been established.

There are no substantial evidence-based data on the use of docetaxel in children for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma, or head and neck cancer, except for poorly differentiated nasopharyngeal carcinoma types II and III.

Overdose. There are several reports of docetaxel overdose. There is currently no specific antidote for docetaxel. In case of overdose, the patient should be hospitalized in a specialized unit and closely monitored for vital functions. An increase in the severity of adverse effects should be expected. The main anticipated complications of overdose include bone marrow suppression, peripheral neurotoxicity, and mucosal inflammation. Following an overdose, patients should promptly receive therapeutic doses of G-CSF. If necessary, other symptomatic measures should be taken.

Adverse Reactions.

Summary of safety profile data for all indications.

Adverse reactions considered to be probably or almost certainly related to docetaxel administration were observed in:

• 1,312 and 121 patients receiving docetaxel monotherapy at doses of 100 mg/m² and 75 mg/m², respectively;
• 258 patients receiving docetaxel in combination with doxorubicin;
• 406 patients receiving docetaxel in combination with cisplatin;
• 92 patients receiving docetaxel in combination with trastuzumab;
• 255 patients receiving docetaxel in combination with capecitabine;
• 332 patients receiving docetaxel in combination with prednisone or prednisolone (data on clinically significant treatment-related adverse reactions are presented);
• 1,276 patients (744 and 532 patients in TAX 316 and GEICAM 9805 studies, respectively) receiving docetaxel in combination with doxorubicin and cyclophosphamide (data on clinically significant treatment-related adverse reactions are presented);
• 300 patients with gastric adenocarcinoma (221 patients from a phase III study and 79 patients from a phase II study) receiving docetaxel in combination with cisplatin and 5-fluorouracil (data on clinically significant treatment-related adverse reactions are presented);
• 174 and 251 patients with head and neck cancer receiving docetaxel in combination with cisplatin and 5-fluorouracil (data on clinically significant treatment-related adverse reactions are presented).

These reactions were described using the National Cancer Institute (NCI) Common Toxicity Criteria (Grade III = G3; Grades III–IV = G3/4; Grade IV = G4) and COSTART and MedDRA dictionary definitions.

Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and adverse reactions with unknown frequency (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

The most frequently reported adverse reactions during docetaxel monotherapy were: neutropenia (reversible and non-cumulative in nature; the nadir of neutrophil count typically occurred on day 7, and the mean duration of severe neutropenia (<500 cells/mm³) was approximately 7 days), anemia, alopecia, nausea, vomiting, stomatitis, diarrhea, and asthenia. The severity of adverse effects associated with docetaxel may increase when combined with other chemotherapeutic agents.

Regarding the use of docetaxel in combination with trastuzumab, adverse effects (of any grade) were observed in ≥10% of patients. Compared to docetaxel monotherapy, this combination increased the frequency of serious adverse effects (40% vs. 31%) and Grade IV adverse effects (34% vs. 23%).

The most common (≥5%) adverse effects of the docetaxel and capecitabine combination observed in a phase III clinical trial in patients with breast cancer previously treated with anthracyclines are listed in the General Characteristics section of the capecitabine medicinal product.

The following adverse reactions commonly occur with docetaxel administration.

Immune system disorders. Hypersensitivity reactions usually occurred within minutes after the start of docetaxel infusion and were generally mild or moderate in severity. The most commonly reported symptoms included skin flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, fever, or chills. Severe adverse reactions manifested as hypotension and/or bronchospasm or generalized rash/erythema (see section "Special precautions for use").

Nervous system disorders. Severe peripheral neurotoxicity requires dose reduction of the drug (see sections "Dosage and administration"). Mild to moderate neurosensory reactions included paresthesia, dysesthesia, or pain sensations, including burning sensations. Neuromotor reactions were predominantly characterized by generalized weakness.

Skin and subcutaneous tissue disorders. Reversible skin reactions, generally mild or moderate in severity, were observed. These reactions included rash, often localized predominantly on the palms and soles (including severe hand-foot syndrome), as well as on the arms, face, or chest, frequently accompanied by pruritus. Rashes most commonly appeared within one week after docetaxel infusion. Severe manifestations occurred less frequently, such as rash with subsequent desquamation, sometimes necessitating interruption or complete discontinuation of docetaxel (see sections "Dosage and administration" and "Special precautions for use"). Severe nail disorders included hypo- or hyperpigmentation, and in some cases pain and onycholysis.

General disorders and administration site conditions. Infusion site reactions were predominantly mild and included hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, hemorrhage, and venous edema.

Cases of fluid retention included peripheral edema and, less frequently, pleural or pericardial effusion, ascites, and weight gain. Peripheral edema typically began in the lower extremities and could become generalized, accompanied by weight gain of 3 kg or more. Fluid retention has a cumulative nature both in frequency and severity (see section "Special precautions for use").

Monotherapy of breast cancer with DOXETAXEL "EBEWE" at a dose of 100 mg/m².

Infections and infestations. Very common: infectious diseases (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7% of cases). Common: infections associated with G4 neutropenia (G3/4: 4.6%).

