TAXELDO

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TACSELD (TAXELDO)

Composition:

Active substance: docetaxel;

1 ml of concentrate contains docetaxel trihydrate equivalent to 20 mg of anhydrous docetaxel;

Excipients: polysorbate 80, anhydrous ethanol.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: pale yellow to brownish-yellow solution.

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01C D02.

Pharmacological Properties

Pharmacodynamics

Docetaxel is an antineoplastic agent whose mechanism of action is based on promoting the assembly of tubulin into stable microtubules and inhibiting their disassembly, leading to a significant reduction in the level of free tubulin. The binding of docetaxel to microtubules does not alter the number of protofilaments.

In vitro studies have demonstrated that docetaxel disrupts the microtubular network, which plays a crucial role in cellular functions both during mitosis and interphase.

Clonogenic analysis in vitro showed cytotoxicity of docetaxel against various murine and human tumor cell lines, as well as against freshly isolated human tumor cells. Docetaxel achieves significant concentrations in interstitial fluid and ensures high cell survival duration. Furthermore, docetaxel exhibits activity against certain cell lines with overexpression of P-glycoprotein encoded by the multidrug resistance gene. In vivo studies revealed that the effect of docetaxel is independent of the administration schedule and demonstrates broad-spectrum antitumor activity against a wide range of tumors, including experimental murine tumors and implanted human tumors.

Pharmacokinetics

Absorption. The pharmacokinetics of docetaxel were studied in phase I trials in cancer patients following doses of 20–115 mg/m². The pharmacokinetic profile of docetaxel is dose-independent and fits a three-compartment model, with half-lives of the α-, β-, and γ-(terminal) phases being 4 minutes, 36 minutes, and between 11.1 and 17.5 hours, respectively, when samples were collected within 24 hours. An additional study evaluating docetaxel pharmacokinetics at similar doses (75–100 mg/m²) in patients over a longer time interval (over 22 days) revealed a longer mean terminal half-life—ranging from 91 to 120 hours. This prolonged half-life in the terminal phase is partly due to relatively slow efflux from the peripheral compartment.

Distribution. After administration of a 100 mg/m² dose infused over 1 hour, the mean peak plasma concentration of the drug was 3.7 µg/mL, with a corresponding AUC of 4.6 µg/mL/h. Mean values for total clearance and volume of distribution at steady state were 21 L/m²/h and 113 L, respectively. Interindividual variability in total clearance reached approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

Elimination. A study using radiolabeled 14C-docetaxel was conducted in three cancer patients. Following oxidative metabolism of the tert-butyl ester group by cytochrome P450, docetaxel was excreted both in urine and feces over 7 days; urinary excretion accounted for 6% and fecal excretion for 75% of the administered radioactive dose. Approximately 80% of the isotope present in feces was eliminated within the first 48 hours as one major inactive metabolite, three minor inactive metabolites, and a very small amount of unchanged drug.

Special Patient Populations

Age and Sex. Population pharmacokinetic analysis was performed in 577 patients. Pharmacokinetic parameters estimated by this model were very similar to those obtained in phase I studies. Neither age nor sex had any influence on the pharmacokinetics of the drug.

Hepatic Impairment. In a small number of patients (n = 23) with mild to moderate hepatic impairment based on blood biochemical tests (alanine aminotransferase [ALT] and aspartate aminotransferase [AST] levels ≥ 1.5 times the upper limit of normal [ULN] together with alkaline phosphatase levels ≥ 2.5 times ULN), total clearance of the drug was reduced by an average of 27% (see section "Dosage and Administration").

Fluid Retention. Docetaxel clearance was not altered in patients with mild or moderate fluid retention; there are no data on docetaxel clearance in patients with severe fluid retention.

Combination Therapy

Doxorubicin. When used in combination with other agents, docetaxel did not affect the clearance of doxorubicin or plasma levels of doxorubicin (and its metabolites). The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide were unchanged when administered concurrently.

Capecitabine. A phase I clinical trial evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect of capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC), nor any effect of docetaxel on the pharmacokinetics of the corresponding capecitabine metabolite, 5’-deoxy-5-fluorouridine (5’-DFUR).

Cisplatin. The clearance of docetaxel administered in combination with cisplatin was similar to that observed with docetaxel monotherapy. The pharmacokinetic profile of cisplatin administered immediately after docetaxel infusion is similar to that seen with cisplatin monotherapy.

Cisplatin and 5-Fluorouracil. Combined administration of docetaxel, cisplatin, and 5-fluorouracil in 12 patients with solid tumors did not alter the pharmacokinetics of any of these drugs.

Prednisone and Dexamethasone. The effect of prednisone on docetaxel pharmacokinetics after standard premedication with dexamethasone was evaluated in 42 patients. No effect of prednisone on docetaxel pharmacokinetics was observed.

Preclinical Safety Data

The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be genotoxic via an aneugenic mechanism, as demonstrated 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 results are consistent with the pharmacological activity of docetaxel.

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

Clinical Characteristics

Indications

Breast cancer. Taxeldo 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.

Adjuvant therapy should be administered to patients with operable breast cancer without lymph node involvement if they meet established international criteria for chemotherapy in the primary treatment of early-stage breast cancer.

Taxeldo 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.

Taxeldo as monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior cytotoxic chemotherapy that included an anthracycline or alkylating agents.

Taxeldo in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer with overexpression of HER-2 by tumor cells who have not previously received chemotherapy for metastatic disease.

Taxeldo in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior therapy that included an anthracycline.

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

Taxeldo 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 condition.

Prostate cancer. Taxeldo in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

Taxeldo in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, is indicated for the treatment of patients with metastatic hormone-sensitive prostate cancer.

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

Head and neck cancer. Taxeldo 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 "Dosage and administration" and "Special precautions").

Contraindications for other medicinal products used in combination with docetaxel should also be considered.

