Docetaxel-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXETAXEL-VISTA (DOCETAXEL-VISTA)

Composition:

Active substance: docetaxel;

1 ml of concentrate contains 20 mg of docetaxel;

Excipients: polysorbate 80, povidone, citric acid anhydrous, ethanol anhydrous.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, oily, pale yellow solution.

Pharmacotherapeutic group. Antineoplastic agents. Taxanes. 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.

In vitro clonogenic assays showed cytotoxicity of docetaxel against various tumor cell lines of mice and humans, as well as against freshly isolated human tumor cells. Docetaxel achieves high concentrations in the extracellular fluid and ensures prolonged cell survival. Furthermore, docetaxel exhibits activity against some (although not all) 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 a broad spectrum of antitumor activity against common tumors, including experimental mouse tumors and implanted human tumors.

Clinical Efficacy and Safety.

Breast Cancer.

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy. Patients with operable breast cancer and lymph node metastases (study TAX 316). Data from a multicenter, open-label, randomized trial support the use of docetaxel in adjuvant therapy for women aged 18 to 70 years with operable breast cancer and lymph node metastases and a Karnofsky Performance Status (KPS) ≥ 80%. After stratification according to the number of involved lymph nodes (1–3, 4+), 1491 patients were randomized into two groups: to receive 75 mg/m² docetaxel administered 1 hour after 50 mg/m² doxorubicin and 500 mg/m² cyclophosphamide (TAC group), or to receive 50 mg/m² doxorubicin followed by 500 mg/m² fluorouracil and 500 mg/m² cyclophosphamide (FAC group). Both regimens were administered every 3 weeks for a total of 6 cycles. Docetaxel was given as a 1-hour infusion, and all other drugs were administered as intravenous boluses on day 1 of each cycle. Patients who developed complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection) received granulocyte colony-stimulating factor (G-CSF) for secondary prophylaxis. Patients in the TAC group received antibiotic prophylaxis with ciprofloxacin (500 mg orally twice daily for 10 days, starting on day 5 of each treatment cycle) or a similar agent. After completion of chemotherapy, patients whose tumors expressed estrogen and/or progesterone receptors received tamoxifen 20 mg once daily for up to 5 years. Adjuvant radiotherapy was administered according to institutional guidelines and was given to 69% of patients in the TAC group and 72% in the FAC group.

Two interim analyses and one final analysis were conducted. The first interim analysis was planned 3 years after the date when half of the required number of participants had been enrolled. The second interim analysis was performed after a total of 400 disease-free survival (DFS) events had been recorded, resulting in a median follow-up duration of 55 months. The final analysis was conducted when all patients had completed their 10-year follow-up visits (except those who had already experienced a DFS event or were lost to follow-up). The primary efficacy endpoint was disease-free survival (DFS); the secondary efficacy endpoint was overall survival (OS).

The final analysis was performed with a median follow-up duration of 96 months. Results showed that disease-free survival in the TAC group was statistically significantly longer than in the FAC group. The 10-year recurrence rate was lower in the TAC group compared to the FAC group (39% vs. 45%, respectively), representing an absolute risk reduction of 6% (p = 0.0043). Overall survival at 10 years was also statistically significantly higher in the TAC group compared to the FAC group (76% vs. 69%, respectively), representing an absolute reduction in mortality risk of 7% (p = 0.002). However, since the benefits observed in patients with metastases in 4 or more lymph nodes were not statistically significant for DFS and OS, the favorable benefit-risk ratio of the TAC regimen was not fully demonstrated in this subgroup of patients.

Overall, the study results demonstrated a positive benefit-risk profile for the TAC regimen compared to the FAC regimen.

A subgroup analysis was performed for each patient group treated with the TAC regimen according to prospectively defined key prognostic factors (see Table 1).

Table 1.

Subgroup analysis results according to prospectively defined key prognostic factors in patients with operable breast cancer and lymph node metastases treated with the TAC regimen (study TAX 316)

*A hazard ratio of less than 1 indicates that the TAC regimen was associated with longer recurrence-free survival and overall survival compared to the FAC regimen.

Patients with operable breast cancer without lymph node metastases eligible for chemotherapy (GEICAM 9805 study). Data from a multicenter, open-label, randomized trial support the use of docetaxel as adjuvant therapy in patients with operable breast cancer without lymph node metastases who are candidates for chemotherapy. A total of 1060 patients were randomized into two groups: to receive 75 mg/m² docetaxel as a 1-hour infusion given 1 hour after 50 mg/m² doxorubicin and 500 mg/m² cyclophosphamide (TAC group, 539 patients) or to receive 50 mg/m² doxorubicin followed by 500 mg/m² fluorouracil and 500 mg/m² cyclophosphamide (FAC group, 521 patients) as adjuvant therapy for patients with operable breast cancer without lymph node metastases and at high risk of recurrence according to the 1998 St. Gallen Consensus Conference criteria (tumor size > 2 cm and/or absence of estrogen receptors (ER) and progesterone receptors (PR), and/or high nuclear pleomorphism/histological differentiation grade (2–3), and/or age under 35 years). Both treatment regimens were administered every 3 weeks, for a total of 6 cycles. Docetaxel was administered as a 1-hour infusion, and all other drugs were given intravenously on day 1 of each 3-week cycle. Following randomization, primary prophylaxis with G-CSF was mandated for 230 patients in the TAC group. The incidence of grade IV neutropenia, febrile neutropenia, and neutropenic infection was lower in patients who received primary prophylaxis with G-CSF (see section "Adverse Reactions"). In both groups, after the last cycle of chemotherapy, patients whose tumors expressed estrogen receptors (ER+) and/or progesterone receptors (PgR+) received tamoxifen 20 mg once daily for up to 5 years. According to the recommendations in place at the participating centers, adjuvant radiotherapy was administered to 57.3% of patients in the TAC group and 51.2% of patients in the FAC group.

One primary analysis and one analysis based on updated data were performed. The primary analysis was conducted when follow-up duration exceeded 5 years in all patients (median follow-up duration was 77 months). The updated data analysis was performed when all patients had completed their 10-year follow-up visits (median follow-up duration was 10 years and 5 months), except for those who had previously experienced a recurrence-free survival (RFS) event or were lost to follow-up. The primary efficacy endpoint was recurrence-free survival (RFS); the secondary efficacy endpoint was overall survival (OS).

With a median follow-up of 77 months, recurrence-free survival in the TAC group was statistically significantly longer than in the FAC group. Patients in the TAC group had a 32% reduction in the risk of recurrence compared to patients in the FAC group (hazard ratio 0.68, 95% CI: 0.49–0.93, p = 0.01). With a median follow-up of 10 years and 5 months, patients in the TAC group had a 16.5% reduction in the risk of recurrence compared to patients in the FAC group (hazard ratio 0.84, 95% CI: 0.65–1.08, p = 0.1646). The RFS data were not statistically significant but still demonstrated a favorable trend for the TAC group.

With a median follow-up of 77 months, overall survival (OS) in the TAC group was also longer, with a 24% reduction in the risk of death observed in patients in the TAC group compared to those in the FAC group (hazard ratio 0.76, 95% CI: 0.46–1.26, p = 0.29). However, the difference in OS between the two groups was not statistically significant.

With a median follow-up of 10 years and 5 months, patients in the TAC group had a 9% reduction in the risk of death compared to patients in the FAC group (hazard ratio 0.91, 95% CI: 0.63–1.32).

After 8 years of follow-up, survival rates were 93.7% in the TAC group and 91.4% in the FAC group; after 10 years of follow-up, survival rates were 91.3% in the TAC group and 89% in the FAC group.

The favorable benefit-risk profile of the TAC group compared to the FAC group remained unchanged.

In the primary analysis (based on a median follow-up of 77 months), predefined subgroups of patients receiving the TAC regimen were analyzed according to prospectively defined key prognostic factors (see Table 2).

Table 2.

Subgroup analysis results according to prospectively defined key prognostic factors in patients with node-negative breast cancer treated with the TAC regimen (analysis of all randomized patients; Intent-to-Treat) (GEICAM 9805 study)

*A TAC/FAC risk ratio of less than 1 indicates that the TAC treatment regimen was associated with longer recurrence-free survival compared to the FAC treatment regimen.

Exploratory analyses were conducted in various subgroups to evaluate recurrence-free survival in patients meeting the 2009 St. Gallen Consensus Conference criteria for chemotherapy (ITT population); results of these analyses are presented in Table 3.

Table 3.

Results of exploratory analyses in different subgroups evaluating recurrence-free survival in patients meeting the 2009 St. Gallen Consensus Conference criteria for chemotherapy (analysis of data from all randomized patients; Intent-to-Treat) (GEICAM 9805 study)

TAC – docetaxel, doxorubicin, and cyclophosphamide; FAC – 5-fluorouracil, doxorubicin, and cyclophosphamide; CI – confidence interval; ER – estrogen receptors; PR – progesterone receptors.

aAbsence of ER/PR receptors or grade 3, or tumor size > 5 cm.

The calculated risk ratio was determined using the Cox proportional hazards model, with treatment groups as the reference.

Docetaxel as monotherapy.

Two randomized comparative phase III studies were conducted in patients with metastatic breast cancer: 326 patients who had failed prior alkylating agent therapy and 392 patients who had failed prior anthracycline therapy, who received docetaxel at the recommended dose and schedule, i.e., 100 mg/m² every 3 weeks. In patients who had failed prior alkylating agent therapy, docetaxel was compared with doxorubicin (75 mg/m² every 3 weeks). While having no effect on overall survival (15 months in the docetaxel group versus 14 months in the doxorubicin group, p = 0.38) or time to disease progression (27 weeks in the docetaxel group versus 23 weeks in the doxorubicin group, p = 0.54), docetaxel increased the response rate (52% versus 37%, p = 0.01) and shortened the time to response (12 weeks versus 23 weeks, p = 0.007). In 3 patients (2%) receiving docetaxel, the drug was discontinued due to fluid retention, and in 15 patients (9%) receiving doxorubicin, the drug was discontinued due to cardiotoxicity (3 cases of congestive heart failure with fatal outcome).

In patients who had failed prior anthracycline therapy, docetaxel was compared with a combination of mitomycin C and vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel increased the response rate (33% versus 12%, p < 0.0001), prolonged time to disease progression (19 weeks versus 11 weeks, p = 0.0004), and prolonged overall survival (11 months versus 9 months, p = 0.01).

During these two phase III studies, the safety profile of docetaxel was consistent with that observed in phase II studies (see section "Adverse Reactions").

An open-label, multicenter, randomized phase III study was conducted to compare docetaxel monotherapy with paclitaxel monotherapy in the treatment of patients with advanced breast cancer who had previously received anthracycline-based therapy. A total of 449 patients were enrolled and randomized into two groups: to receive either docetaxel monotherapy at a dose of 100 mg/m² as a 1-hour infusion or paclitaxel monotherapy at a dose of 175 mg/m² as a 3-hour infusion. Both treatment regimens were administered every 3 weeks.

While not affecting the primary endpoint, i.e., overall response rate (32% versus 25%, p = 0.10), docetaxel prolonged median time to disease progression (24.6 weeks versus 15.6 weeks; p < 0.01) and median survival (15.3 months versus 12.7 months; p = 0.03).

The docetaxel monotherapy group experienced a higher incidence of grade III/IV adverse events (55.4%) compared to the paclitaxel treatment group (23%).

Docetaxel in combination with doxorubicin.

One large-scale randomized phase III study was conducted involving 429 patients with metastatic breast cancer who had not previously received anticancer therapy. In this study, patients received either doxorubicin (50 mg/m²) in combination with docetaxel (75 mg/m²) (AT group), or doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²) (AC group). Both treatment regimens were administered on day 1 of each 3-week cycle.

• Time to disease progression (TTP) was statistically significantly longer in the AT group than in the AC group, p = 0.0138. Median TTP was 37.3 weeks (95% CI: 33.4–42.1) in the AT group and 31.9 weeks (95% CI: 27.4–36.0) in the AC group.
• Overall response rate (ORR) was statistically significantly higher in the AT group than in the AC group, p = 0.009. ORR was 59.3% (95% CI: 52.8–65.9) in the AT group compared to 46.5% (95% CI: 39.8–53.2) in the AC group.

In this study, the AT group experienced higher incidences of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infection (8% versus 2.4%), diarrhea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) compared to the AC group. Conversely, the AC group had a higher incidence of severe anemia (15.8% versus 8.5%) and higher rates of severe cardiotoxic reactions: congestive heart failure (3.8% versus 2.8%), absolute decrease in left ventricular ejection fraction (LVEF) of ≥20% (13.1% versus 6.1%), and absolute decrease in LVEF of ≥30% (6.2% versus 1.1%). Treatment-related deaths occurred in 1 patient in the AT group (due to congestive heart failure) and in 4 patients in the AC group (1 due to septic shock, 3 due to congestive heart failure).

Quality of life, assessed using the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire, was similar in both groups and remained stable during treatment and follow-up.

Docetaxel in combination with trastuzumab.

Docetaxel in combination with trastuzumab was studied in the treatment of patients with metastatic breast cancer whose tumors exhibited HER2 overexpression and who had not previously received chemotherapy for metastatic disease. The study included 186 patients who were randomized into two groups: to receive docetaxel (100 mg/m²) in combination with trastuzumab or without trastuzumab; 60% of patients had previously received adjuvant anthracycline-based chemotherapy. Docetaxel in combination with trastuzumab was effective regardless of prior adjuvant anthracycline therapy. The primary method for determining HER2 expression in this pivotal study was immunohistochemistry (IHC). In a small subset of patients, fluorescence in situ hybridization (FISH) was used. In this study, 87% of patients had HER2 overexpression at the IHC 3+ level, and 95% of patients enrolled in the study had HER2 overexpression at the IHC 3+ level and/or positive FISH results. Efficacy data are summarized in Table 4.

Table 4.

Results of efficacy assessment of treatment of metastatic breast cancer with docetaxel in combination with trastuzumab or without trastuzumab

PFS – time to disease progression; NE – not evaluable or not reached.

1 Full analysis population (Intent-to-Treat population).

2 Median survival calculated.

Docetaxel in combination with capecitabine.

Data from a single multicenter, randomized, controlled Phase III clinical trial support the use of docetaxel in combination with capecitabine for the treatment of patients with locally advanced or metastatic breast cancer after prior cytotoxic chemotherapy including an anthracycline. In this trial, 255 patients were randomized to receive either docetaxel (75 mg/m² as a 1-hour intravenous infusion every 3 weeks) or capecitabine (1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period). A total of 256 patients were randomized to the docetaxel monotherapy group (100 mg/m² as a 1-hour intravenous infusion every 3 weeks). Survival was higher in the group receiving docetaxel in combination with capecitabine (p = 0.0126). Median survival was 442 days (docetaxel + capecitabine) compared to 352 days (docetaxel monotherapy). The overall objective response rate in the entire randomized population (investigator-assessed) was 41.6% (docetaxel + capecitabine) versus 29.7% (docetaxel monotherapy); p = 0.0058. Time to disease progression was significantly longer in the group receiving docetaxel in combination with capecitabine (p < 0.0001). Median time to disease progression was 186 days (docetaxel + capecitabine) compared to 128 days (docetaxel monotherapy).

Non-small cell lung cancer.

Patients previously treated with chemotherapy with or without radiotherapy. In a Phase III trial involving patients previously treated for their disease, time to disease progression (12.3 weeks vs. 7 weeks) and overall survival were statistically significantly higher in patients receiving docetaxel at a dose of 75 mg/m² compared to those receiving best supportive care (BSC). The 1-year survival rate was also statistically significantly higher in the docetaxel group (40%) compared to the BSC group (16%).

Compared to patients in the BSC group, patients receiving docetaxel (75 mg/m²) required fewer opioid analgesics (p < 0.01), non-opioid analgesics (p < 0.01), other medications used for this disease (p = 0.06), and radiotherapy (p < 0.01).

The overall response rate among evaluable patients was 6.8%, and the median duration of response was 26.1 weeks.

Docetaxel in combination with platinum agents in patients previously untreated with chemotherapy.

In a Phase III trial, 1218 patients with unresectable non-small cell lung cancer (NSCLC) stage IIIB or IV and a KPS of 70% or higher, who had not previously received chemotherapy for this disease, were randomized into three groups: to receive every 3 weeks docetaxel (T) 75 mg/m² as a 1-hour infusion, immediately followed by cisplatin (Cis) 75 mg/m² over 30–60 minutes (regimen TCis); or docetaxel 75 mg/m² as a 1-hour infusion every 3 weeks in combination with carboplatin (AUC = 6 mg/mL × min) administered over 30–60 minutes; or vinorelbine (V) 25 mg/m² over 6–10 minutes on days 1, 8, 15, and 22, followed by cisplatin 100 mg/m² on day 1 of each cycle, repeated every 4 weeks (regimen VCis).

Survival data, median time to disease progression, and response rates in the two treatment groups are presented in Table 5.

Table 5.

Efficacy results in the treatment of unresectable stage IIIB or IV NSCLC with docetaxel in combination with cisplatin (TCis regimen) versus vinorelbine in combination with cisplatin (VCis regimen)

*Data adjusted for multiple comparisons, with corrections for stratification factors (disease stage and region where treatment was administered), are presented for the entire evaluable patient population.

Secondary endpoints included change in pain, overall quality of life as measured by the EuroQoL-5D questionnaire, lung cancer symptom scale score, and changes in overall functional status assessed by the Karnofsky Performance Scale. Results for these endpoints supported the corresponding findings established for the primary endpoints.

It was not possible to demonstrate that the combination of docetaxel/carboplatin is equivalent or at least not inferior in efficacy compared to the comparator combination (VCis).

Prostate cancer.

Metastatic castration-resistant prostate cancer

The safety and efficacy of docetaxel in combination with prednisone or prednisolone in patients with metastatic castration-resistant prostate cancer were evaluated in a randomized, multicenter, phase III trial (TAX 327). A total of 1006 patients with KPS ≥ 60 were randomized into the following treatment groups:

• Docetaxel 75 mg/m² every 3 weeks; a total of 10 cycles.
• Docetaxel 30 mg/m² administered weekly for the first 5 weeks of a 6-week treatment cycle; a total of 5 cycles.
• Mitoxantrone 12 mg/m² every 3 weeks; a total of 10 cycles.

In all three treatment regimens, drugs were administered in combination with continuous prednisone or prednisolone at a dose of 5 mg twice daily.

Patients receiving docetaxel every three weeks showed a statistically significant improvement in overall survival compared to those receiving mitoxantrone. The survival benefit in patients receiving weekly docetaxel was not statistically significant compared to the control group receiving mitoxantrone. Efficacy endpoints for the docetaxel treatment groups compared to the control group are summarized in Table 6.

Table 6.

Efficacy outcomes in the treatment of hormone-refractory metastatic prostate cancer with docetaxel 75 mg/m² every 3 weeks, weekly docetaxel 30 mg/m², or mitoxantrone 12 mg/m² every 3 weeks

†Stratified log-rank test.

*Statistical significance threshold of 0.0175.

**PSA – prostate-specific antigen.

Since the safety profile of docetaxel was somewhat better with weekly administration compared to administration every 3 weeks, some patients may derive greater benefit from weekly docetaxel.

No statistically significant difference in overall quality of life was observed between the treatment groups.

Metastatic hormone-sensitive prostate cancer

STAMPEDE study

The safety and efficacy of docetaxel administered concurrently with standard of care (ADT) in patients with locally advanced or metastatic hormone-sensitive prostate cancer at high risk were evaluated in a randomized, multicenter, multi-arm, multi-stage (MAMS) trial with continuous transition between phases II/III (STAMPEDE – MRC PR08). Overall, 1776 male patients were allocated to the required treatment groups:

• Standard of care + docetaxel 75 mg/m² administered every 3 weeks for 6 cycles.
• Standard of care as monotherapy.

The docetaxel treatment regimen was given in combination with prednisone or prednisolone 5 mg twice daily continuously.

Of the 1776 randomized patients, 1086 (61%) had metastatic disease; 362 were randomized to the docetaxel plus standard of care group, and 724 received standard of care as monotherapy.

In these patients with metastatic prostate cancer, median overall survival was significantly longer in the docetaxel treatment groups compared to the group receiving standard of care as monotherapy, with median overall survival being 19 months longer when docetaxel was added to standard of care (HR 0.76, 95% CI: 0.62–0.92, p = 0.005).

Efficacy results in patients with metastatic prostate cancer for the docetaxel group compared to the control group are summarized in Table 7.

Table 7.

Efficacy of docetaxel in combination with prednisone or prednisolone and standard of care in the treatment of patients with metastatic hormone-sensitive prostate cancer (STAMPEDE study)

a p-value calculated based on the likelihood ratio test, adjusted for all stratification factors (except for central and planned hormonal therapy) and stratified by study period.

b Treatment failure-free survival: time from randomization to the first occurrence of at least one of the following events: biochemical failure (defined as a 50% increase in PSA level above the nadir [lowest level achieved due to chemotherapy] during 24 weeks and above 4 ng/mL, confirmed by repeat measurement or treatment); disease progression: local progression (lymph nodes) or development of distant metastases; skeletal event; or death from prostate cancer.

CHAARTED study.

The safety and efficacy of docetaxel administered at the start of androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer were evaluated in a randomized, multicenter, phase III trial (CHAARTED). A total of 790 male patients were randomized into two treatment groups:

• ADT + docetaxel 75 mg/m² initiated at the start of ADT, administered every 3 weeks for 6 cycles;
• ADT as monotherapy.

Median overall survival was significantly longer in the docetaxel treatment group compared to the group receiving ADT alone, with median overall survival being 13.6 months longer when docetaxel was added to ADT (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.47–0.80, p = 0.0003).

Efficacy results or comparisons between the docetaxel treatment group and the control group are summarized in Table 8.

Table 8.

Efficacy of docetaxel and ADT in the treatment of patients with metastatic hormone-sensitive prostate cancer (CHAARTED study)

a Time-to-event variables: Stratified log-rank test. Response rate variables: Fisher’s exact test.

*p-value for illustrative purposes.

**Prostate-specific antigen (PSA) response: PSA level < 0.2 ng/mL confirmed by two consecutive measurements at least 4 weeks apart.

b Time to castration-resistant prostate cancer = time from randomization to PSA progression or clinical progression (i.e., worsening of symptomatic bone metastases, progression per Response Evaluation Criteria in Solid Tumors [RECIST], or clinical deterioration due to cancer as assessed by the investigator), whichever occurred first.

c Time to clinical progression = time from randomization to clinical progression (i.e., worsening of symptomatic bone metastases, progression per RECIST, or clinical deterioration due to cancer as assessed by the investigator).

Gastric adenocarcinoma.

A multicenter, open-label, randomized study was conducted to evaluate the safety and efficacy of docetaxel in patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not previously received chemotherapy for metastatic disease. A total of 445 patients with KPS > 70 were randomized into two groups: one receiving docetaxel (T) (75 mg/m² on day 1) in combination with cisplatin (C) (75 mg/m² on day 1) and 5-fluorouracil (F) (750 mg/m²/day for 5 days), or cisplatin (100 mg/m² on day 1) and 5-fluorouracil (1000 mg/m²/day for 5 days). The treatment cycle duration was 3 weeks in the TCF group and 4 weeks in the CF group. The median number of cycles per patient was 6 (range: 1–16) in the TCF group compared to 4 (range: 1–12) in the CF group. Time to disease progression (TTP) was considered as the primary endpoint. A 32.1% reduction in the risk of progression was observed in the TCF group, with a statistically significantly longer TTP (p = 0.0004). Overall survival was also statistically significantly longer (p = 0.0201) in the TCF group, with a 22.7% reduction in the risk of death. Efficacy data are summarized in Table 9.

Table 9.

Efficacy of docetaxel in combination with cisplatin and 5-fluorouracil (TCF regimen) compared to cisplatin and 5-fluorouracil combination (CF regimen) in the treatment of patients with gastric adenocarcinoma.

*Non-stratified log-rank test.

Subgroup analyses by age, gender, and race consistently favored the TCF regimen compared to the CF regimen.

An updated survival analysis based on further follow-up (median follow-up duration of 41.6 months) no longer demonstrated a statistically significant difference between the two treatment groups, although it continued to indicate a trend favoring the TCF regimen. The analysis showed that the advantage of TCF over CF was most clearly evident between 18 and 30 months of follow-up.

Overall, quality-of-life and clinical efficacy assessments consistently indicated improvement in the TCF group. Patients treated with the TCF regimen experienced a significantly longer time to irreversible deterioration in overall health status by 5% according to the QLQ-C30 questionnaire (p = 0.0121) and a significantly longer time to irreversible deterioration in functional status measured by the Karnofsky index (p = 0.0088), compared to patients receiving the CF regimen.

Head and neck cancer.

• Induction chemotherapy followed by radiotherapy (TAX 323 study).

The safety and efficacy of docetaxel in induction therapy for patients with squamous cell carcinoma of the head and neck (SCCHN) were evaluated in a multicenter, open-label, randomized Phase III trial (TAX 323). A total of 358 patients with unresectable locally advanced SCCHN and WHO performance status of 0 or 1 were randomized into two groups. Patients in the docetaxel treatment group received docetaxel 75 mg/m² (T), followed by cisplatin 75 mg/m² (P), and then 5-fluorouracil (F) at 750 mg/m²/day administered as a continuous infusion over 5 days. This regimen was repeated every 3 weeks for up to 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after two cycles. At least 4 weeks but no more than 7 weeks after completion of chemotherapy, patients without disease progression received radiotherapy (RT) for 7 weeks according to institutional guidelines (treatment regimen TPF/RT). Patients in the control group received cisplatin 100 mg/m² (P), followed by 5-fluorouracil (F) at 1000 mg/m²/day for 5 days. This regimen was repeated every 3 weeks for up to 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after two cycles. At least 4 weeks but no more than 7 weeks after completion of chemotherapy, patients without disease progression received radiotherapy (RT) according to institutional guidelines (treatment regimen PF/RT). Locoregional radiotherapy was delivered using standard fractionation (1.8–2.0 Gy once daily, 5 days per week, to a total dose of 66–70 Gy) or accelerated fractionation/hyperfractionation (twice daily with a minimum interval of 6 hours between fractions, 5 days per week). For accelerated fractionation, the recommended total dose was 70 Gy; for hyperfractionation, it was 74 Gy. Surgical resection of the tumor was permitted after chemotherapy (before or after radiotherapy). Patients in the TPF group received antibiotic prophylaxis with ciprofloxacin (500 mg orally twice daily for 10 days, starting on day 5 of each treatment cycle) or a comparable agent. The primary endpoint of this study—progression-free survival (PFS)—was statistically significantly longer in the TPF group compared to the PF group; p = 0.0042 (median PFS 11.4 months vs. 8.3 months, respectively), with a median follow-up duration of 33.7 months. Median overall survival (OS) was also statistically significantly longer in the TPF group than in the PF group (median OS 18.6 months vs. 14.5 months, respectively), with a 28% reduction in risk of death, p = 0.0128. Efficacy results are presented in Table 10.

Table 10.

Efficacy of docetaxel in induction therapy for patients with unresectable locally advanced SCCHN (analysis of data from all randomized patients; Intent-to-Treat)

A risk ratio of less than 1 indicates a favorable outcome for the docetaxel + cisplatin + 5-fluorouracil regimen.

*Cox model (adjusted for primary tumor site, clinical tumor stage according to TNM T and N classification, and WHO performance status).

**Log-rank test.

***χ² (chi-squared) test.

Quality of life measures.

Patients treated with the TPF regimen showed a statistically significant lesser deterioration in quality of life on the global health status scale compared to patients treated with the PF regimen (p = 0.01, using the EORTC QLQ-C30 scale).

Clinical benefit measures.

Functional status assessment scores (using the Head and Neck module (PSS-HN), designed to evaluate patient speech intelligibility, ability to eat in public, and dietary normality) demonstrated a statistically significant advantage of the TPF regimen over the PF regimen. The median time to first deterioration in WHO functional status was significantly longer in the TPF group compared to the PF group. Pain intensity improved during treatment in both groups, indicating adequate pain control.

Induction chemotherapy followed by chemoradiotherapy (TAX 324 study).

The safety and efficacy of docetaxel in induction therapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were evaluated in a randomized, multicenter, open-label Phase III trial (TAX 323). A total of 501 patients with locally advanced SCCHN and WHO performance status of 0 or 1 were randomized into two groups. The study population included patients with technically unresectable tumors, those with low likelihood of benefit from surgery, and those for whom an organ-preserving strategy was chosen. Efficacy and safety were assessed solely based on survival outcomes; organ preservation success was not formally evaluated.

Patients in the docetaxel group received 75 mg/m² docetaxel (T) as a 1-hour intravenous infusion on day 1, followed by 100 mg/m² cisplatin (P) as an intravenous infusion lasting from 30 minutes to 3 hours, then 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from day 1 to day 4. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression proceeded to chemoradiotherapy (CRT) per protocol (treatment arm TPF/CRT). Patients in the control group received 100 mg/m² cisplatin (P) as an intravenous infusion lasting from 30 minutes to 3 hours on day 1, followed by 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from day 1 to day 5. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received CRT per protocol (treatment arm PF/CRT).

Beginning no earlier than 3 weeks and no later than 8 weeks after the start of the last induction chemotherapy cycle (days 22 to 56 of the last cycle), patients in both groups were to undergo a 7-week course of CRT. During radiotherapy, carboplatin (AUC 1.5) was administered weekly as a 1-hour intravenous infusion, for up to 7 doses. Radiation was delivered using megavoltage equipment at 2 Gy fractions once daily, 5 days per week for 7 weeks, to a total cumulative dose of 70–72 Gy. Surgical intervention at the primary tumor site and/or neck region could be recommended at any time after completion of CRT. All patients in the docetaxel group received prophylactic antibiotics.

The primary efficacy endpoint in this study, overall survival (OS), was significantly longer in the docetaxel group compared to the PF group (log-rank test, p = 0.0058), with a median OS of 70.6 months versus 30.1 months, respectively. This corresponds to a 30% reduction in the risk of death in the TPF group compared to the PF group (hazard ratio (HR) 0.70; 95% confidence interval (CI): 0.54–0.90), with a median follow-up duration of 41.9 months. Analysis of the secondary endpoint, progression-free survival (PFS), showed a 29% reduction in the risk of disease progression or death in the TPF group and a 22-month increase in median PFS (35.5 months in the TPF group versus 13.1 months in the PF group). This difference was also statistically significant (HR 0.71; 95% CI: 0.56–0.90; log-rank test, p = 0.004). Efficacy results are summarized in Table 11.

Table 11.

Efficacy of docetaxel as induction therapy in patients with locally advanced SCCHN (analysis of all randomized patients; Intent-to-Treat)

A risk ratio of less than 1 indicates a favorable outcome for the use of the docetaxel + cisplatin + 5-fluorouracil regimen.

*Unadjusted log-rank test.

**Unadjusted log-rank test without correction for multiple comparisons.

***χ2 (chi-square) test without correction for multiple comparisons.

NA – not applicable.

Pediatric population.

The European Medicines Agency has waived the requirement to submit results of docetaxel studies for all pediatric subpopulations with breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma, and head and neck cancer, except for poorly differentiated nasopharyngeal carcinoma types II and III (data on use of the drug in children are provided in section "Children"). Pharmacokinetics.

Absorption.

Docetaxel pharmacokinetics were studied in phase I trials in cancer patients receiving doses of 20–115 mg/m². The pharmacokinetic profile of docetaxel is dose-independent and corresponds to a three-compartment pharmacokinetic model, with half-lives of α-, β-, and γ-(terminal) phases of 4 minutes, 36 minutes, and between 11.1 and 17.5 hours, respectively, based on sampling over a period up to 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 partially due to 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. Inter-individual variability in total docetaxel clearance reached approximately 50%. Docetaxel is bound to plasma proteins by more than 95%.

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 excreted 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 groups.

Age and sex.

Population pharmacokinetic analysis of docetaxel 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 an effect on the pharmacokinetics of the drug.

Hepatic dysfunction.

In a small number of patients (n = 23) with mild to moderate liver function abnormalities based on biochemical blood tests (ALT and AST levels ≥ 1.5 times the upper limit of normal (ULN) together with alkaline phosphatase levels ≥ 2.5 times ULN), the 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; data on docetaxel clearance in patients with severe fluid retention are not available.

Combination therapy.

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 not altered when administered concomitantly.

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

Docetaxel clearance when 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 observed with cisplatin monotherapy. Combined administration of docetaxel, cisplatin, and 5-fluorouracil in 12 patients with solid tumors did not alter the pharmacokinetics of any of these drugs.

The effect of prednisone on docetaxel pharmacokinetics after standard premedication with dexamethasone was studied 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 in in vitro micronucleus and chromosomal aberration tests in CHO-K1 cells and in an in vivo micronucleus test 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 the testes observed in toxicity studies in rodents indicate that docetaxel may impair male fertility.

Clinical characteristics.

Indications.

Breast cancer.

The medicinal product Docetaxel-Vista 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 patients meet accepted international criteria for chemotherapy in primary treatment of early-stage breast cancer.

The medicinal product Docetaxel-Vista 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.

The medicinal product Docetaxel-Vista as monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior cytotoxic therapy containing an anthracycline or an alkylating agent. The medicinal product Docetaxel-Vista in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer with HER-2 overexpression by tumor cells who have not previously received chemotherapy for metastatic disease.

The medicinal product Docetaxel-Vista in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior therapy containing an anthracycline.

Non-small cell lung cancer.

The medicinal product Docetaxel-Vista is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.

The medicinal product Docetaxel-Vista 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.

The medicinal product Docetaxel-Vista in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

The medicinal product Docetaxel-Vista 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.

The medicinal product Docetaxel-Vista 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.

The medicinal product Docetaxel-Vista 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 instructions").

Contraindications for other medicinal products should be taken into account when combining them with docetaxel.

Safety precautions.

Docetaxel is an antineoplastic agent and a potentially toxic substance; therefore, caution must be exercised during the preparation and administration of the solution. Medical gloves should be worn when handling docetaxel. If the concentrate or infusion solution comes into contact with the skin, it should be immediately and thoroughly washed with soap and water. If the concentrate or infusion solution contacts mucous membranes, the affected area should be immediately and thoroughly rinsed with water.

Interaction with other medicinal products and other types of interactions.

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

When docetaxel is co-administered with CYP3A4 inhibitors, the frequency of docetaxel adverse reactions 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 is recommended (see section "Special instructions"). 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 in the presence of prednisone 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 formal in vivo interaction studies with other medicinal products have not been conducted, in vitro data indicate that drugs with high plasma protein binding (e.g., erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate) do not impair docetaxel binding to plasma proteins. Furthermore, dexamethasone does not impair docetaxel binding 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 one uncontrolled study suggest a potential interaction between docetaxel and carboplatin. When these agents were administered in combination, the clearance of carboplatin 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 per day (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 should be performed with oral dexamethasone 8 mg administered 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion (see section "Dosage and administration").

Hematological changes during treatment with the medicinal product.

The most common adverse reaction during docetaxel therapy is neutropenia. The lowest neutrophil counts were observed on average on day 7 of treatment, although the time to reach the nadir of neutropenia may be shorter in patients who have previously received multiple courses of antineoplastic therapy. All patients receiving docetaxel should undergo 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 treatment with docetaxel, a dose reduction in the next chemotherapy cycle or appropriate symptomatic treatment is recommended.

In patients receiving combination therapy with docetaxel, cisplatin, and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infections occurred less frequently when granulocyte colony-stimulating factor (G-CSF) was used. 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 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. 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 recommended when administering the medicinal product to patients with neutropenia, particularly those at increased risk of gastrointestinal complications. Although most such cases occurred during the first or second chemotherapy cycle with docetaxel, enterocolitis may develop at any time and can be fatal on the first day of onset. Patients should be carefully monitored for early signs of serious gastrointestinal toxic reactions (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 marked hypotension, bronchospasm, generalized rash/erythema, or (very rarely) anaphylaxis with fatal outcome 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 previous history of hypersensitivity reaction to paclitaxel may be at increased risk of hypersensitivity reaction to docetaxel, including more severe reactions. These patients should be closely monitored at 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 extensive skin rash with subsequent desquamation of the epithelium, requiring interruption or permanent 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 treatment. Patients should be informed about the signs and symptoms of serious skin reactions and monitored closely. If signs and symptoms suggestive of these reactions occur, discontinuation of docetaxel should be considered.

Fluid retention.

Patients with significant fluid retention, such as pleural effusion, pericardial effusion, or 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. In patients receiving concomitant radiotherapy, cases of radiation pneumonitis have been observed. In the event of new pulmonary symptoms or worsening of existing symptoms, close monitoring, urgent evaluation, and appropriate treatment are required. Docetaxel therapy should be discontinued until diagnosis is established. Early supportive treatment may help improve the patient's condition. The benefit of resuming docetaxel therapy should be carefully evaluated.

Patients with hepatic impairment.

Patients with elevated transaminase levels (ALT and/or AST) >1.5 times the upper limit of normal (ULN) and alkaline phosphatase >2.5 times ULN during monotherapy with docetaxel 100 mg/m² are at higher risk of developing severe adverse reactions, including fatal outcomes due to toxic effects of the drug, such as sepsis and gastrointestinal bleeding, as well as 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 the start of treatment and before each new chemotherapy cycle. 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, but docetaxel should generally not be used unless there is a compelling need.

In a pivotal clinical study of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, exclusion criteria included elevated ALT and/or AST >1.5 times ULN, alkaline phosphatase >2.5 times ULN, and bilirubin >ULN; therefore, dose reduction of docetaxel cannot be recommended for such patients. The medicinal product should generally not be used in this patient group unless there is a compelling need. There are no data on the use of docetaxel in combination therapy for other indications in patients with hepatic impairment.

Patients with renal impairment.

There are no data on the treatment of patients with severe renal impairment using docetaxel.

Neurotoxicity.

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

Cardiotoxicity.

In patients receiving docetaxel in combination with trastuzumab, particularly after prior anthracycline 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 fatal outcome. If docetaxel is to be used in combination with trastuzumab, cardiac function should be evaluated before the start of therapy. Regular monitoring of cardiac function (e.g., every 3 months) during treatment with these agents is recommended to identify patients who may develop cardiac dysfunction. Further information is provided in the "Summary of Product Characteristics" for trastuzumab.

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

Disorders of the visual organs.

Cases of crystalline macular edema (CME) have been observed in patients receiving docetaxel. Patients with 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").

Second primary malignancy.

Cases of second primary malignancy have been observed during treatment with docetaxel in combination with antineoplastic agents known to be associated with the development of second primary malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma) may occur months or years after treatment with docetaxel. Patients should be monitored for 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 impaired renal function, hyperuricemia, bulky tumors, rapid progression) should be closely monitored. Correction of dehydration and treatment of elevated uric acid levels are recommended before the start of therapy.

Other warnings.

Women of childbearing potential should use contraception during treatment and for 2 months after discontinuation of docetaxel therapy.

Men should use contraception during treatment and for 4 months after discontinuation of docetaxel therapy (see section "Use during pregnancy or breastfeeding").

Concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., 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 the use of docetaxel 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.

Gastrointestinal reactions.

Symptoms such as abdominal pain, tenderness and pain on palpation of the abdomen, fever, and diarrhea (with or without neutropenia) may indicate serious gastrointestinal toxicity and require immediate evaluation and treatment.

Congestive heart failure (CHF).

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

Patients with metastases in ≥4 lymph nodes.

Since the benefits observed in patients with metastases in 4 or more lymph nodes were not statistically significant for disease-free survival (DFS) and overall survival (OS), the benefit-risk ratio of the TAC regimen in these patients was not fully demonstrated in the final analysis (see section "Pharmacological properties").

Elderly patients.

Safety data analysis in patients aged 60 years and older receiving the combination of docetaxel plus 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.

Among 333 patients who received docetaxel every 3 weeks in a prostate cancer study, 209 were aged 65 years or older, and 68 were aged 75 years or older. In patients receiving docetaxel every 3 weeks, treatment-related nail changes occurred ≥10% more frequently in patients aged 65 years or older compared to younger patients. Treatment-related increases in body temperature, diarrhea, loss of appetite, and peripheral edema occurred ≥10% more frequently in patients aged 75 years or older compared to patients under 65 years of age.

Warnings for use in hormone-sensitive prostate cancer.

Among 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 or older compared to younger patients, neutropenia, anemia, diarrhea, dyspnea, and upper respiratory tract infections occurred more frequently (at least 10% more frequently).

Warnings for use in gastric adenocarcinoma.

Among 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 a gastric cancer study, 74 were aged 65 years or older, and 4 were aged 75 years or older. The incidence of serious adverse effects was higher in elderly patients than in younger patients. In patients aged 65 years or older, adverse effects (all grades) such as fatigue, stomatitis, and neutropenic infection occurred ≥10% more frequently than in younger patients.

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

Warnings regarding excipients.

This medicinal product contains ethanol in an amount of 50% of the total volume of the concentrate, i.e., up to 0.395 g (0.5 ml) per vial, equivalent to 10 ml of beer or 4 ml of wine.

This may be harmful for patients suffering from alcoholism, as well as in the treatment of children and patients belonging to high-risk groups, such as those with liver disease or epilepsy.

The potential effect of the medicinal product on the central nervous system should be taken into account. Instructions for use and handling of the medicinal product.

(Special precautions for disposal of unused medicinal products or waste).

Docetaxel belongs to antineoplastic agents and, like any other potentially toxic substance, requires safety precautions during handling and preparation of its solutions. Protective gloves are recommended when handling the medicinal product.

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

Preparation of solution for intravenous administration.

Do not use other docetaxel products containing 2 vials (concentrate and solvent) with this medicinal product (Docetaxel-Vista 20 mg/1 ml concentrate for infusion solution, containing only 1 vial).

Docetaxel 20 mg/1 ml concentrate for infusion solution does not require prior reconstitution and is ready for addition to the infusion solution. The vial is for single use and should be used immediately after first opening.

If vials have been stored in the refrigerator, the required number of Docetaxel-Vista concentrate for infusion solution vials should be left at room temperature (below 25°C) for 5 minutes before use.

To achieve the required patient dose, several vials of Docetaxel-Vista concentrate for infusion solution may be needed. Using aseptic technique, the required amount of Docetaxel-Vista concentrate for infusion solution should be withdrawn using a calibrated syringe.

The concentration of docetaxel in the vial is 20 mg/ml.

The required amount of Docetaxel-Vista concentrate for infusion solution should be added to a 250 ml infusion bag or bottle containing 5% glucose solution or 0.9% sodium chloride solution (9 mg/ml) for injection.

If a patient requires a docetaxel dose greater than 200 mg, a larger volume of infusion solution should be used to avoid exceeding a docetaxel concentration of 0.74 mg/ml.

Shake the infusion bag or bottle to mix its contents with the added concentrate.

The prepared infusion solution should be used within 8 hours at a temperature below 25°C (including the duration of the infusion itself).

Before administration, the docetaxel infusion solution, like all parenteral medicinal products, should be carefully inspected. Solutions containing precipitate must not be used.

Unused medicinal product or waste materials should be destroyed according to local regulations.

Use during pregnancy or breastfeeding.

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 should immediately inform their physician if pregnancy occurs. Due to the genotoxic risk, women of childbearing potential should use effective contraceptive methods during treatment and for 2 months after discontinuation of docetaxel therapy. Men should use effective contraceptive methods during treatment and for 4 months after discontinuation of docetaxel therapy.

Pregnancy

There are no data on the use of docetaxel in pregnant women. In animal studies, docetaxel showed embryotoxic and fetotoxic effects in rabbits and rats. Like other cytotoxic medicinal products, docetaxel may cause harm to the fetus if administered to pregnant women. Therefore, docetaxel should not be administered during pregnancy, except when there is a compelling need.

Breastfeeding period.

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 should be discontinued during docetaxel therapy.

Fertility.

Preclinical studies in male experimental animals have shown that docetaxel may affect male fertility (see section "Non-clinical safety data"). Men undergoing docetaxel therapy should seek consultation regarding sperm cryopreservation before starting treatment.

Ability to affect reaction rate when driving or operating machinery.

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

The alcohol content of this medicinal product and its adverse effects 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 effect of the alcohol content and adverse effects of this medicinal product on the ability to drive or operate machinery and advised not to drive or operate machinery if they experience these adverse effects during treatment.

Method of Administration and Dosage

The use of docetaxel should be restricted to departments specialized 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 at a dose of 16 mg per day (e.g., 8 mg twice daily) for 3 days is recommended (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 administration 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 administration of granulocyte colony-stimulating factor (G-CSF) may be considered. Docetaxel is administered intravenously over one hour 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").

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 at 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. Subsequently, docetaxel doses were administered immediately after completion of trastuzumab infusions, provided the previously administered trastuzumab was well tolerated by the patient. Specific dosing and administration instructions 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. Specific instructions for 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, immediately followed by cisplatin 75 mg/m² administered intravenously over 30–60 minutes. For the treatment of patients in whom prior platinum-based chemotherapy has failed, 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. Concomitantly, prednisone or prednisolone should be administered continuously at a dose of 5 mg orally twice daily (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 a dose of 5 mg orally twice daily.

Gastric Adenocarcinoma

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

Head and Neck Cancer

Patients should receive antiemetic premedication and appropriate hydration (before and after cisplatin administration). To reduce the risk of hematological toxicity associated with chemotherapy, prophylactic administration of G-CSF may be considered. All patients enrolled in the TAX 323 and TAX 324 clinical trials who were assigned to docetaxel-containing treatment groups 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 intravenously over 1 hour, immediately followed on day 1 of the cycle by cisplatin 75 mg/m² administered intravenously over 1–3 hours; immediately after completion of cisplatin infusion, a continuous infusion of 5-fluorouracil (750 mg/m²/day) is initiated and maintained for 5 days. 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 likelihood of surgical intervention or requiring an organ-preserving approach), the recommended dose of docetaxel is 75 mg/m², administered intravenously over 1 hour, immediately followed on day 1 of the cycle by cisplatin 100 mg/m² administered intravenously over 0.5–3 hours; immediately after completion of cisplatin infusion, a continuous infusion of 5-fluorouracil (1000 mg/m²/day) is initiated and maintained for 4 days. This regimen is repeated every 3 weeks for 3 cycles. After chemotherapy, patients should receive chemoradiotherapy.

Specific instructions for dose adjustment of cisplatin and 5-fluorouracil are provided in their 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 significant 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), consideration should be given to primary prophylaxis with G-CSF. 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 "Adverse Reactions"). Patients who develop grade 3 or 4 stomatitis should have the docetaxel dose reduced to 60 mg/m².

In Combination with Cisplatin

For patients in whom, during the previous cycle of treatment with docetaxel 75 mg/m² in combination with cisplatin, the nadir platelet count was < 25,000 cells/mm³; for patients who developed febrile neutropenia during docetaxel therapy; and for patients who experienced severe non-hematological toxicities, the docetaxel dose should be reduced to 65 mg/m² in subsequent cycles. Specific instructions for cisplatin dose adjustment are provided in the "Summary of Product Characteristics" for cisplatin.

In Combination with Capecitabine Specific instructions for capecitabine dose adjustment are provided in the "Summary of Product Characteristics" for capecitabine.

• Patients who develop grade II toxicity that persists at the time of the next scheduled docetaxel/capecitabine administration 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 who experience grade III toxicity for the first time, 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 therapy should be discontinued.

Specific instructions for trastuzumab dose adjustment 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 infection during neutropenia despite G-CSF administration, the docetaxel dose should be reduced from 75 to 60 mg/m². If episodes of complicated neutropenia recur, 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 the platelet count recovers to > 100,000 cells/mm³. If toxicities persist despite these measures, docetaxel therapy should be discontinued (see section "Special Instructions").

Table 12.

Recommended dose adjustment measures for patients receiving the combination of docetaxel, cisplatin, and 5-fluorouracil

Specific dose adjustments for cisplatin and 5-fluorouracil are described in the respective "Summary of Product Characteristics".

In pivotal clinical trials of docetaxel, patients who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infectious diseases) during therapy were recommended 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 hepatic impairment.

According to pharmacokinetic data from monotherapy studies with docetaxel at a dose of 100 mg/m², the recommended dose of docetaxel in patients with elevated transaminase levels (ALT and/or AST) greater than 1.5 times the upper limit of normal (ULN) and alkaline phosphatase greater than 2.5 times ULN is 75 mg/m². For patients with elevated serum bilirubin (> ULN) and/or ALT and AST levels greater than 3.5 times UL, 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 medical 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, and 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 medical need.

There are no data on the use of docetaxel in combination therapy for other indications in patients with hepatic impairment.

Elderly patients.

According to population pharmacokinetic analysis, no specific dosage recommendations are required for 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 "Summary of Product Characteristics for capecitabine").

Children.

The medicinal product 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 in pediatric patients are not available.

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 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 have been 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 intensification of the drug's adverse effects can be expected. In particular, bone marrow suppression, peripheral neurotoxic effects, and mucosal inflammation are anticipated. As soon as overdose is confirmed, therapeutic doses of G-CSF should be administered to the patient as promptly as possible.

If necessary, other appropriate symptomatic measures should be taken.

Adverse Reactions.

Summary of safety profile data for all indications.

Data on adverse reactions considered likely related to docetaxel use were obtained from studies involving the following patients:

• 1312 and 121 patients receiving docetaxel as 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 (TAX 327) receiving docetaxel in combination with prednisone or prednisolone (clinically significant treatment-related adverse reactions are presented);
• 1276 patients (744 and 532 patients in studies TAX 316 and GEICAM 9805, respectively) receiving docetaxel in combination with doxorubicin and cyclophosphamide (clinically significant treatment-related adverse reactions are presented);
• 300 patients with adenocarcinoma of the stomach (221 patients from the Phase III portion and 79 patients from the Phase II portion of the clinical study) receiving docetaxel in combination with cisplatin and 5-fluorouracil (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 (clinically significant treatment-related adverse reactions are presented);
• 545 patients [STAMPEDE study] receiving docetaxel in combination with prednisone or prednisolone and androgen deprivation therapy (ADT).

Adverse reactions were described according to the National Cancer Institute (NCI) Common Toxicity Criteria (Grade III = G3; Grade III–IV = G3/4; Grade IV = G4), Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART), and Medical Dictionary for Regulatory Activities (MedDRA) terminology.

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

Within each category, adverse effects are listed in decreasing order of severity. The most common adverse reactions observed with docetaxel monotherapy were neutropenia (reversible and noncumulative; nadir of neutrophil count typically occurs on Day 7; mean duration of severe neutropenia [< 500 cells/mm³] is approximately 7 days), anemia, alopecia, nausea, vomiting, stomatitis, diarrhea, and asthenia. The severity of adverse effects associated with docetaxel may increase when the drug is combined with other chemotherapeutic agents.

When docetaxel was combined with trastuzumab, adverse effects (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–capecitabine combination observed in a Phase III clinical trial in patients with breast cancer who had failed prior anthracycline therapy are described in the "General characteristics of the capecitabine medicinal product" section.

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

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

Immune system disorders.

Hypersensitivity reactions usually occurred within minutes after the start of docetaxel infusion and ranged from mild to 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 neurotoxic reactions require dose reduction of the drug (see sections "Dosage and administration" and "Adverse reactions"). Mild to moderate neurosensory reactions included paresthesia, dysesthesia, or pain, including burning sensations. Neuromotor reactions presented as generalized weakness.

Skin and subcutaneous tissue disorders.

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

General disorders and administration site reactions.

Infusion site reactions were predominantly mild and included hyperpigmentation, inflammation, erythema, dryness, phlebitis, hemorrhage, and swelling of the vein used for infusion.

Fluid retention events included peripheral edema, less frequently pleural or pericardial effusion, ascites, and weight gain. Peripheral edema typically 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 for use").

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

Infections and infestations. Very common: infections (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 reactions (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: hypotension; 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 administration; non-cardiac chest pain (severe: 0.4%).

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

Description of individual adverse reactions observed in patients with breast cancer treated with docetaxel 100 mg/m² as monotherapy.

Blood and lymphatic system disorders.

Rare: bleeding or hemorrhage associated with Grade III/IV thrombocytopenia.

Nervous system disorders.

Recovery from nervous system toxicity was documented in 35.3% of patients who developed neuropathy 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 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 median cumulative dose at discontinuation was greater than 1000 mg/m², and the median time to reversible 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 reaction were reported during early treatment cycles.

Adverse reactions observed in patients with non-small cell lung cancer treated with docetaxel monotherapy at a dose of 75 mg/m².

Infections and infestations. 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).

Metabolism and nutrition 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: 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 elevated blood bilirubin (< 2%).

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

Infections and infestations. 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%).

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 (no severe cases).

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 (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 administration.

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

Adverse reactions observed in patients with non-small cell lung cancer treated with docetaxel at a dose of 75 mg/m² in combination with cisplatin.

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: 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 administration; pain.

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

Adverse reactions observed in patients with breast cancer treated with 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.

Metabolism and nutrition 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: increased 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; increased fatigue; mucositis; pain; acute respiratory illness; chest pain; chills.
Common: lethargy.

Investigations. Very common: weight gain.

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

Blood and lymphatic system disorders.

Very common: hematological toxicity with combined trastuzumab and docetaxel therapy increased compared to docetaxel monotherapy (32% of Grade III/IV neutropenia vs. 22% using NCI-CTC [National Cancer Institute – Common Toxicity Criteria] 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 patients on monotherapy).

Cardiac disorders.

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

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

Infections and infestations. Common: oral 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: increased 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%); increased fatigue/general weakness (G3/4: 5%); peripheral edema (G3/4: 1%).
Common: lethargy; pain.

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

Adverse reactions observed in patients with prostate cancer treated with docetaxel at a dose of 75 mg/m² in combination with prednisone or prednisolone.

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: increased 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: increased fatigue (G3/4: 3.9%); fluid retention (severe: 0.6%).

Adverse reactions observed in patients with high-risk localized or metastatic hormone-sensitive prostate cancer treated with docetaxel at a dose of 75 mg/m² in combination with prednisone or prednisolone and ADT (STAMPEDE study)

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%)a, 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%)a, 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 observed with docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with lymph node-positive (study TAX 316) and lymph node-negative (study GEICAM 9805) breast cancer – pooled data

Infections and infestations. 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%).

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%).
Uncommon: syncope (G3/4: 0%); neurotoxicity symptoms (G3/4: 0%); somnolence (G3/4: 0%).

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

Cardiac disorders. Common: arrhythmia (G3/4: 0.2%).

Vascular disorders. Very common: hot flushes (G3/4: 0.5%).
Common: 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%).

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

Nervous system disorders. In the TAX 316 study, peripheral sensory neuropathy began during treatment and persisted during follow-up in 84 patients (11.3%) in the TAC group and 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 2 patients (0.3%) in the FAC group. In the GEICAM 9805 study, peripheral sensory neuropathy that began during the treatment period persisted during follow-up in 10 patients (1.9%) in the TAC group and 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 1 patient (0.2%) in the FAC group.

Cardiac disorders. In the TAX 316 study, heart failure developed in 26 patients (3.5%) in the TAC group and 17 patients (2.3%) in the FAC group. In all patients except one in each group, heart failure 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, heart failure developed during follow-up in 3 patients (0.6%) in the TAC group and 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 heart failure, one patient in the TAC group died due to dilated cardiomyopathy, and in the FAC group, congestive heart failure persisted in one patient (0.2%).

Skin and subcutaneous tissue disorders. In the TAX 316 study, alopecia persisted after chemotherapy completion and during follow-up in 687 of 744 patients (92.3%) in the TAC group and 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 16 patients (2.2%) in the FAC group.

In the GEICAM 9805 study, alopecia that began during treatment and persisted during follow-up (median follow-up duration: 10 years and 5 months) was recorded in 49 patients (9.2%) in the TAC group and 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 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 1 patient (0.2%) in the FAC group.

Reproductive system and breast disorders. In the TAX 316 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 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 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 5 patients (1%) 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 4 patients (0.8%) in the FAC group.

General disorders and administration site reactions. In the TAX 316 study, peripheral edema that began during treatment and persisted during follow-up after chemotherapy completion was observed in 119 of 744 patients (16%) in the TAC group and 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 4 patients (0.5%) in the FAC group.

In the TAX 316 study, lymphedema 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 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), lymphedema persisted in 6 patients (0.8%) in the TAC group and 1 patient (0.1%) in the FAC group.

In the TAX 316 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 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 16 patients (2.2%) in the FAC group. In the GEICAM 9805 study, peripheral edema that began during treatment and persisted during follow-up was observed in 4 patients (0.8%) in the TAC group and 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, and in the FAC group, peripheral edema persisted in 1 patient (0.2%). Lymphedema that began during treatment and persisted during follow-up was observed in 5 patients (0.9%) in the TAC group and 2 patients (0.4%) in the FAC group. At the end of the follow-up period, lymphedema persisted in 4 patients (0.8%) in the TAC group and 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 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 2 patients (0.4%) in the FAC group.

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

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

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

Table 13

Adverse reactions observed in patients with gastric adenocarcinoma treated with docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil.

Infectious and parasitic diseases. 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%).

Description of individual adverse reactions observed in patients with gastric adenocarcinoma treated with docetaxel 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 used 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 not receiving G-CSF prophylaxis (see section "Dosage and administration").

Adverse reactions observed in patients with head and neck cancer treated with docetaxel 75 mg/m² in combination with cisplatin and 5-fluorouracil. Induction chemotherapy followed by radiotherapy (study TAX 323)

Infectious and parasitic diseases. 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 (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).

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 (