Blood and lymphatic system disorders. Very common: neutropenia (G4: 76.4%); anemia (G3/4: 8.9%); febrile neutropenia. Common: thrombocytopenia (G4: 0.2%).

Immune system disorders. Very common: hypersensitivity reaction (G3/4: 5.3%).

Metabolism and nutrition disorders. Very common: anorexia.

Nervous system disorders. Very common: peripheral sensory neuropathy (G3: 4.1%); peripheral motor neuropathy (G3/4: 4%); dysgeusia (severe: 0.07%).

Cardiac disorders. Common: arrhythmia (G3/4: 0.7%). Uncommon: heart failure.

Vascular disorders. Common: arterial hypotension; arterial hypertension; hemorrhagic complications.

Respiratory, thoracic and mediastinal disorders. Very common: dyspnea (severe: 2.7%).

Gastrointestinal disorders. Very common: stomatitis (G3/4: 5.3%); diarrhea (G3/4: 4%); nausea (G3/4: 4%); vomiting (G3/4: 3%). Common: constipation (severe: 0.2%); abdominal pain (severe: 1%); gastrointestinal hemorrhage (severe: 0.3%). Uncommon: esophagitis (severe: 0.4%).

Skin and subcutaneous tissue disorders. Very common: alopecia; skin reactions (G3/4: 5.9%); nail disorders (severe: 2.6%).

Musculoskeletal and connective tissue disorders. Very common: myalgia (severe: 1.4%). Common: arthralgia.

General disorders and administration site conditions. Very common: fluid retention (severe: 6.5%); asthenia (severe: 11.2%); pain. Common: local reactions after infusion; non-cardiac chest pain (severe: 0.4%).

Investigations. Common: increased blood bilirubin levels G3/4 (<5%); increased alkaline phosphatase levels G3/4 (<4%); increased AST levels G3/4 (<3%); increased ALT levels G3/4 (<2%).

Description of specific adverse reactions observed in patients with breast cancer receiving monotherapy with docetaxel at a dose of 100 mg/m².

Blood and lymphatic system disorders. Rare: episodes of bleeding or hemorrhage associated with Grade III/IV thrombocytopenia.

Nervous system disorders. Reversible neurotoxicity occurred in 35.3% of patients after monotherapy with docetaxel at a dose of 100 mg/m². Symptoms of toxicity resolved spontaneously within 3 months.

Skin and subcutaneous tissue disorders. Very rare: one case of irreversible alopecia was reported at the end of the study. 73% of skin reactions were reversible and resolved within 21 days.

General disorders and administration site conditions. The mean cumulative dose of docetaxel during the treatment period exceeded 1000 mg/m², and the median time to resolution of fluid retention was 16.4 weeks (range from 0 to 42 weeks). The onset of moderate to severe fluid retention was delayed in patients who received premedication (mean cumulative dose: 818.9 mg/m²) compared to patients who did not receive premedication (mean cumulative dose: 489.7 mg/m²); however, several cases of this adverse effect were reported during early treatment cycles.

Monotherapy of non-small cell lung cancer with DOXETAXEL "EBEWE" at a dose of 75 mg/m².

Infections and infestations. Very common: infectious diseases (G3/4: 5%).

Blood and lymphatic system disorders. Very common: neutropenia (G4: 54.2%); anemia (G3/4: 10.8%); thrombocytopenia (G4: 1.7%). Common: febrile neutropenia.

Immune system disorders. Common: hypersensitivity reaction (no severe cases reported).

Metabolism and nutrition disorders. Very common: anorexia.

Nervous system disorders. Very common: peripheral sensory neuropathy (G3/4: 0.8%). Common: peripheral motor neuropathy (G3/4: 2.5%).

Cardiac disorders. Common: arrhythmia (non-severe).

Vascular disorders. Common: arterial hypotension.

Gastrointestinal disorders. Very common: nausea (G3/4: 3.3%); stomatitis (G3/4: 1.7%); vomiting (G3/4: 0.8%); diarrhea (G3/4: 1.7%). Common: constipation.

Skin and subcutaneous tissue disorders. Very common: alopecia; skin reactions (G3/4: 0.8%). Common: nail disorders (severe: 0.8%).

Musculoskeletal and connective tissue disorders. Common: myalgia.

General disorders and administration site conditions. Very common: asthenia (severe: 12.4%); fluid retention (severe: 0.8%); pain.

Investigations. Common: increased blood bilirubin levels G3/4 (<2%).

DOXETAXEL "EBEWE" at a dose of 75 mg/m² in combination with doxorubicin for the treatment of breast cancer.

Infections and infestations. Very common: infectious diseases (G3/4: 7.8%).

Blood and lymphatic system disorders. Very common: neutropenia (G4: 91.7%); anemia (G3/4: 9.4%); febrile neutropenia; thrombocytopenia (G4: 0.8%).

Immune system disorders. Common: hypersensitivity reactions (G3/4: 1.2%).

Metabolism and nutrition disorders. Common: anorexia.

Nervous system disorders. Very common: peripheral sensory neuropathy (G3: 0.4%). Common: peripheral motor neuropathy (G3/4: 0.4%).