Special safety precautions

Taxeldo belongs to antineoplastic agents and, like any other potentially toxic agent, requires adherence to safety measures during handling and preparation of solutions. Protective gloves are recommended when handling the product.

If the concentrate for solution for infusion Taxeldo or the infusion solution comes into contact with the skin, it should be immediately and thoroughly washed off with soap and water. If the concentrate for solution for infusion Taxeldo or the infusion solution comes into contact with mucous membranes, it should be immediately and thoroughly rinsed with water.

Interaction with other medicinal products and other forms of interaction

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

In vitro studies have demonstrated that the metabolism of docetaxel may be altered when co-administered with agents that induce, inhibit, or are metabolized by cytochrome P450-3A (and thus may cause competitive inhibition), such as cyclosporine, ketoconazole, and erythromycin. Therefore, concomitant administration of these medicinal products should be prescribed with caution, considering the risk of clinically significant interactions.

When used in combination with CYP3A4 inhibitors, the frequency of docetaxel adverse effects may increase due to reduced metabolism. If co-administration of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) cannot be avoided, careful clinical monitoring and dose adjustment of docetaxel during treatment with strong CYP3A4 inhibitors are recommended (see section "Special precautions"). A pharmacokinetic study in 7 patients demonstrated that concomitant administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole resulted in a significant 49% reduction in docetaxel clearance.

The pharmacokinetics of docetaxel during concomitant prednisone administration was studied in patients with metastatic prostate cancer. Docetaxel is metabolized by the CYP3A4 enzyme, and prednisone is a known inducer of CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.

Docetaxel is highly bound to plasma proteins (> 95%). Although potential interactions of this drug with other medicinal products have not been formally studied in vivo, in vitro data indicate that drugs with high plasma protein binding (such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate) do not impair the binding of docetaxel to plasma proteins. In addition, 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 are not altered when these agents are administered concomitantly. Limited data from one uncontrolled study suggest a possible interaction between docetaxel and carboplatin. When these agents are used in combination, carboplatin clearance was nearly 50% higher than levels observed during carboplatin monotherapy in previous studies.

Special precautions for use

In patients with breast cancer or non-small cell lung cancer, in the absence of contraindications, premedication with oral corticosteroids such as dexamethasone 16 mg daily (e.g. 8 mg twice daily) for 3 days, starting 1 day before administration of docetaxel, may reduce the frequency and severity of fluid retention and hypersensitivity reactions. In patients with prostate cancer, premedication consists of oral dexamethasone 8 mg administered 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion.

Hematologic changes during treatment. The most common adverse reaction during docetaxel therapy is neutropenia. The lowest neutrophil counts are typically observed on day 7 of treatment, although the time to reach the nadir of neutropenia may be shorter in patients who have previously received multiple cycles of cytotoxic chemotherapy. All patients receiving docetaxel require careful monitoring of peripheral blood counts. Docetaxel may be re-administered in a new chemotherapy cycle only after neutrophil counts have recovered to ≥1500 cells/mm³ following the previous cycle (see section "Dosage and administration").

If severe neutropenia (<500 cells/mm³ for 7 days or longer) develops during docetaxel therapy, dose reduction in the next chemotherapy cycle or appropriate symptomatic treatment is recommended (see section "Dosage and administration").

In patients receiving combination therapy with docetaxel, cisplatin, and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infections occurred less frequently when G-CSF was administered. Patients receiving TCF therapy should receive prophylactic G-CSF to reduce the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia, or neutropenic infections). Patients receiving TCF therapy should be closely monitored (see sections "Dosage and administration" and "Adverse reactions").

In patients receiving docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred less frequently when patients received primary prophylaxis with G-CSF. For 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 in patients with neutropenia, particularly those at increased risk of gastrointestinal complications. Although most cases occurred during the first or second cycle of docetaxel chemotherapy, enterocolitis may develop at any time and may be fatal even on the first day after onset. Patients should be carefully monitored for early signs of serious gastrointestinal toxicities (see subsection "Hematologic changes during treatment" above, as well as sections "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 discontinuation of therapy. However, severe reactions such as marked hypotension, bronchospasm, generalized rash/erythema, or, in rare cases, potentially fatal anaphylaxis, require immediate discontinuation of docetaxel and appropriate treatment. Re-administration of docetaxel is contraindicated in patients who have experienced a severe hypersensitivity reaction. Patients with a prior history of hypersensitivity to paclitaxel have an increased risk of developing hypersensitivity to docetaxel, including more severe reactions. These patients should be closely monitored at the start of docetaxel therapy.

Skin reactions. Cases of localized erythema of the skin of the extremities (on palms and soles), associated with edema and subsequent epidermal desquamation, have been observed. Severe symptoms such as extensive skin rashes with subsequent desquamation have also been reported, necessitating interruption or permanent discontinuation of docetaxel therapy (see section "Dosage and administration").

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

Fluid retention. Patients with significant fluid retention (e.g. pleural effusion, pericardial effusion, ascites) should be carefully 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. Radiation pneumonitis has been observed in patients who received concomitant radiotherapy.

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

Patients with hepatic impairment. Patients with elevated transaminases (ALT and/or AST) >1.5 times ULN and alkaline phosphatase >2.5 times ULN during monotherapy with docetaxel 100 mg/m² are at higher risk of severe adverse reactions, including fatal outcomes due to drug toxicity (e.g. sepsis, gastrointestinal bleeding), febrile neutropenia, infections, thrombocytopenia, stomatitis, and asthenia. Therefore, the recommended dose of docetaxel in patients with elevated liver enzymes is 75 mg/m². Liver enzyme levels should be assessed before treatment initiation and before each new chemotherapy cycle (see section "Dosage and administration").

For patients with elevated serum bilirubin (>ULN) and/or ALT and AST >3.5 times ULN, accompanied by alkaline phosphatase >6 times ULN, dose reduction is not recommended; however, docetaxel should not be administered unless there is a compelling clinical need.