Cardiac disorders. Common: heart failure; arrhythmia (non-severe).

Vascular disorders. Uncommon: hypotension.

Gastrointestinal disorders. Very common: nausea (G3/4: 5%); stomatitis (G3/4: 7.8%); diarrhea (G3/4: 6.2%); vomiting (G3/4: 5%); constipation.

Skin and subcutaneous tissue disorders. Very common: alopecia; nail disorders (severe: 0.4%); skin reactions (non-severe).

Musculoskeletal and connective tissue disorders. Common: myalgia.

General disorders and administration site conditions. Very common: asthenia (severe: 8.1%); fluid retention (severe: 1.2%); pain. Common: local reactions after infusion.

Investigations. Common: increased blood bilirubin levels G3/4 (<2.5%); increased alkaline phosphatase levels G3/4 (<2.5%). Uncommon: increased AST levels G3/4 (<1%); increased ALT levels G3/4 (<1%).

DOXETAXEL "EBEWE" at a dose of 75 mg/m² in combination with cisplatin for the treatment of non-small cell lung cancer.

Infections and infestations. Very common: infections (G3/4: 5.7%).

Blood and lymphatic system disorders. Very common: neutropenia (G4: 51.5%); anemia (G3/4: 6.9%); thrombocytopenia (G4: 0.5%). Common: febrile neutropenia.

Immune system disorders. Very common: hypersensitivity reactions (G3/4: 2.5%).

Metabolism and nutrition disorders. Very common: anorexia.

Nervous system disorders. Very common: peripheral sensory neuropathy (G3: 3.7%); peripheral motor neuropathy (G3/4: 2%).

Cardiac disorders. Common: arrhythmia (G3/4: 0.7%). Uncommon: heart failure.

Vascular disorders. Common: arterial hypotension (G3/4: 0.7%).

Gastrointestinal disorders. Very common: nausea (G3/4: 9.6%); vomiting (G3/4: 7.6%); diarrhea (G3/4: 6.4%); stomatitis (G3/4: 2%). Common: constipation.

Skin and subcutaneous tissue disorders. Very common: alopecia; nail disorders (severe: 0.7%); skin reactions (G3/4: 0.2%).

Musculoskeletal and connective tissue disorders. Very common: myalgia (severe: 0.5%).

General disorders and administration site conditions. Very common: asthenia (severe: 9.9%); fluid retention (severe: 0.7%); fever (G3/4: 1.2%). Common: local reactions after infusion; pain.

Investigations. Common: increased blood bilirubin levels G3/4 (2.1%); increased ALT levels G3/4 (1.3%). Uncommon: increased AST levels G3/4 (0.5%); increased alkaline phosphatase levels G3/4 (0.3%).

DOXETAXEL "EBEWE" at a dose of 100 mg/m² in combination with trastuzumab for the treatment of breast cancer.

Blood and lymphatic system disorders. Very common: neutropenia (G3/4: 32%); febrile neutropenia (including neutropenia associated with fever and antibiotic use) or neutropenic sepsis.

Metabolism and nutrition disorders. Very common: anorexia.

Psychiatric disorders. Very common: insomnia.

Nervous system disorders. Very common: paresthesia; headache; dysgeusia; hypoesthesia.

Eye disorders. Very common: lacrimation; conjunctivitis.

Cardiac disorders. Common: heart failure.

Vascular disorders. Very common: lymphedema.

Respiratory, thoracic and mediastinal disorders. Very common: epistaxis; throat and larynx pain; nasopharyngitis; dyspnea; cough; rhinorrhea.

Gastrointestinal disorders. Very common: nausea; diarrhea; vomiting; constipation; stomatitis; dyspepsia; abdominal pain.

Skin and subcutaneous tissue disorders. Very common: alopecia; erythema; rash; nail disorders.

Musculoskeletal and connective tissue disorders. Very common: myalgia; arthralgia; limb pain; bone pain; back pain.

General disorders and administration site conditions. Very common: asthenia; peripheral edema; fever; increased fatigue; mucosal inflammation; pain; acute respiratory illness; chest pain; chills. Common: lethargy.

Investigations. Very common: weight gain.

Description of specific adverse reactions observed in patients with breast cancer receiving docetaxel at a dose of 100 mg/m² in combination with trastuzumab.

Cardiac disorders. Symptomatic heart failure was reported in 2.2% of patients receiving docetaxel and trastuzumab and was absent in patients receiving docetaxel monotherapy. Prior adjuvant therapy with anthracyclines was administered in 64% of patients in the combination therapy group (docetaxel and trastuzumab) and in 55% of patients in the docetaxel monotherapy group.

Blood and lymphatic system disorders. Very common: hematological toxicity of combination therapy with trastuzumab and docetaxel increased compared to docetaxel monotherapy (32% of Grade III/IV neutropenia vs. 22% using NCI-CTC criteria [National Cancer Institute – Common Toxicity Criteria]). It should be noted that the frequency of this adverse reaction in this patient group may be underestimated, as even with docetaxel monotherapy at a dose of 100 mg/m², neutropenia occurs in 97% of patients, with 76% being Grade IV (based on the nadir of neutrophil count in blood). The frequency of febrile neutropenia or neutropenic sepsis also increases in patients receiving the combination of Herceptin and docetaxel (23% vs. 17% compared to patients on docetaxel monotherapy).

DOXETAXEL "EBEWE" at a dose of 75 mg/m² in combination with capecitabine for the treatment of breast cancer.

Infections and infestations. Common: oral mucosal candidiasis (G3/4: <1%).

Blood and lymphatic system disorders. Very common: neutropenia (G3/4: 63%); anemia (G3/4: 10%). Common: thrombocytopenia (G3/4: 3%).

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 1%); decreased appetite. Common: dehydration (G3/4: 2%).

Nervous system disorders. Very common: dysgeusia (G3/4: <1%); paresthesia (G3/4: <1%). Common: dizziness; headache (G3/4: <1%); peripheral neuropathy.

Eye disorders. Very common: lacrimation.

Respiratory, thoracic and mediastinal disorders. Very common: throat and larynx pain (G3/4: 2%). Common: dyspnea (G3/4: 1%); cough (G3/4: <1%); epistaxis (G3/4: <1%).

Gastrointestinal disorders. Very common: stomatitis (G3/4: 18%); diarrhea (G3/4: 14%); nausea (G3/4: 6%); vomiting (G3/4: 4%); constipation (G3/4: 1%); abdominal pain (G3/4: 2%); dyspepsia. Common: upper abdominal pain; dry mouth.

Skin and subcutaneous tissue disorders. Very common: hand-foot syndrome (G3/4: 24%); alopecia (G3/4: 6%); nail disorders (G3/4: 2%). Common: dermatitis; erythematous rash (G3/4: <1%); nail discoloration; onycholysis (G3/4: 1%).

Musculoskeletal and connective tissue disorders. Very common: myalgia (G3/4: 2%); arthralgia (G3/4: 1%). Common: limb pain (G3/4: <1%); back pain (G3/4: 1%).

General disorders and administration site conditions. Very common: asthenia (G3/4: 3%); fever (G3/4: 1%); increased fatigue/general weakness (G3/4: 5%); peripheral edema (G3/4: 1%). Common: lethargy; pain.

Investigations. Common: weight loss; weight gain; increased blood bilirubin levels G3/4 (9%).

DOXETAXEL "EBEWE" at a dose of 75 mg/m² in combination with prednisone or prednisolone for the treatment of prostate cancer.

Infections and infestations. Very common: infections (G3/4: 3.3%).

Blood and lymphatic system disorders. Very common: neutropenia (G3/4: 32%); anemia (G3/4: 4.9%). Common: thrombocytopenia (G3/4: 0.6%); febrile neutropenia.

Immune system disorders. Common: hypersensitivity reactions (G3/4: 0.6%).

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 0.6%).

Nervous system disorders. Very common: peripheral sensory neuropathy (G3/4: 1.2%); dysgeusia (G3/4: 0%). Common: peripheral motor neuropathy (G3/4: 0%).

Eye disorders. Common: lacrimation (G3/4: 0.6%).

Cardiac disorders. Common: deterioration of left ventricular function (G3/4: 0.3%).

Respiratory, thoracic and mediastinal disorders. Common: epistaxis (G3/4: 0%); dyspnea (G3/4: 0.6%); cough (G3/4: 0%).

Gastrointestinal disorders. Very common: nausea (G3/4: 2.4%); diarrhea (G3/4: 1.2%); stomatitis/pharyngitis (G3/4: 0.9%); vomiting (G3/4: 1.2%).

Skin and subcutaneous tissue disorders. Very common: alopecia; nail disorders (non-severe). Common: skin desquamation (G3/4: 0.3%).

Musculoskeletal and connective tissue disorders. Common: arthralgia (G3/4: 0.3%); myalgia (G3/4: 0.3%).

General disorders and administration site conditions. Very common: increased fatigue (G3/4: 3.9%); fluid retention (non-severe: 0.6%).

DOXETAXEL "EBEWE" at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy for the treatment of lymph node-positive (TAX316) and lymph node-negative (GEICAM 9895) breast cancer – summary data.

Infections and infestations. Very common: infectious diseases (G3/4: 2.4%); neutropenic infection (G3/4: 2.7%).

Blood and lymphatic system disorders. Very common: anemia (G3/4: 3%); neutropenia (G3/4: 59.2%); thrombocytopenia (G3/4: 1.6%); febrile neutropenia (G3/4: data not available).

Immune system disorders. Common: hypersensitivity reactions (G3/4: 0.6%).

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 1.5%).

Nervous system disorders. Very common: dysgeusia (G3/4: 0.6%); peripheral sensory neuropathy (G3/4: 0.1%). Common: peripheral motor neuropathy (G3/4: 0%); neurocortical disorders (G3/4: 0.3%); cerebellar disorders (G3/4: 0.1%). Uncommon: syncope (G3/4: 0%); neurotoxicity (G3/4: 0%); somnolence (G3/4: 0%).