In a pivotal clinical trial of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated ALT and/or AST >1.5 times ULN, alkaline phosphatase >2.5 times ULN, and bilirubin >ULN were exclusion criteria. Therefore, dose reduction of docetaxel cannot be recommended for such patients. The drug should not be administered to this patient population unless there is a compelling clinical need. Data on the use of docetaxel in combination therapy for other indications in patients with hepatic impairment are lacking.

Patients with renal impairment. There are no data on the use of docetaxel in patients with severe renal impairment.

Neurotoxicity. The occurrence of severe peripheral neurotoxic effects requires dose reduction (see section "Dosage and administration").

Cardiotoxicity. In patients receiving docetaxel in combination with trastuzumab, particularly after prior anthracycline-based chemotherapy (doxorubicin or epirubicin), cases of heart failure have been observed. This heart failure may be moderate or severe and is associated with a high risk of death (see section "Adverse reactions"). If docetaxel is to be used in combination with trastuzumab, cardiac function should be assessed before treatment initiation. Cardiac function should be monitored regularly (e.g. every 3 months) during treatment to identify patients who may develop cardiac dysfunction. Further information is provided in the trastuzumab product information.

Cases of ventricular arrhythmias, including ventricular tachycardia (sometimes fatal), have been reported in patients receiving docetaxel in combination with doxorubicin, 5-fluorouracil, and/or cyclophosphamide (see section "Adverse reactions"). A cardiological evaluation is recommended before starting treatment.

Ocular disorders. Cases of crystalline maculopathy (CM) have been reported in patients receiving docetaxel. Patients with visual disturbances should undergo urgent and complete ophthalmological examination. If CM is diagnosed, docetaxel should be discontinued and appropriate treatment initiated (see section "Adverse reactions").

Second primary malignancy. Second primary malignancies have been reported in patients receiving docetaxel in combination with anticancer agents associated with second primary malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma) may develop months or years after docetaxel treatment. Patients should be monitored for the possible development of second primary malignancies (see section "Adverse reactions").

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

Other warnings.

Women of childbearing potential must use contraception during treatment and for 2 months after discontinuation of docetaxel. Men must use contraception during treatment and for 4 months after discontinuation of docetaxel (see section "Use in pregnancy or lactation").

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

Additional warnings for docetaxel use in adjuvant therapy of breast cancer

Complicated neutropenia. In patients who develop complicated neutropenia (prolonged neutropenia, febrile neutropenia, or infections), the use of G-CSF and dose reduction of docetaxel should be considered (see section "Dosage and administration").

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

Congestive heart failure (CHF). Patients should be monitored for possible signs of CHF during and after treatment. An increased risk of CHF has been demonstrated in patients receiving TAC therapy for node-positive breast cancer during the first year after treatment (see sections "Adverse reactions" and "Pharmacodynamic properties").

Patients with ≥4 metastatic lymph nodes. Since the benefits observed in patients with ≥4 metastatic lymph nodes were not statistically significant for disease-free survival (DFS) and overall survival (OS), a positive benefit-risk ratio for 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 docetaxel in combination with capecitabine showed increased incidence of treatment-related adverse events of grade 3–4 severity, serious treatment-related adverse events, and early discontinuation due to adverse events 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 333 patients who received docetaxel every three weeks in a prostate cancer study, 209 were over 65 years of age and 68 were aged 75 years or older. When docetaxel was administered every three weeks, treatment-related nail changes occurred in patients aged ≥65 years at a frequency ≥10% higher than in younger patients. Treatment-related events of increased body temperature, diarrhea, loss of appetite, and peripheral edema occurred in patients aged ≥75 years at a frequency ≥10% higher than in patients under 65 years of age.

Warnings for use in hormone-sensitive prostate cancer

Of 545 patients who received docetaxel every 3 weeks in a hormone-sensitive prostate cancer study (STAMPEDE [Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy]), 296 were over 65 years of age and 48 were aged 75 years or older. In the majority of patients over 65 years of age in the docetaxel group, hypersensitivity reactions, neutropenia, anemia, fluid retention, dyspnea, and nail changes were reported compared to patients under 65 years of age. None of these increases in frequency 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 frequent).

Warnings for use in gastric adenocarcinoma

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

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

Warnings regarding excipients. This medicinal product contains ethanol, amounting to 50% of the total volume of the concentrate, i.e. up to 0.395 g (0.5 mL) per vial; in terms of alcohol content, this is equivalent to 10 mL of beer or 4 mL of wine.

The product is harmful for patients suffering from alcoholism.

The ethanol content should be considered when prescribing the product to pregnant women or breastfeeding mothers, children, and patients in high-risk groups, such as patients with liver disease or epilepsy.

The possible effect of the product on the central nervous system should be taken into account.

Preparation of solution for intravenous infusion. Do not use other docetaxel products with packaging containing 2 vials (concentrate and solvent) with this medicinal product (Taxeldo, 20 mg/mL concentrate for solution for infusion, packaged in a single vial).

Taxeldo, 20 mg/mL concentrate for solution for infusion, does not require prior reconstitution and is ready for dilution into the infusion solution.

Each vial is for single use only and the product should be used immediately after opening. If not used immediately, the user is responsible for the duration and conditions of storage.

If vials have been stored in a refrigerator, allow the required number of packages to reach room temperature (up to 25°C) for 5 minutes before use.

To achieve the required patient dose, several vials of Taxeldo concentrate for solution for infusion may be needed. Using a calibrated syringe with a 21G needle, withdraw the required amount of Taxeldo concentrate under aseptic conditions.

The Taxeldo vial contains docetaxel at a concentration of 20 mg/mL. The required volume of concentrate should be added in a single injection (one puncture) into an infusion bag or bottle containing 250 mL of 5% glucose solution or 0.9% sodium chloride solution (9 mg/mL) for injection.

If the required docetaxel dose exceeds 190 mg, a larger volume of infusion solution should be used to avoid exceeding a docetaxel concentration of 0.74 mg/mL.

Gently shake the infusion bag or bottle to ensure thorough mixing of the concentrate with the infusion solution.

The prepared infusion solution should be used within 6 hours at a temperature below 25°C (including the 1-hour infusion period). 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.

After adding the medicinal product to the infusion solution according to recommendations, the docetaxel infusion solution remains stable for 6 hours when stored at temperatures up to 25°C. Additionally, physical and chemical stability of the infusion solution prepared according to recommendations has been demonstrated for 48 hours when stored not in PVC bags at 2–8°C.

Before administration, the infusion solution of Taxeldo, like all parenteral products, should be visually inspected; solutions containing precipitate must not be used.

The docetaxel infusion solution is supersaturated and may crystallize over time. If crystals appear, the solution must not be used and should be discarded.

Unused medicinal product or waste materials must be disposed of in accordance with local regulations.

Use during pregnancy or lactation

Pregnancy.

Women of childbearing potential. Contraception in men and women.

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

Due to the genotoxic risk (see section "Non-clinical safety data"), women of childbearing potential must use effective contraception during treatment and for 2 months after discontinuation of docetaxel. Men must use effective contraception during treatment and for 4 months after discontinuation of docetaxel.

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 cause harm to the fetus if administered during pregnancy. Therefore, docetaxel must not be administered during pregnancy except when there is a compelling clinical need.

Lactation. Docetaxel is a lipophilic substance, but it is unknown whether it passes into breast milk. Therefore, considering the risk of adverse effects in breastfed infants, breastfeeding must be discontinued during docetaxel treatment.

Fertility. Animal studies have shown that docetaxel may affect male fertility (see section "Non-clinical safety data"). Therefore, men receiving docetaxel should be advised to consult about sperm cryopreservation before starting treatment.

Ability to influence 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 possible effects of the drug on their ability to drive or operate machinery and advised not to engage in such activities if they experience these adverse effects during treatment.

Method of Administration and Dosage

The use of docetaxel should be restricted to departments specializing in cytotoxic chemotherapy. Docetaxel must be administered exclusively 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 with oral corticosteroids such as dexamethasone 16 mg daily (e.g., 8 mg twice daily) for 3 days may be used (if not contraindicated); the first dose should be taken one day before the first administration of docetaxel (see section "Special Instructions"). To reduce the risk of hematological toxicity associated with docetaxel, prophylactic use of granulocyte colony-stimulating factor (G-CSF) may be considered.

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

To reduce the risk of hematological toxicity associated with docetaxel, prophylactic use of granulocyte colony-stimulating factor (G-CSF) may be considered.

Docetaxel is administered as a one-hour intravenous infusion every 3 weeks.

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

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

In combination with trastuzumab (administered weekly), docetaxel is given at the recommended dose of 100 mg/m² every 3 weeks. In the pivotal clinical trial with docetaxel, the first infusion of the drug was administered the day after the first dose of trastuzumab. Subsequent doses of docetaxel were administered immediately after completion of trastuzumab infusion, provided the patient tolerated the most recently administered trastuzumab well. Dosage and administration details for trastuzumab are described in the summary of product characteristics for trastuzumab.

In combination with capecitabine, docetaxel is administered at the recommended dose of 75 mg/m² every 3 weeks; capecitabine is administered at a dose of 1250 mg/m² twice daily (no later than 30 minutes after meals) for 2 weeks followed by a 1-week break. Details on dose calculation of capecitabine according to body surface area are provided in the summary of product characteristics for capecitabine.

Non-Small Cell Lung Cancer. For the treatment of patients with non-small cell lung cancer who have not previously received chemotherapy, docetaxel is recommended at a dose of 75 mg/m², followed immediately by cisplatin 75 mg/m² administered over 30–60 minutes. For the treatment of patients who have previously failed platinum-based chemotherapy, monotherapy with docetaxel at a dose of 75 mg/m² is recommended.

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 also 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 taken continuously at 5 mg orally twice daily.

Gastric Adenocarcinoma. The recommended dose of docetaxel is 75 mg/m², administered as a 1-hour intravenous infusion, followed immediately by cisplatin 75 mg/m² administered as an intravenous infusion over 1–3 hours (both drugs are administered only on day 1 of the cycle); immediately after completion of cisplatin infusion, a continuous 5-day infusion of 5-fluorouracil (750 mg/m²/day) is initiated. This cycle is repeated every 3 weeks. Patients should receive premedication with antiemetics and appropriate hydration (adequate fluid intake) during cisplatin administration. To reduce the risk of hematological toxicity associated with chemotherapy, prophylactic use of G-CSF is required (see also subsection "Dose Adjustment During Treatment" below).

Head and Neck Cancer. Patients should receive premedication with antiemetics and appropriate hydration (before and after cisplatin administration). To reduce the risk of hematological toxicity associated with chemotherapy, prophylactic use of G-CSF may be considered. All patients enrolled in clinical trials TAX 323 and TAX 324 in groups receiving docetaxel received antibiotics for prophylaxis.

• Induction chemotherapy followed by radiotherapy (based on data from study TAX 323). For induction chemotherapy of unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of docetaxel is 75 mg/m² administered as a 1-hour intravenous infusion, followed immediately on day 1 of the cycle by cisplatin 75 mg/m² administered as an intravenous infusion over 1–3 hours; immediately after completion of cisplatin infusion, a continuous 5-day infusion of 5-fluorouracil (750 mg/m²/day) is initiated. This regimen is repeated every 3 weeks for 4 cycles. After chemotherapy, patients should receive radiotherapy.
• Induction chemotherapy followed by chemoradiotherapy (based on data from study TAX 324). For induction chemotherapy of locally advanced SCCHN (technically unresectable, with low probability of surgical intervention or requiring an organ-preserving approach), the recommended dose of docetaxel is 75 mg/m² administered as a 1-hour intravenous infusion, followed immediately on day 1 of the cycle by cisplatin 100 mg/m² administered as an intravenous infusion over 0.5–3 hours; immediately after completion of cisplatin infusion, a continuous 4-day infusion of 5-fluorouracil (1000 mg/m²/day) is initiated. This regimen is repeated every 3 weeks for 3 cycles. After chemotherapy, patients should receive chemoradiotherapy.