Eye disorders. Very common: conjunctivitis (G3/4: <0.1%). Common: lacrimation (G3/4: <0.1%).

Cardiac disorders. Common: arrhythmia (G3/4: 0.2%); congestive heart failure.

Vascular disorders. Very common: vasodilation (G3/4: 0.5%). Common: arterial hypotension (G3/4: 0%); phlebitis (G3/4: 0%). Uncommon: lymphedema (G3/4: 0%).

Respiratory, thoracic and mediastinal disorders. Common: cough (G3/4: 0%).

Gastrointestinal disorders. Very common: nausea (G3/4: 5%); stomatitis (G3/4: 6%); vomiting (G3/4: 4.2%); diarrhea (G3/4: 3.4%); constipation (G3/4: 0.5%). Common: abdominal pain (G3/4: 0.4%). Uncommon: colitis/enteritis/colonic perforation.

Skin and subcutaneous tissue disorders. Very common: alopecia (G3/4: 0.1%); skin manifestations of toxicity (G3/4: 0.6%); nail disorders (G3/4: 0.4%).

Musculoskeletal and connective tissue disorders. Very common: myalgia (G3/4: 0.7%); arthralgia (G3/4: 0.2%).

Reproductive system and breast disorders. Very common: amenorrhea (G3/4: data not available).

General disorders and administration site conditions. Very common: asthenia (G3/4: 10%); fever (G3/4: data not available); peripheral edema (G3/4: 0.2%).

Investigations. Common: weight gain (G3/4: 0%); weight loss (G3/4: 0.2%).

Description of specific adverse reactions observed in patients receiving adjuvant therapy with DOXETAXEL "EBEWE" at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide for the treatment of lymph node-positive (TAX316) and lymph node-negative (GEICAM 9895) breast cancer.

Nervous system disorders. In the study of lymph node-positive breast cancer (TAX316), peripheral sensory neuropathy persisted during the follow-up period in 84 patients (11.3%) in the TAC group and in 15 patients (2%) in the FAC group. At the end of the follow-up period (median follow-up: 8 years), peripheral sensory neuropathy was observed in 10 patients (1.3%) in the TAC group and in 2 patients (0.3%) in the FAC group.

In the GEICAM 9805 study, peripheral sensory neuropathy that began during the treatment period persisted during the follow-up period in 10 patients (1.9%) in the TAC group and in 4 patients (0.8%) in the FAC group. At the end of the follow-up period (median follow-up: 10 years and 5 months), peripheral sensory neuropathy persisted in 3 patients (0.6%) in the TAC group and in 1 patient (0.2%) in the FAC group.

Cardiac disorders. In the TAX316 study, congestive heart failure was observed in 26 patients (3.5%) in the TAC group and in 17 patients (2.3%) in the FAC group. Except for one patient, congestive heart failure was diagnosed in all patients in each group more than 30 days after the end of the treatment period. Two patients in the TAC group and four patients in the FAC group died due to heart failure.

In the GEICAM 9805 study, heart failure was recorded in 3 patients (0.6%) in the TAC group and in 3 patients (0.6%) in the FAC group during the follow-up period. At the end of the follow-up period (actual median follow-up: 10 years and 5 months), no patient had chronic heart failure (CHF) in the TAC group, but one patient in this group died due to dilated cardiomyopathy; CHF was observed in one patient (0.2%) in the FAC group.

Skin and subcutaneous tissue disorders. In the TAX316 study, alopecia that persisted during the follow-up period after the end of chemotherapy was reported in 687 out of 744 (92.3%) patients receiving TAC therapy and in 645 out of 736 (87.6%) patients treated with the FAC regimen.

At the end of the follow-up period (actual median follow-up: 8 years), alopecia persisted in 29 patients in the TAC group (3.9%) and in 16 patients in the FAC group (2.2%).

In the GEICAM 9805 study, alopecia that began during the treatment period and persisted during follow-up was observed in 49 patients (9.2%) in the TAC group and in 35 patients (6.7%) in the FAC group. Alopecia associated with the investigational drug began or worsened during the follow-up period in 42 patients (7.9%) in the TAC group and in 30 patients (5.8%) in the FAC group.

At the end of the follow-up period (median follow-up duration: 10 years and 5 months), alopecia persisted in 3 patients (0.6%) in the TAC group and in 1 patient (0.2%) in the FAC group.

Reproductive system and breast disorders. In the TAX316 study, amenorrhea that began during the treatment period and persisted during follow-up after the end of chemotherapy was observed in 202 out of 744 patients (27.2%) in the TAC group and in 125 out of 736 patients (17.0%) in the FAC group. At the end of the follow-up period (median follow-up duration: 8 years), amenorrhea persisted in 121 out of 744 patients (16.3%) in the TAC group and in 86 patients (11.7%) in the FAC group.

In the GEICAM 9805 study, amenorrhea that began during the treatment period and persisted during follow-up was observed in 18 patients (3.4%) in the TAC group and in 5 patients (1.0%) in the FAC group. At the end of the follow-up period (median follow-up duration: 10 years and 5 months), amenorrhea persisted in 7 patients (1.3%) in the TAC group and in 4 patients (0.8%) in the FAC group.

General disorders and administration site conditions.

In the TAX316 study, peripheral edema that developed during the treatment period and persisted during follow-up after the end of chemotherapy was observed in 119 out of 744 patients in the TAC group (16.0%) and in 23 out of 736 patients in the FAC group (3.1%). At the end of the follow-up period (actual median follow-up: 8 years), peripheral edema persisted in 19 patients in the TAC group (2.6%) and in 4 patients in the FAC group (0.5%).

In the TAX316 study, lymphedema that developed during the treatment period and persisted after the end of chemotherapy was observed in 11 out of 744 patients in the TAC group (1.5%) and in 1 out of 736 patients in the FAC group (0.1%). At the end of the follow-up period (actual median follow-up: 8 years), lymphedema persisted in 6 patients in the TAC group (0.8%) and in 1 patient in the FAC group (0.1%).

In the TAX316 study, asthenia that began during the treatment period and persisted after the end of chemotherapy was observed in 236 out of 744 patients in the TAC group (31.7%) and in 180 out of 736 patients in the FAC group (24.5%). At the end of the follow-up period (actual median follow-up: 8 years), asthenia was present in 29 patients in the TAC group (3.9%) and in 16 patients in the FAC group (2.2%).

In the GEICAM 9805 study, peripheral edema that began during the treatment period persisted during the follow-up period in 4 patients (0.8%) in the TAC group and in 2 patients (0.4%) in the FAC group. At the end of the follow-up period (median follow-up: 10 years and 5 months), no patients (0%) in the TAC group had these edemas, and peripheral edema was present in 1 patient (0.2%) in the FAC group.

Lymphedema that began during the treatment period persisted during the follow-up period in 5 patients (0.9%) in the TAC group and in 2 patients (0.4%) in the FAC group. At the end of the follow-up period, lymphedema was observed in 4 patients (0.8%) in the TAC group and in 1 patient (0.2%) in the FAC group.

Asthenia that began during the treatment period and persisted during follow-up was observed in 12 patients (2.3%) in the TAC group and in 4 patients (0.8%) in the FAC group. At the end of follow-up, asthenia was observed in 2 patients (0.4%) in the TAC group and in 2 patients (0.4%) in the FAC group.

Acute leukemia/myelodysplastic syndrome. During 10 years of follow-up in the TAX316 study, acute leukemia was detected in 3 out of 744 patients (0.4%) in the TAC group and in 1 out of 736 patients (0.1%) in the FAC group. During the follow-up period (median follow-up duration: 8 years), 1 patient (0.1%) in the TAC group and 1 patient (0.1%) in the FAC group died from acute myeloid leukemia. Myelodysplastic syndrome was diagnosed in 2 out of 744 patients (0.3%) in the TAC group and in 1 out of 736 patients (0.1%) in the FAC group.

After 10 years of follow-up in the GEICAM 9805 study, acute leukemia occurred in 1 out of 532 (0.2%) patients in the TAC group. No cases were observed in the FAC group.

No patient in any treatment group was diagnosed with myelodysplastic syndrome.

Neutropenic complications.

The data presented in the table below indicate that the incidence of neutropenia, febrile neutropenia, and Grade IV neutrophil infections decreased in patients who initially received prophylactic G-CSF before it became mandatory in the TAC group of the GEICAM study.

Neutrophil complications in patients receiving TAC with and without prior prophylactic use of G-CSF (GEICAM 9805)

DOCETAXEL "EBEWE" at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil for the treatment of gastric adenocarcinoma.

Infections and infestations. Very common: neutropenic infections; infectious diseases (G3/4: 11.7%).

Blood and lymphatic system disorders. Very common: anemia (G3/4: 20.9%); neutropenia (G3/4: 83.2%); thrombocytopenia (G3/4: 8.8%); febrile neutropenia.

Immune system disorders. Very common: hypersensitivity reactions (G3/4: 1.7%).

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 11.7%).

Nervous system disorders. Very common: peripheral sensory neuropathy (G3/4: 8.7%). Common: dizziness (G3/4: 2.3%); peripheral motor neuropathy (G3/4: 1.3%).

Eye disorders. Common: increased lacrimation (G3/4: 0%).

Ear and labyrinth disorders. Common: hearing impairment (G3/4: 0%).

Cardiac disorders. Common: arrhythmia (G3/4: 1.0%).

Gastrointestinal disorders. Very common: diarrhea (G3/4: 19.7%); nausea (G3/4: 16%); stomatitis (G3/4: 23.7%); vomiting (G3/4: 14.3%). Common: constipation (G3/4: 1%); abdominal pain (G3/4: 1%); esophagitis/dysphagia/odynophagia (G3/4: 0.7%).

Skin and subcutaneous tissue disorders. Very common: alopecia (G3/4: 4%). Common: rash with pruritus (G3/4: 0.7%); nail disorders (G3/4: 0.7%); increased skin desquamation (G3/4: 0%).

General disorders and administration site conditions. Very common: lethargy (G3/4: 19%); fever (G3/4: 2.3%); fluid retention (severe/life-threatening: 1%).