Details on dose adjustments for cisplatin and 5-fluorouracil are provided in the respective summaries of product characteristics.

Dose Adjustment 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 one week, or if severe acute or progressively worsening cumulative skin reactions occur, or if severe peripheral neuropathy develops, the dose of docetaxel should be reduced from 100 to 75 mg/m² and/or from 75 to 60 mg/m². If such reactions occur even at the 60 mg/m² dose level, the drug should be discontinued.

Adjuvant Therapy of Breast Cancer. For patients receiving adjuvant therapy with docetaxel, doxorubicin, and cyclophosphamide (TAC regimen), primary prophylaxis with G-CSF should be considered. Patients who develop febrile neutropenia and/or neutropenic infection should have the docetaxel dose reduced to 60 mg/m² in all subsequent treatment cycles (see sections "Special Instructions" and "Side Effects"). Patients who develop grade 3 or 4 stomatitis must have the docetaxel dose reduced to 60 mg/m².

In Combination with Cisplatin. For patients who during the previous cycle while receiving docetaxel 75 mg/m² in combination with cisplatin experienced a nadir platelet count < 25,000 cells/mm³, for patients who developed febrile neutropenia during docetaxel therapy, and for patients who experienced serious non-hematological toxicities, the docetaxel dose should be reduced to 65 mg/m² in subsequent cycles. Details on dose adjustment of cisplatin are provided in the summary of product characteristics for cisplatin.

In Combination with Capecitabine. Details on dose adjustment of capecitabine are provided in the summary of product characteristics for capecitabine.

• Patients who experience grade II toxicity that persists until the next scheduled administration of docetaxel/capecitabine should have treatment interrupted until toxicity resolves to grade 0–I, then resumed at 100% of the initial dose.
• 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 should have treatment interrupted until toxicity resolves to grade 0–I, then resumed with docetaxel at a dose of 55 mg/m².
• If further toxicities occur or if grade IV toxicity develops, docetaxel treatment should be discontinued.

Details on dose adjustment of trastuzumab are provided in the summary of product characteristics for trastuzumab.

In Combination with Cisplatin and 5-Fluorouracil. If a patient develops an episode of febrile neutropenia, prolonged neutropenia, or neutropenia-associated infection despite G-CSF administration, the docetaxel dose should be reduced from 75 to 60 mg/m². If episodes of complicated neutropenia continue, the dose should be further reduced from 60 to 45 mg/m². If a patient develops grade IV thrombocytopenia, the docetaxel dose should be reduced from 75 to 60 mg/m². A treatment cycle should not be repeated in subsequent cycles until the neutrophil count recovers to > 1500 cells/mm³ and platelet count to > 100,000 cells/mm³. If toxicities persist despite these measures, docetaxel therapy must be discontinued (see section "Special Instructions").

Table 1

Recommended dose adjustment measures for patients receiving combination therapy with docetaxel, cisplatin, and 5-fluorouracil

For dose adjustment recommendations for cisplatin and 5-fluorouracil, refer to the respective summaries of product characteristics.

In pivotal clinical trials of docetaxel, patients who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infectious complications) during therapy with G-CSF were advised to receive prophylactic G-CSF (e.g., from day 6 to day 15 of the cycle) in all subsequent chemotherapy cycles.

Special patient groups

Patients with impaired liver function. According to pharmacokinetic data from monotherapy studies with docetaxel at a dose of 100 mg/m², the recommended dose of docetaxel is 75 mg/m² in patients with elevated transaminase levels (ALT and/or AST) greater than 1.5 times the upper limit of normal (ULN) and alkaline phosphatase levels greater than 2.5 times ULN. In patients with increased serum bilirubin (> ULN) and/or ALT and AST levels greater than 3.5 times ULN, accompanied by alkaline phosphatase levels elevated more than 6 times ULN, dose reduction is not recommended; however, docetaxel should not be administered at all unless there is a compelling clinical need.

In the pivotal clinical trial of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated levels of ALT and/or AST > 1.5 times ULN, alkaline phosphatase > 2.5 times ULN, or bilirubin > ULN were among the exclusion criteria; therefore, dose reduction of docetaxel cannot be recommended for such patients. The drug should not be administered to these patients unless there is a compelling clinical need.

There are no data on the use of docetaxel in combination therapy for other indications in patients with impaired liver function.

Elderly patients. Based on population pharmacokinetic analysis data, there are no specific recommendations for dose adjustment in elderly patients.

When docetaxel is used in combination with capecitabine, a reduced starting dose of capecitabine (75%) is recommended for patients aged 60 years and older (see the summary of product characteristics for capecitabine).

Children

There are no data on the efficacy and safety of docetaxel for use in pediatric patients.

The safety and efficacy of docetaxel for the treatment of nasopharyngeal carcinoma in children aged 1 month to 18 years have not yet been established.

There is a lack of 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, and head and neck cancers, except for poorly differentiated nasopharyngeal carcinoma types II and III.

Overdose. There have been several case reports of docetaxel overdose. There is currently no specific antidote for docetaxel. In the event of overdose, the patient should be hospitalized in a specialized unit and closely monitored for vital functions. An exacerbation of the drug's adverse effects is expected. The most likely complications include bone marrow suppression, peripheral neurotoxicity, and mucosal inflammation. Upon confirmation of overdose, therapeutic doses of G-CSF should be administered to the patient as soon as possible. Symptomatic measures should be applied as needed.

Adverse Reactions

Adverse reactions are described using the National Cancer Institute (NCI) Common Toxicity Criteria [NCI] (Grade III = G3; Grades III–IV = G3/4; Grade IV = G4) and definitions from COSTART and MedDRA dictionaries.

The frequency of adverse effects was categorized as follows: very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10,000 and < 1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

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

The most frequently reported adverse reactions during docetaxel monotherapy include: neutropenia (reversible and non-cumulative in nature; the nadir of neutrophils 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 co-administered with other chemotherapeutic agents.

When docetaxel is used 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 unresponsive to anthracyclines are detailed in the summary of product characteristics for capecitabine.

For the combination with androgen deprivation therapy (ADT) and prednisone or prednisolone (STAMPEDE trial), adverse events occurring during the first 6 cycles of docetaxel treatment and reported at least 2% more frequently in the docetaxel group compared to the control group are presented using the CTCAE scale (Common Terminology Criteria for Adverse Events).

The following adverse reactions were most commonly observed with docetaxel use.

Immune system disorders. Hypersensitivity reactions typically occurred within minutes after the start of docetaxel infusion and ranged from mild to moderate in severity. Most frequently reported symptoms included skin flushing, rash (with or without pruritus), chest tightness, back pain, dyspnea, fever, or chills. Severe reactions included arterial hypotension and/or bronchospasm or generalized rash/erythema (see section "Special precautions").

Nervous system disorders. Severe peripheral neurotoxic reactions require dose reduction of the drug (see sections "Dosage and administration" and "Special precautions"). Mild to moderate neurosensory reactions included paresthesia, dysesthesia, or pain sensations, including burning sensations. Neuromotor reactions manifested as generalized weakness.

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

General disorders and administration site reactions. Local reactions at the infusion site were predominantly mild and included hyperpigmentation, inflammation, erythema, dry skin, phlebitis or extravasation, venous swelling.

Fluid retention events included peripheral edema, and less frequently pleural or pericardial effusion, ascites, and weight gain. Peripheral edema usually began in the lower extremities and could become generalized, leading to an increase in body weight of 3 kg or more. Fluid retention is cumulative in both frequency and severity (see section "Special precautions").

Adverse reactions in patients with breast cancer receiving docetaxel monotherapy at a dose of 100 mg/m²

Infections and parasitic diseases. Very common: infections (G3/4: 5.7%; including sepsis and pneumonia, fatal in 1.7% of cases). Common: neutropenia-associated infections G4 (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 reactions (G3/4: 5.3%).

Metabolic and nutritional 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 drug administration; non-cardiac chest pain (severe: 0.4%).

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

Specific adverse reactions in patients with breast cancer receiving docetaxel monotherapy at a dose of 100 mg/m²

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

Nervous system disorders. Data indicate reversibility of neurological effects in 35.3% of patients who developed such effects after monotherapy with docetaxel 100 mg/m². These disorders resolved spontaneously within 3 months.

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

General disorders and administration site conditions. The median cumulative dose at drug discontinuation was greater than 1000 mg/m², and the median time to reversible development of fluid retention was 16.4 weeks (range: 0 to 42 weeks). Development of moderate to severe fluid retention occurred later in patients who received premedication (median cumulative dose: 818.9 mg/m²) compared to those who did not (median cumulative dose: 489.7 mg/m²); however, several cases of this adverse effect were reported during early treatment cycles.

Adverse reactions in patients with breast cancer receiving docetaxel monotherapy at a dose of 75 mg/m²

Infections and parasitic diseases. Very common: infections (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 reactions (no severe cases).

Metabolic and nutritional disorders. 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 (no severe cases).

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

Adverse reactions in patients with breast cancer receiving docetaxel at a dose of 75 mg/m² in combination with doxorubicin

Infections and parasitic diseases. Very common: infections (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%).

Metabolic and nutritional 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 (no severe cases).

Vascular disorders. Uncommon: arterial 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 (no severe cases).

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 drug administration.

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

Adverse reactions in patients with breast cancer receiving docetaxel at a dose of 75 mg/m² in combination with cisplatin

Infections and parasitic diseases. 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%).

Metabolic and nutritional 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 drug administration; pain.

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

Adverse reactions in patients with breast cancer receiving docetaxel at a dose of 100 mg/m² in combination with trastuzumab

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

Metabolic and nutritional disorders. Very common: anorexia.

Psychiatric disorders. Very common: insomnia.

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

Cardiac disorders. Common: heart failure.

Eye disorders. Very common: lacrimation, conjunctivitis.

Vascular disorders. Very common: lymphedema.

Respiratory, thoracic and mediastinal disorders. Very common: epistaxis; pharyngolaryngeal 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; fatigue; mucositis; pain; acute respiratory infection; chest pain; chills. Common: lethargy.

Investigations. Very common: weight gain.

Specific adverse reactions in patients with breast cancer receiving docetaxel at a dose of 100 mg/m² in combination with trastuzumab

Blood and lymphatic system disorders. Very common: hematological toxicity of combined trastuzumab and docetaxel therapy 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 effect in this patient group may be underestimated, as even with docetaxel monotherapy at 100 mg/m², neutropenia occurs in 97% of patients, with 76% at Grade IV (based on nadir neutrophil count). The frequency of febrile neutropenia or neutropenic sepsis also increases in patients receiving the combination of Herceptin and docetaxel (23% vs. 17% compared to docetaxel monotherapy).

Cardiac disorders. Symptomatic heart failure was observed in 2.2% of patients receiving the combination of trastuzumab and docetaxel, compared to 0% in patients on monotherapy. In the study group receiving the combination of docetaxel and trastuzumab, 64% of patients had previously received anthracyclines as adjuvant therapy, compared to 55% in the monotherapy group.

Adverse reactions in patients with breast cancer receiving docetaxel at a dose of 75 mg/m² in combination with capecitabine

Infections and parasitic diseases. 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%).

Metabolic and nutritional 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: pharyngolaryngeal 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%); fatigue/generalized weakness (G3/4: 5%); peripheral edema (G3/4: 1%). Common: lethargy; pain.

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

Adverse reactions in patients with breast cancer receiving docetaxel at a dose of 75 mg/m² in combination with prednisone or prednisolone

Infections and parasitic diseases. 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%).

Metabolic and nutritional 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: left ventricular dysfunction (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 (no severe cases). Common: desquamative rash (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: fatigue (G3/4: 3.9%); fluid retention (severe: 0.6%).

Description of adverse reactions observed in patients with locally advanced (or metastatic) hormone-sensitive prostate cancer at high risk receiving docetaxel therapy at a dose of 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE trial)

Blood and lymphatic system disorders. Very common: neutropenia (G3/4: 12%), anemia, febrile neutropenia (G3/4: 15%).

Immune system disorders. Common: hypersensitivity (G3/4: 1%).

Endocrine disorders. Common: diabetes mellitus (G3/4: 1%).

Metabolism and nutrition disorders. Common: loss of appetite.

Psychiatric disorders. Very common: insomnia (G3: 1%).

Nervous system disorders. Very common: peripheral sensory neuropathy (≥ G3: 2%), headache. Common: dizziness.

Eye disorders. Common: blurred vision.

Cardiac disorders. Common: hypotension (G3: 0%).

Respiratory, thoracic and mediastinal disorders. Very common: dyspnea (G3: 1%), cough (G3: 0%), upper respiratory tract infection (G3: 1%). Common: pharyngitis (G3: 0%).

Gastrointestinal disorders. Very common: diarrhea (G3: 3%), stomatitis (G3: 0%), constipation (G3: 0%), nausea (G3: 1%), dyspepsia, abdominal pain (G3: 0%), flatulence. Common: vomiting (G3: 1%).

Skin and subcutaneous tissue disorders. Very common: alopecia (G3: 3%), nail changes (G3: 1%). Common: rash.

Musculoskeletal and connective tissue disorders. Very common: myalgia.

General disorders and administration site conditions. Very common: lethargy (G3/4: 2%), influenza-like symptoms (G3: 0%), asthenia (G3: 0%), fluid retention. Common: pyrexia (G3: 1%), oral candidiasis, hypocalcemia (G3: 0%), hypophosphatemia (G3/4: 1%), hypokalemia (G3: 0%).

Adverse reactions during adjuvant therapy with docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer (pooled data)

Infections and parasitic diseases. Very common: infections (G3/4: 2.4%); neutropenic infections (G3/4: 2.6%).

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: NC).

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

Metabolic and nutritional 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%). Uncommon: syncope (G3/4: 0%); neurotoxicity symptoms (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%).

Vascular disorders. Very common: hot flushes (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: 5.0%); stomatitis (G3/4: 6.0%); vomiting (G3/4: 4.2%); diarrhea (G3/4: 3.4%); constipation (G3/4: 0.5%). Common: abdominal pain (G3/4: 0.4%).

Skin and subcutaneous tissue disorders. Very common: alopecia (persistent: < 3%); skin toxicity manifestations (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%).

General disorders and administration site conditions. Very common: asthenia (G3/4: 10%); fever (G3/4: NC); peripheral edema (G3/4: 0.2%).

Reproductive system and breast disorders. Very common: amenorrhea (G3/4: NC).

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

Specific adverse reactions observed during adjuvant therapy with docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide in patients with node-positive (TAX 316) and node-negative (GEICAM 9805) breast cancer.

Nervous system disorders. In the TAX316 study, peripheral sensory neuropathy began during the treatment period and persisted during follow-up 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 duration: 8 years), peripheral sensory neuropathy persisted 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 treatment persisted during follow-up 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 duration: 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 (CHF) developed in 26 patients (3.5%) in the TAC group and in 17 patients (2.3%) in the FAC group. In all patients except one in each group, CHF was diagnosed more than 30 days after treatment initiation. Two patients in the TAC group and four patients in the FAC group died due to heart failure.

In the GEICAM 9805 study, CHF developed during the follow-up period in 3 patients (0.6%) in the TAC group and in 3 patients (0.6%) in the FAC group.

At the end of the follow-up period (actual median follow-up duration: 10 years and 5 months), no patient in the TAC group had CHF, and 1 patient in the TAC group died due to dilated cardiomyopathy, while CHF persisted in 1 patient (0.2%) in the FAC group.

Skin and subcutaneous tissue disorders. In the TAX316 study, alopecia that persisted during follow-up was observed in 687 of 744 patients (92.3%) in the TAC group and in 645 of 736 patients (87.6%) in the FAC group.

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

In the GEICAM 9805 study, alopecia that began during treatment 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 related to the investigational drug began or worsened during follow-up 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 treatment and persisted during follow-up after chemotherapy completion was observed in 202 of 744 patients (27.2%) in the TAC group and in 125 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 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 treatment 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 reactions. In the TAX316 study, peripheral edema that began during treatment and persisted during follow-up after chemotherapy completion was observed in 119 of 744 patients (16.0%) in the TAC group and in 23 of 736 patients (3.1%) in the FAC group. At the end of the follow-up period (actual median follow-up duration: 8 years), peripheral edema persisted in 19 patients (2.6%) in the TAC group and in 4 patients (0.5%) in the FAC group.

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

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

In the GEICAM 9805 study, peripheral edema that began during treatment persisted during follow-up 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 duration: 10 years and 5 months), no patient (0%) in the TAC group had peripheral edema, while peripheral edema persisted in 1 patient (0.2%) in the FAC group. Lymphatic edema that began during treatment persisted during follow-up 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, lymphatic edema persisted in 4 patients (0.8%) in the TAC group and in 1 patient (0.2%) in the FAC group.

Asthenia that began during treatment 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 the follow-up period, asthenia persisted in 2 patients (0.4%) in the TAC group and in 2 patients (0.4%) in the FAC group.

Acute leukemia / myelodysplastic syndrome. Over 10 years of follow-up in the TAX 316 study, acute leukemia was diagnosed in 3 of 744 patients (0.4%) in the TAC group and in 1 of 736 patients (0.1%) in the FAC group. During follow-up (median follow-up duration: 8 years), 1 patient (0.1%) in the TAC group and 1 patient (0.1%) in the FAC group died due to acute myeloid leukemia. Myelodysplastic syndrome was diagnosed in 2 of 744 patients (0.3%) in the TAC group and in 1 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 of 532 patients (0.2%) 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. Table 13 shows that the incidence of Grade IV neutropenia, febrile neutropenia, and neutropenic infection decreased in patients receiving primary prophylaxis with G-CSF after such prophylaxis became mandatory in the TAC group of the GEICAM study.

Table 2

Neutropenic complications in patients receiving TAC with or without primary prophylaxis with G-CSF (GEICAM 9805 study)

Adverse reactions in patients with gastric adenocarcinoma during docetaxel therapy at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil

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: 1.0%), abdominal pain (G3/4: 1.0%), esophagitis/dysphagia/odynophagia (G3/4: 0.7%).

Skin and subcutaneous tissue disorders. Very common: alopecia (G3/4: 4.0%). 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: 19.0%), fever (G3/4: 2.3%), fluid retention (severe/life-threatening: 1%).

Specific adverse reactions in patients with gastric adenocarcinoma during docetaxel therapy at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders. Febrile neutropenia and neutropenic infections occurred in 17.2% and 13.5% of patients, respectively, regardless of whether G-CSF was administered. G-CSF was administered for secondary prophylaxis in 19.3% of patients (10.7% of all chemotherapy cycles). Febrile neutropenia and neutropenic infections occurred in 12.1% and 3.4% of patients receiving G-CSF, and in 15.6% and 12.9% of patients who did not receive G-CSF prophylaxis (see section "Dosage and administration").

Adverse reactions in patients with head and neck cancer during docetaxel therapy at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil.

Induction chemotherapy followed by radiotherapy (study TAX 323)

Infections and infestations. Very common: infections (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 (G3/4: 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 thrombosis (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, increased skin dryness, 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 (study TAX 324)

Infections and infestations. Very common: infections (G3/4: 3.6%). Common: 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 (G3/4: 83.5%), anemia (G3/4: 12.4%), thrombocytopenia (G3/4: 4.0%), febrile neutropenia.

Immune system disorders. Uncommon: hypersensitivity reactions.

Metabolism and nutrition disorders. Very common: anorexia (G3/4: 12.0%).

Nervous system disorders. Very common: dysgeusia/parosmia (G3/4: 0.4%), peripheral sensory neuropathy (G3/4: 1.2%). Common: dizziness (G3/4: 2.0%), 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 thrombosis.

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%).

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 administered in combination with other antineoplastic agents associated with the development of second primary malignancies has been linked to cases of second primary malignancies (frequency unknown), including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma. In pivotal clinical trials in patients with breast cancer receiving the TAC regimen, cases of acute myeloid leukemia and myelodysplastic syndrome were observed (frequency unknown).

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

Immune system disorders. There have been several reports of anaphylactic shock, sometimes fatal. Hypersensitivity reactions (frequency unknown) have been reported in patients who previously experienced hypersensitivity reactions to paclitaxel during docetaxel administration.

Nervous system disorders. Docetaxel administration has been associated with rare cases of seizures or transient loss of consciousness. These reactions were sometimes observed during infusion.

Eye disorders. Very rare cases of transient visual disturbances (flashes, flickering lights, scotoma), usually occurring during infusion and often accompanied by hypersensitivity reactions, have been reported. These disorders resolved spontaneously after infusion was stopped. Rare cases of excessive lacrimation, with or without concomitant conjunctivitis, due to obstruction of the lacrimal duct have been reported.

Cystoid macular edema (CME) has been observed in patients receiving docetaxel.

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

Cardiac disorders. Rare cases of myocardial infarction have been reported.

Ventricular arrhythmias, including ventricular tachycardia (frequency unknown), sometimes fatal, have been observed 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 resulting from gastrointestinal disorders, including enterocolitis and gastrointestinal perforation, have been reported. Rare cases of intestinal obstruction and bowel obstruction have also been reported.

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

Renal and urinary disorders. Cases of renal dysfunction and renal failure have been reported. In approximately 20% of these cases, no risk factors for acute renal failure, such as concomitant use of nephrotoxic drugs or gastrointestinal disorders, were identified.

Skin and subcutaneous tissue disorders. Very rare cases of systemic lupus erythematosus and severe skin adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis have been reported during docetaxel therapy. In some cases, these adverse events may have been influenced by concomitant factors. Cases of scleroderma-like skin lesions, usually preceded by peripheral lymphedema, have also been reported. Cases of persistent alopecia (frequency unknown) have been reported.

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

Cases of recurrent injection site reaction (recurrent skin reaction at a site where extravasation had previously occurred, after docetaxel administration at another site) have been reported (frequency unknown).

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

Rare cases of dehydration and pulmonary edema have been reported.

Metabolism and nutrition disorders. Cases of electrolyte imbalance have been reported. Hyponatremia, mainly associated with dehydration, vomiting, and pneumonia, has been observed. Hypokalemia, hypomagnesemia, and hypocalcemia have been observed, usually in association with gastrointestinal disorders, particularly diarrhea. Tumor lysis syndrome, potentially fatal (frequency unknown), has been reported.

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

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

**Shelf life. **2 years.

Storage conditions. Store in a refrigerator (at a temperature of +2 °C to +8 °C). Keep in the original packaging. Keep out of reach of children.

Incompatibilities. This medicinal product must not be mixed with any other medicinal product except those specified in the section "Special instructions for use".

Packaging. 1 ml (20 mg), 4 ml (80 mg), or 8 ml (160 mg) in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's address and location of its operations. Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.