Blood and lymphatic system disorders. Febrile neutropenia and neutropenic infections occurred in 17.2% and 13.5% of patients, respectively, regardless of G-CSF use. Secondary prophylaxis with G-CSF was administered in 19.3% of patients (10.7% of cycles). Febrile neutropenia and neutropenic infections were observed in 12.1% and 3.4% of patients receiving prophylactic G-CSF, and in 15.6% and 12.9% of patients not receiving prophylactic G-CSF, respectively.

DOCETAXEL "EBEWE" at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil for the treatment of head and neck cancer.

• Induction chemotherapy followed by radiotherapy (TAH 323):

Infections and infestations. Very common: infectious diseases (G3/4: 6.3%); neutropenic infections.

Benign, malignant and unspecified neoplasms (including cysts and polyps). Common: pain due to malignant tumor (G3/4: 0.6%).

Blood and lymphatic system disorders. Very common: neutropenia (G4: 76.3%); anemia (G3/4: 9.2%); thrombocytopenia (G3/4: 5.2%). Common: febrile neutropenia.

Immune system disorders. Common: hypersensitivity reactions (no severe cases reported).

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 0.6%).

Nervous system disorders. Very common: dysgeusia/parosmia; peripheral sensory neuropathy (G3/4: 0.6%). Common: dizziness.

Eye disorders. Common: increased lacrimation; conjunctivitis.

Ear and labyrinth disorders. Common: hearing impairment.

Cardiac disorders. Common: myocardial ischemia (G3/4: 1.7%). Uncommon: arrhythmia (G3/4: 0.6%).

Vascular disorders. Common: venous disorders (G3/4: 0.6%).

Gastrointestinal disorders. Very common: nausea (G3/4: 0.6%); stomatitis (G3/4: 4.0%); diarrhea (G3/4: 2.9%); vomiting (G3/4: 0.6%). Common: constipation; esophagitis/dysphagia/odynophagia (G3/4: 0.6%); abdominal pain; dyspepsia; gastrointestinal hemorrhage (G3/4: 0.6%).

Skin and subcutaneous tissue disorders. Very common: alopecia (G3/4: 10.9%). Common: rash with pruritus; dry skin; increased skin desquamation (G3/4: 0.6%).

Musculoskeletal and connective tissue disorders. Common: myalgia (G3/4: 0.6%).

General disorders and administration site conditions. Very common: lethargy (G3/4: 3.4%); fever (G3/4: 0.6%); fluid retention; edema.

Investigations. Common: weight gain.

• Induction chemotherapy followed by chemoradiotherapy (TAH 324):

Infections and infestations. Very common: infectious diseases (G3/4: 3.6%). Common: constipation, neutropenic infections.

Benign, malignant and unspecified neoplasms (including cysts and polyps). Common: pain due to malignant tumor (G3/4: 1.2%).

Blood and lymphatic system disorders. Very common: neutropenia (G4: 83.5%); anemia (G3/4: 12.4%); thrombocytopenia (G3/4: 4%); febrile neutropenia.

Immune system disorders. Uncommon: hypersensitivity reactions.

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 12%).

Nervous system disorders. Very common: dysgeusia/parosmia (G3/4: 0.4%); peripheral sensory neuropathy (G3/4: 1.2%). Common: dizziness (G3/4: 2%); peripheral motor neuropathy (G3/4: 0.4%).

Eye disorders. Common: increased lacrimation. Uncommon: conjunctivitis.

Ear and labyrinth disorders. Very common: hearing impairment (G3/4: 1.2%).

Cardiac disorders. Common: arrhythmia (G3/4: 2.0%). Uncommon: myocardial ischemia.

Vascular disorders. Uncommon: venous disorders.

Gastrointestinal disorders. Very common: nausea (G3/4: 13.9%); stomatitis (G3/4: 20.7%); vomiting (G3/4: 8.4%); diarrhea (G3/4: 6.8%); esophagitis/dysphagia/odynophagia (G3/4: 12.0%); constipation (G3/4: 0.4%). Common: dyspepsia (G3/4: 0.8%); abdominal pain (G3/4: 1.2%); gastrointestinal hemorrhage (G3/4: 0.4%).

Skin and subcutaneous tissue disorders. Very common: alopecia (G3/4: 4.0%); rash with pruritus. Common: increased skin dryness; increased skin desquamation.

Musculoskeletal and connective tissue disorders. Common: myalgia (G3/4: 0.4%).

General disorders and administration site conditions. Very common: lethargy (G3/4: 4.0%); fever (G3/4: 3.6%); fluid retention (G3/4: 1.2%); edema (G3/4: 1.2%).

Investigations. Very common: weight loss. Uncommon: weight gain.

Post-marketing surveillance data.

Benign, malignant and unspecified neoplasms (including cysts and polyps). Docetaxel administration in combination with other chemotherapeutic agents and/or radiotherapy has been associated with very rare cases of acute myeloid leukemia and manifestation of myelodysplastic syndrome.

Recurrences of primary malignant neoplasms (frequency unknown) have been reported, including non-Hodgkin's lymphomas associated with docetaxel treatment in combination with other chemotherapeutic agents and/or radiotherapy, which are associated with recurrences of primary malignant neoplasms. Cases of acute myeloid leukemia and myelodysplastic syndrome (frequency: uncommon) have also been reported in patients enrolled in pivotal clinical trials for breast cancer treatment using the TAC regimen.

Blood and lymphatic system disorders. Bone marrow suppression and other hematological adverse effects have been reported. Cases of disseminated intravascular coagulation syndrome have also been reported, often associated with sepsis or multi-organ failure.

Immune system disorders. Several cases of anaphylactic shock, sometimes fatal, have been reported. Isolated cases of hypersensitivity reactions (frequency unknown) to docetaxel have been reported in patients who previously experienced hypersensitivity reactions to paclitaxel.

Nervous system disorders. Isolated cases of seizures or transient loss of consciousness have been observed during docetaxel infusion. These reactions sometimes occur during drug infusion.

Eye disorders. Very rare cases of transient visual disturbances (flashes, flickering lights, scotoma), usually occurring during drug infusion and associated with hypersensitivity reactions, have been observed. These reactions were reversible and resolved after infusion discontinuation. In isolated cases, excessive lacrimation with or without conjunctivitis due to obstruction of the lacrimal ducts, leading to excessive tearing, has been reported. Cases of cystoid macular edema (CME) have been observed in patients receiving docetaxel therapy.

Ear and labyrinth disorders. Isolated cases of ototoxicity, hearing impairment, and/or hearing loss have been reported.

Cardiac disorders. Rare cases of myocardial infarction have been reported. Cases of ventricular arrhythmias, including ventricular tachycardia (frequency unknown), sometimes fatal, have been reported in patients receiving docetaxel in combination regimens with doxorubicin, 5-fluorouracil and/or cyclophosphamide.

Vascular disorders. Rare cases of venous thromboembolic events have been reported.

Respiratory, thoracic and mediastinal disorders. Rare cases of acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis, and respiratory failure, sometimes fatal, have been reported. Rare cases of radiation pneumonitis have been observed in patients receiving concomitant radiotherapy.

Gastrointestinal disorders. Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, with potentially fatal outcomes (frequency unknown), have been reported.

Rare cases of dehydration as a consequence of gastrointestinal disorders, including enterocolitis and gastrointestinal perforation, ischemic colitis, colitis of other etiology, and neutropenic enterocolitis, have been reported. Rare cases of intestinal obstruction and bowel obstruction have also been reported.

Hepatobiliary disorders. Very rarely, cases of hepatitis, sometimes fatal (predominantly in patients with pre-existing hepatic dysfunction prior to initiation of chemotherapy), have been reported.

Skin and subcutaneous tissue disorders. Very rarely, during docetaxel treatment, cutaneous lupus erythematosus and bullous skin eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis have occurred. In some cases, development of adverse events may be influenced by concomitant factors. Cases of scleroderma-like lesions, preceded by peripheral lymphedema, have also been reported during docetaxel therapy. Cases of persistent alopecia have been reported.

Renal and urinary disorders. Cases of impaired renal function and renal failure have been reported. Approximately 20% of such cases were not associated with risk factors for acute renal failure, such as concomitant use of nephrotoxic drugs and gastrointestinal disorders.

General disorders and administration site conditions. Rare cases of radiation recall phenomenon (acute radiation reactions during chemotherapy, occurring weeks, months, or years after radiotherapy) have been reported.

Fluid retention was not associated with acute episodes of oliguria or arterial hypotension.

Injection site reactions (recurrent skin reaction at a previous extravasation site after docetaxel administration at another site) at previous extravasation sites have been observed (frequency unknown).

Rare cases of dehydration and pulmonary edema have been reported.

Metabolic and nutritional disorders. Cases of hyponatremia, mainly associated with dehydration, vomiting, and pneumonia, have been reported.

Hypokalemia, hypomagnesemia, and hypocalcemia have been observed in gastrointestinal disorders, particularly diarrhea.

Musculoskeletal system disorders. Myositis associated with docetaxel use has been reported (frequency unknown).

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization of the medicinal product is an important procedure. It allows continued monitoring of the benefit-risk profile of the drug. Healthcare professionals are requested to report all suspected adverse reactions via national adverse reaction reporting systems.

Shelf life. 2 years.

Storage conditions. Store in the original packaging, out of reach of children, at a temperature not exceeding 25°C. Do not freeze.

Incompatibilities. This medicinal product should not be mixed with other medicinal products in the same infusion bottle (except with 5% glucose solution or 0.9% sodium chloride solution).

Packaging. 2 mL (20 mg), 8 mL (80 mg), or 16 mL (160 mg) in a vial; 1 vial per carton.

Prescription category. Prescription only.

Manufacturer.

FAREVA Unterach GmbH

FAREVA Unterach GmbH

(complete manufacturing cycle)

EBEWE Pharma Ges.m.b.H. Nfg. KG

EBEWE Pharma Ges.m.b.H. Nfg. KG

(batch release)

Manufacturer's address and place of business.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria.