Taxotere®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TACOTERE® (TAXOTERE®)

Composition:

Active substance: docetaxel;

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

Excipients: polysorbate 80, ethanol anhydrous.

Pharmaceutical form. Concentrate for solution for infusion.

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

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01C D02.

Pharmacological properties.

Pharmacodynamics.

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

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

Clonogenic analysis in vitro showed cytotoxicity of docetaxel against various murine and human tumor cell lines, as well as against freshly isolated human tumor cells. Docetaxel achieves significant concentrations in the interstitial fluid and ensures high cellular retention. 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 in experimental models against both murine tumors and implanted human tumors.

Clinical efficacy and safety.

Breast cancer.

Taxotere® 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 study 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 as a 1-hour infusion 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 treatment regimens were administered every 3 weeks for a total of 6 cycles. Docetaxel was given as a 1-hour infusion, while all other drugs were administered as intravenous bolus injections on day 1 of each treatment 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 the last chemotherapy cycle, patients whose tumors expressed estrogen and/or progesterone receptors received tamoxifen 20 mg once daily for up to 5 years in both groups. 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 patients had been enrolled. The second interim analysis was performed after recording a total of 400 disease-free survival (DFS) events, 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). Ten-year overall survival was also statistically significantly higher in the TAC group compared to the FAC group (76% vs. 69%, respectively), representing an absolute risk reduction in mortality of 7% (p = 0.002). Since the benefits observed in patients with metastases in 4 or more lymph nodes were not statistically significant for DFS and OS, the final analysis did not fully demonstrate a favorable benefit-risk ratio of the TAC regimen in patients with metastases in 4 or more lymph nodes.

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 group of patients 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 risk 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 node-negative breast cancer eligible for chemotherapy (GEICAM 9805 study). Data from a multicenter, open-label, randomized study support the use of docetaxel (Taxotere®) as adjuvant therapy in patients with operable node-negative breast cancer who are candidates for chemotherapy. A total of 1060 patients were randomized into two groups: to receive 75 mg/m² of docetaxel (Taxotere®) administered as a 1-hour infusion 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 operable node-negative breast cancer patients 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 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 intravenously on day 1 of each 3-week cycle. Following randomization, primary prophylaxis with G-CSF was mandated in 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 completion 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 institutional guidelines, adjuvant radiotherapy was administered to 57.3% of patients in the TAC group and 51.2% 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 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 experienced a recurrence-free survival [RFS] event or were lost to follow-up prior to this time. 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 those in the FAC group (risk 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 those in the FAC group (risk ratio 0.84, 95% CI: 0.65–1.08, p = 0.1646). The RFS data were not statistically significant but still showed a favorable trend for the TAC group.

With a median follow-up of 77 months, overall survival (OS) was also longer in the TAC group, with a 24% reduction in the risk of death observed in the TAC group compared to the FAC group (risk 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, the risk of death was reduced by 9% in the TAC group compared to the FAC group (risk 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 in favor of the TAC group compared to the FAC group remained unchanged.

In the primary analysis (with 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 hazard ratio less than 1 indicates that the TAC treatment regimen was associated with longer recurrence-free survival compared to the FAC treatment regimen.

Exploratory analyses of recurrence-free survival were performed in various subgroups of 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 subgroup analyses of 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.

Taxotere® 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, all receiving 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). Docetaxel did not affect overall survival (median duration was 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). However, 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). The drug was discontinued in 3 patients (2%) receiving docetaxel due to fluid retention, and in 15 patients (9%) receiving doxorubicin 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 improved 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 versus paclitaxel monotherapy in the treatment of patients with advanced breast cancer who had previously received anthracycline-based therapy. A total of 449 patients were randomized into two groups: to receive 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 regimens were administered every 3 weeks.

While no significant difference was observed in the primary endpoint, i.e., overall response rate (32% versus 25%, p = 0.10), docetaxel significantly 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 group (23.0%).

Taxotere® in combination with doxorubicin.

One large randomized Phase III study was conducted involving 429 patients with metastatic breast cancer who had not previously received anticancer therapy. Patients were randomized to receive 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 regimens were administered on Day 1 of each 3-week cycle.

• Time to progression (TTP) was statistically significantly longer in the AT group compared to the AC group (p = 0.0138). Median TTP was 37.3 weeks (95% CI: 33.4–42.1) in the AT group versus 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 compared to the AC group (p = 0.009). ORR was 59.3% (95% CI: 52.8–65.9) in the AT group versus 46.5% (95% CI: 39.8–53.2) in the AC group.

In this study, the AT group had higher incidences of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infections (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 higher rates of severe anemia (15.8% versus 8.5%) and higher incidence of severe cardiotoxic reactions: congestive heart failure (3.8% versus 2.8%), absolute decrease in left ventricular ejection fraction (LVEF) by ≥20% (13.1% versus 6.1%), and absolute decrease in LVEF by ≥30% (6.2% versus 1.1%). Drug-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.

Taxotere® in combination with trastuzumab.

Docetaxel in combination with trastuzumab was studied in patients with metastatic breast cancer whose tumors overexpressed HER2 and who had not previously received chemotherapy for metastatic disease. The study included 186 patients randomized to receive docetaxel (100 mg/m²) either in combination with trastuzumab or without trastuzumab. Sixty percent of patients had previously received adjuvant anthracycline-based chemotherapy. The efficacy of docetaxel plus trastuzumab was demonstrated regardless of prior adjuvant anthracycline therapy. The primary method for determining HER2 expression in this pivotal study was immunohistochemistry (IHC). A small subset of patients was assessed using fluorescence in situ hybridization (FISH). In this study, 87% of patients had HER2 overexpression at the IHC 3+ level, and 95% of enrolled patients had HER2 overexpression at IHC 3+ level and/or positive FISH results. Efficacy data are summarized in Table 4.

Table 4

Efficacy results of treatment with docetaxel in combination with trastuzumab or without trastuzumab in metastatic breast cancer

PFS – progression-free survival; NE – not estimable or not reached.

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

2Median survival calculated.

Taxotere® 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 failure of prior cytotoxic chemotherapy that included 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 receive docetaxel monotherapy (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 patient population (investigator-assessed) was 41.6% (docetaxel + capecitabine) versus 29.7% (docetaxel monotherapy); p = 0.0058. Progression-free survival was longer in the group receiving docetaxel in combination with capecitabine (p < 0.0001). Median time to 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 progression (12.3 weeks vs. 7 weeks) and overall survival were statistically significantly longer in patients receiving docetaxel at 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 disease-related symptoms (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.

Taxotere® in combination with platinum agents in patients previously untreated with chemotherapy.

In a phase III trial, 1218 patients with unresectable stage IIIB or IV non-small cell lung cancer (NSCLC), with 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 progression, and response rates in the two study groups are presented in Table 5.

Table 5

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

*Data adjusted for multiple comparisons, with corrections for stratification factors (disease stage and region where treatment was conducted), 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, score on the lung cancer symptom scale, and changes in overall functional status assessed by the Karnofsky performance scale. Results for these endpoints were consistent with those observed for the primary endpoints.

It was not possible to demonstrate that the docetaxel/carboplatin combination was equivalent or at least not inferior 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, study drugs were administered in combination with continuous prednisone or prednisolone at a dose of 5 mg twice daily.

Patients receiving docetaxel every 3 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 docetaxel treatment groups compared to the control group are summarized in Table 6.

Table 6

Efficacy results in the treatment of hormone-refractory metastatic prostate cancer with docetaxel 75 mg/m² every 3 weeks, docetaxel 30 mg/m² weekly, 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 the drug was somewhat better with weekly docetaxel administration compared to docetaxel every 3 weeks, some patients may benefit more from weekly docetaxel treatment.

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 monotherapy standard of care group, 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 center and planned hormonal therapy) and stratified by trial period.

b 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 [maximum decrease due to chemotherapy] within 24 weeks and above 4 ng/mL, confirmed by repeat measurement or treatment); disease progression: local progression (lymph nodes) or detection 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 as monotherapy, with a median overall survival 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).

Results of efficacy outcomes or comparisons between the docetaxel and control groups 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. Variables for response rates: Fisher's exact test.

*p-value for illustrative purposes.

**Response in prostate-specific antigen: 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 according to 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 bone metastasis symptoms, progression according to RECIST, or clinical deterioration due to cancer as assessed by the investigator).

Gastric adenocarcinoma.

To evaluate the safety and efficacy of docetaxel in the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not previously received chemotherapy for metastatic disease, a multicenter, open-label, randomized study was conducted. A total of 445 patients with KPS > 70 were enrolled and randomized into two groups: one receiving docetaxel (T) (75 mg/m² on day 1 of treatment) in combination with cisplatin (C) (75 mg/m² on day 1 of treatment) 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 the primary endpoint. A 32.1% reduction in the risk of progression was observed in the TCF group, along with a statistically significant 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 additional follow-up with a median duration of 41.6 months no longer demonstrated a statistically significant difference between the two treatment groups, although it continued to indicate benefits favoring the TCF regimen, showing a clear advantage of TCF over CF during the period 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 longer time to irreversible deterioration in overall health status by 5% according to the QLQ-C30 questionnaire (p = 0.0121) and a longer time to irreversible deterioration in performance status according to 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 (T) at 75 mg/m², followed by cisplatin (P) at 75 mg/m², and then 5-fluorouracil (F) at 750 mg/m²/day as a continuous infusion over 5 days. This regimen was administered 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 2 cycles. Within 4 to 7 weeks after completion of chemotherapy, patients without disease progression received radiotherapy (RT) over 7 weeks according to institutional guidelines (treatment regimen TPF/RT). Patients in the control group received cisplatin (P) at 100 mg/m² followed by 5-fluorouracil (F) at 1,000 mg/m²/day for 5 days. This regimen was administered 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 2 cycles. Within 4 to 7 weeks after completion of chemotherapy, patients without disease progression received radiotherapy (RT) over 7 weeks 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, and for hyperfractionation, 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 similar 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 was also statistically significantly longer in the TPF group compared to 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 all randomized patients; Intent-to-Treat)

A risk ratio of less than 1 indicates benefit in favor of the docetaxel + cisplatin + 5-fluorouracil regimen.

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

**Log-rank test.

***χ² (chi-squared) test.

Quality of life outcomes.

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 outcomes.

Functional status assessment scores (using the Head and Neck-specific subscales [PSS-HN], developed to evaluate patients' 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 performance status was statistically significantly longer in the TPF group compared to the PF group. In both groups, pain intensity improved during treatment, indicating adequate pain control.

• Induction chemotherapy followed by chemoradiotherapy (TAX 324 study).

The safety and efficacy of docetaxel for induction therapy in 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 324). A total of 501 patients with locally advanced SCCHN and a WHO performance status of 0 or 1 were enrolled and randomized into two groups. The study population included patients with technically unresectable tumors, those with a 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, with organ preservation success not formally evaluated. Patients in the docetaxel group received 75 mg/m² docetaxel (T) as an intravenous infusion on day 1, followed by 100 mg/m² cisplatin (P) as an intravenous infusion lasting between 30 minutes and 3 hours, and 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 regimen TPF/CRT). Patients in the control group received 100 mg/m² cisplatin (P) as an intravenous infusion lasting between 30 minutes and 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 proceeded to chemoradiotherapy (CRT) per protocol (treatment regimen PF/CRT).

Starting no earlier than 3 weeks and no later than 8 weeks after the initiation of the last cycle of induction chemotherapy (days 22 to 56 after the last cycle), patients in both groups underwent a 7-week course of CRT. During radiotherapy, carboplatin (AUC 1.5) was administered weekly as a 1-hour intravenous infusion, for a maximum of 7 doses. Radiotherapy was delivered using megavoltage equipment at 2 Gy fractions once daily, 5 days per week, over 7 weeks, to a total 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 statistically 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 in the TPF group versus 30.1 months in the PF group, representing 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), based on 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 presented 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 effect of the docetaxel + cisplatin + 5-fluorouracil regimen.

*Unadjusted log-rank test.

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

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

NR – not relevant.

Pediatric population.

The European Medicines Agency has waived the obligation to submit results of studies of the medicinal product Taxotere® in all subgroups of pediatric patients 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 medicinal product in children are provided in section "Children").

Pharmacokinetics.

Absorption. The pharmacokinetics of docetaxel were studied in phase I trials in cancer patients after administration 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-phases being 4 minutes, 36 minutes, and 11.1 hours, respectively. The prolonged half-life in the final phase is partly due to relatively slow efflux from the peripheral compartment.

Distribution. After administration of a 100 mg/m² dose infused over 1 hour, the mean peak plasma concentration of the drug was 3.7 µg/mL, with a corresponding AUC of 4.6 µg/mL/h. Mean values of total clearance and volume of distribution at steady state were 21 L/m²/h and 113 L, respectively. Inter-individual variability in total 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. After oxidative metabolism of the tert-butyl ester group by cytochrome P450, docetaxel was eliminated 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 populations. Age and gender. Population pharmacokinetic analysis was performed in 577 patients. Pharmacokinetic parameters estimated by this model were very similar to those obtained in phase I trials. Neither age nor gender had any effect on the pharmacokinetics of the drug.

Hepatic dysfunction. In a small number of patients (n = 23) with mild to moderate hepatic impairment 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), total clearance of the drug was reduced by an average of 27% (see section "Dosage and administration").

Fluid retention. Docetaxel clearance was unchanged 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 trial evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa showed no effect of capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC), nor any effect of docetaxel on the pharmacokinetics of the corresponding capecitabine metabolite 5’-deoxy-5-fluorouridine (5’-DFUR).

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 seen 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 medicinal products.

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

Clinical characteristics.

Indications.

Breast cancer. Taxotere® 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 the patients meet established international criteria for chemotherapy in the primary treatment of early-stage breast cancer.

Taxotere® 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.

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

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

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

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

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

Taxotere® 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. Taxotere® 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. Taxotere® 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").

Also consider contraindications for other medicinal products prescribed in combination with docetaxel.

Interaction with other medicinal products and other types of interactions.

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

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

When used in combination with CYP3A4 inhibitors, the frequency of docetaxel adverse effects may increase due to reduced metabolism. If concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) cannot be avoided, careful clinical monitoring and dose adjustment of docetaxel during treatment with strong CYP3A4 inhibitors are recommended (see section "Special instructions"). In a pharmacokinetic study involving 7 patients, concomitant administration of docetaxel with the potent 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 extensively 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 studies on interactions of this drug with other medicinal products have not been conducted, in vitro data indicate that drugs with high plasma protein binding (such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate) do not impair the binding of docetaxel to plasma proteins. Additionally, dexamethasone does not impair the plasma protein binding of docetaxel. Docetaxel does not affect the plasma protein binding of digoxin.

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

Special precautions for use.

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

Hematological changes during treatment. The most common adverse reaction during docetaxel therapy is neutropenia. The lowest neutrophil levels 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/mL³ following the completion of the previous cycle (see section "Dosage and administration").

If severe neutropenia (<500 cells/mL³ for 7 days or longer) develops during treatment with docetaxel, dose reduction of the drug in the next chemotherapy cycle or appropriate symptomatic treatment is recommended (see section "Dosage and administration").

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

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

Gastrointestinal reactions. Caution is advised in patients with neutropenia, particularly those at increased risk of gastrointestinal complications. Although most such cases occurred during the first or second chemotherapy cycle with docetaxel, enterocolitis may develop at any time and may lead to death as early as the first day after onset. Patients should be carefully monitored for early signs of serious gastrointestinal toxic reactions (see sections "Dosage and administration," "Special precautions for use" (Hematological changes during treatment), and "Adverse reactions").

Hypersensitivity reactions. Patients should be carefully monitored for possible hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may develop within minutes after the start of docetaxel infusion; therefore, all necessary 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 in very rare cases potentially fatal anaphylaxis, require immediate discontinuation of docetaxel and appropriate treatment. Re-administration of docetaxel is contraindicated in patients who have experienced a severe hypersensitivity reaction. Patients with a prior history of hypersensitivity reaction to paclitaxel may have an 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 epidermal desquamation, have been reported. Severe symptoms such as extensive skin rashes with subsequent epidermal desquamation have also been reported, necessitating interruption or permanent discontinuation of docetaxel therapy (see section "Dosage and administration").

Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, have been reported during docetaxel therapy. Patients should be informed about signs and symptoms of serious skin reactions and closely monitored. If signs or 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. Radiation pneumonitis has been observed in patients who received concomitant radiotherapy.

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 a diagnosis is established. Early supportive therapy may help improve the patient's condition. The benefit of resuming docetaxel therapy should be carefully evaluated.

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

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

In a pivotal clinical study of docetaxel in combination with cisplatin and 5-fluorouracil for gastric adenocarcinoma, elevated 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 need. Data on the use of docetaxel in combination therapy for other indications in patients with hepatic impairment are lacking.

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

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

Cardiotoxicity. Cases of heart failure have been reported in patients receiving docetaxel in combination with trastuzumab, particularly if anthracyclines (doxorubicin or epirubicin) were administered in a previous chemotherapy course. This heart failure may be moderate or severe and is associated with a high risk of death (see section "Adverse reactions"). If docetaxel is to be used in combination with trastuzumab, cardiac function should be evaluated before starting therapy. Regular monitoring of cardiac function (e.g., every 3 months) during treatment is recommended to identify patients who may develop cardiac dysfunction. Further information is available in the "Summary of Product Characteristics" for trastuzumab.

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

Ocular disorders. Cases of crystalline 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. Second primary malignancies have been reported during treatment with docetaxel in combination with antineoplastic agents known to be associated with second malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma) may develop months or years after docetaxel-based therapy. Patients should be monitored for the possible development of second primary malignancies (see section "Adverse reactions").

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

Other warnings. Contraceptive methods should be used throughout the entire treatment period (for both men and women) and for at least 6 months after treatment discontinuation (only for men) (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 docetaxel use in adjuvant breast cancer therapy.

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

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

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

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 "Pharmacodynamic properties").

Elderly patients.

Safety data analysis in patients aged 60 years and older receiving the combination of docetaxel + capecitabine showed increased incidence of treatment-related adverse events of grade 3–4, 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 breast cancer therapy

There are no data on the use of docetaxel in combination with doxorubicin and cyclophosphamide in patients aged 70 years and older.

Warnings for use in castration-resistant prostate cancer

Among 333 patients who received docetaxel every three weeks in a prostate cancer study (TAX327), 209 patients were over 65 years of age and 68 were 75 years or older. When docetaxel was administered every three weeks, treatment-related nail changes occurred ≥10% more frequently in patients aged 65 years and older compared to younger patients. Treatment-related fever, diarrhea, loss of appetite, and peripheral edema occurred ≥10% more frequently in patients aged 75 years and older compared to those 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 patients were over 65 years of age and 48 were 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 and older compared to younger patients, neutropenia, anemia, diarrhea, dyspnea, and upper respiratory tract infections were reported more frequently (at least 10% more frequent).

Warnings for use in gastric adenocarcinoma

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 patients were over 65 years of age and 4 were 75 years or older. The frequency of serious adverse effects was higher in elderly patients compared to younger ones. In patients aged 65 years and older, lethargy, stomatitis, and neutropenic infection occurred ≥10% more frequently than in younger patients (all grades).

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

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

The product is harmful for patients suffering from alcoholism.

The alcohol content of the product should be taken into account when prescribing it to pregnant women or breastfeeding women, as well as to children and patients at high risk, e.g., patients with liver disease or epilepsy.

The potential impact of the product on the central nervous system should be considered.

Instructions for use and handling (special precautions for disposal of unused medicinal products or waste). Taxotere® belongs to antineoplastic agents and, like any other potentially toxic agent, requires adherence to safety measures during handling and preparation of solutions with Taxotere®. Protective gloves are recommended when handling the product.

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

Preparation of solution for intravenous administration. Do not use other docetaxel products packaged in 2 vials (concentrate and solvent) with this product (Taxotere®, 20 mg/mL concentrate for infusion solution, containing only 1 vial).

Taxotere®, 20 mg/mL concentrate for infusion solution, does not require prior reconstitution and is ready for addition to the infusion solution.

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

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

Several vials of Taxotere® concentrate for infusion solution may be needed to achieve the required patient dose. Using aseptic technique, withdraw the required amount of Taxotere® concentrate for infusion solution using a calibrated syringe with a 21G needle.

The Taxotere® vial, 20 mg/mL, contains docetaxel at a concentration of 20 mg/mL. The required amount of Taxotere® concentrate for infusion solution should be added as a single injection (one puncture) into an infusion bag or vial of

250 mL containing 5% glucose solution or 0.9% sodium chloride solution (9 mg/mL) for injection.

If the patient requires a docetaxel dose greater than 190 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 vial to mix its contents with the added concentrate.

The prepared infusion solution should be used within 6 hours at a temperature below 25°C (including 1 hour of infusion). From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the user is responsible for storage duration and conditions.

After adding the medicinal product to the infusion solution according to recommendations, the docetaxel infusion solution remains stable for 6 hours when stored at temperatures up to 25°C. Additionally, physical and chemical stability of the infusion solution prepared according to recommendations has been demonstrated for 48 hours when stored in non-PVC bags at 2–8°C.

Before administration, the infusion solution of Taxotere®, like all parenteral products, should be carefully inspected; solutions containing precipitate should not be used.

The docetaxel infusion solution is supersaturated, and the drug may crystallize over time. If crystals appear, the solution should no longer be used and must be discarded.

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

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of docetaxel in pregnant women. In animal studies, docetaxel showed embryotoxic and fetotoxic effects and reduced fertility in animals. 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 in cases of compelling need. Women of childbearing potential receiving docetaxel should be advised to avoid pregnancy and to inform their physician immediately if pregnancy occurs.

Effective contraceptive methods should be used throughout the entire treatment period.

Breastfeeding. Docetaxel is a lipophilic substance, but it is unknown whether it passes into breast milk. Considering the risk of adverse effects in breastfed infants, breastfeeding should be discontinued during docetaxel therapy.

Fertility. In preclinical studies, docetaxel showed genotoxic effects and affected fertility in male experimental animals. Therefore, men receiving docetaxel are advised to use appropriate contraceptive methods during treatment and for 6 months after its discontinuation. They should seek consultation regarding sperm cryopreservation before starting therapy.

Ability to affect reaction speed when driving vehicles or operating machinery.

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

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

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 16 mg per day (e.g., 8 mg twice daily) for 3 days may be used (if not contraindicated); the first dose should be taken one day before the first administration of docetaxel (see section "Special Instructions"). To reduce the risk of hematological toxicity associated with docetaxel, prophylactic use of granulocyte colony-stimulating factor (G-CSF) may be considered.

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

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

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

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

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

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

In combination with trastuzumab (administered weekly), docetaxel is given at the recommended dose of 100 mg/m² every 3 weeks. In the pivotal clinical trial with docetaxel, the first infusion of the drug was administered the day after the first dose of trastuzumab. Subsequently, docetaxel doses were administered immediately after completion of trastuzumab infusion, provided the recently administered trastuzumab was well tolerated by the patient. Dosing and administration specifics 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 given 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. Dose calculation specifics for capecitabine according to body surface area are described in the "Summary of Product Characteristics" for capecitabine.

Non-Small Cell Lung Cancer. For the treatment of patients with non-small cell lung cancer who have not previously received chemotherapy, docetaxel is recommended at a dose of 75 mg/m², followed immediately by cisplatin 75 mg/m² administered over 30–60 minutes. For 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. Prednisone or prednisolone should also be administered continuously at 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 taken continuously at 5 mg orally twice daily.

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

Head and Neck Cancer. Patients should receive antiemetic premedication and adequate hydration (before and after cisplatin administration). To reduce the risk of hematological toxicity associated with chemotherapy, prophylactic use of G-CSF may be considered. All patients enrolled in the TAX 323 and TAX 324 clinical trials in the docetaxel 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 as a 1-hour intravenous infusion, immediately followed on day 1 of the cycle by cisplatin 75 mg/m² as a 1–3 hour infusion; immediately after completion of cisplatin infusion, continuous infusion of 5-fluorouracil (750 mg/m²/day) is initiated and continued 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 as a 1-hour intravenous infusion, immediately followed on day 1 of the cycle by cisplatin 100 mg/m² as a 0.5–3 hour infusion; immediately after completion of cisplatin infusion, continuous infusion of 5-fluorouracil (1000 mg/m²/day) is initiated and continued for 4 days. This regimen is repeated every 3 weeks for 3 cycles. After chemotherapy, patients should receive chemoradiotherapy.

Specifics of dose adjustments for cisplatin and 5-fluorouracil are described in their respective "Summary 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 neutrophil count remains <500 cells/mm³ for more than one week, or if severe acute or 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 persist at the 60 mg/m² dose level, the drug should be discontinued.

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

In Combination with Cisplatin. For patients who, during the previous course of treatment with docetaxel 75 mg/m² in combination with cisplatin, experienced a nadir platelet count <25,000 cells/mm³, for patients who developed febrile neutropenia during docetaxel therapy, and for patients who experienced severe non-hematological toxicities, the docetaxel dose should be reduced to 65 mg/m² in subsequent cycles. Specifics of cisplatin dose adjustment are described in the "Summary of Product Characteristics" for cisplatin.

In Combination with Capecitabine. Specifics of capecitabine dose adjustment are described in the "Summary of Product Characteristics" for capecitabine.

• Patients who develop grade II toxicity that persists at the time of the next 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 point during the treatment cycle or a first occurrence of grade III toxicity should have treatment interrupted until toxicity resolves to grade 0–I, then resumed with docetaxel at 55 mg/m².
• If further toxicities occur or if grade IV toxicity develops, docetaxel treatment should be discontinued.

Specifics of trastuzumab dose adjustment are described 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 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. The next treatment cycle should not be repeated until the neutrophil count recovers to >1500 cells/mm³ and platelet count to >100,000 cells/mm³. If toxicities persist despite these measures, docetaxel therapy should be discontinued (see section "Special Instructions").

Table 12

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

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 complications) during therapy with G-CSF were advised to receive prophylactic G-CSF (e.g., from day 6 to day 15 of the cycle) in all subsequent chemotherapy cycles.

Special patient groups.

Patients with impaired liver function. According to pharmacokinetic data from monotherapy studies with docetaxel at a dose of 100 mg/m², the recommended dose of docetaxel is 75 mg/m² for patients with elevated transaminase levels (ALT and/or AST) greater than 1.5 times the upper limit of normal (ULN) and alkaline phosphatase levels greater than 2.5 times ULN. For patients with increased serum bilirubin (> ULN) and/or ALT and AST levels greater than 3.5 times UL, accompanied by alkaline phosphatase levels greater 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, exclusion criteria included elevated ALT and/or AST levels greater than 1.5 times ULN, alkaline phosphatase levels greater than 2.5 times ULN, and bilirubin levels above ULN. Therefore, dose reduction of docetaxel cannot be recommended for such patients. The drug should not be administered to this patient group 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 impaired liver function.

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

When docetaxel is used in combination with capecitabine, a reduction of the initial capecitabine dose to 75% is recommended for patients aged 60 years and older (see the "Summary of Product Characteristics" for capecitabine).

Children.

Taxotere® is not recommended for use in children due to limited evidence on the safety and/or efficacy of the drug in this patient population.

Results from studies on the efficacy and safety of Taxotere® in pediatric patients have not been obtained.

The safety and efficacy of Taxotere® 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 Taxotere® in children for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma, or head and neck cancers, except for poorly differentiated nasopharyngeal carcinoma types II and III.

Overdose. There are several case reports of docetaxel overdose. There is no known specific antidote for docetaxel. In case of overdose, the patient should be hospitalized in a specialized unit and closely monitored for vital functions. An exacerbation of the drug's adverse effects is expected. Primarily, complications such as bone marrow suppression, peripheral neurotoxicity, and mucosal inflammation are anticipated. After confirming an overdose, therapeutic doses of G-CSF should be administered to the patient as soon as possible. If necessary, other appropriate symptomatic measures should be implemented.

Adverse Reactions

Summary of safety profile data for all indications. Data on adverse reactions considered likely related to docetaxel administration 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 listed);
• 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 listed);
• 300 patients with gastric adenocarcinoma (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 listed);
• 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 listed);
• 545 patients [STAMPEDE study], receiving docetaxel in combination with prednisone or prednisolone and androgen deprivation therapy (ADT).

These reactions were described using the National Cancer Institute (NCI) Common Toxicity Criteria (G3 – Grade 3; G3/4 – Grades 3–4; G4 – Grade 4), COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms) coding dictionary, and MedDRA (Medical Dictionary for Regulatory Activities) terminology.

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

Within each group, adverse effects are listed in decreasing order of severity.

The most common adverse reactions observed with docetaxel monotherapy were neutropenia (reversible and noncumulative; median time to nadir of neutrophil count is 7 days; median duration of severe neutropenia [< 500 cells/mm³] is 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 used in combination with trastuzumab, adverse effects (of any grade) were observed in ≥ 10% of patients. Compared to docetaxel monotherapy, this combination increased the frequency of serious adverse effects (40% vs. 31%) and Grade IV adverse effects (34% vs. 23%).

The most common (≥5%) adverse effects of the docetaxel and capecitabine combination observed in a phase III clinical trial in patients with breast cancer who had failed prior anthracycline therapy are presented in the "General characteristics" section of the capecitabine product information.

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 adverse reactions most commonly observed with docetaxel are listed below.

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

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

Skin and subcutaneous tissue disorders. Reversible skin reactions, usually mild or moderate in severity, were observed. These reactions included rash, often localized on the palms and soles (including severe palmar-plantar 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 epithelial desquamation, sometimes necessitating interruption or complete discontinuation of docetaxel (see sections "Dosage and administration" and "Special precautions"). Severe 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, or dryness of the skin, phlebitis or extravasation, and swelling of the vein used for infusion.

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

Adverse reactions observed in patients with breast cancer treated with TAxOTER® as 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%).

Metabolic and nutritional disorders. Very common: anorexia.

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

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

Vascular disorders. Common: 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 reactions. Very common: fluid retention (severe: 6.5%); asthenia (severe: 11.2%); pain. Common: local reactions after drug administration; non-cardiac chest pain (severe: 0.4%).

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

Description of individual adverse reactions observed in patients with breast cancer treated with TAxOTER® at a dose of 100 mg/m² as monotherapy

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

Nervous system disorders. Data are available on reversibility of nervous system disorders in 35.3% of patients who developed such disorders after monotherapy with docetaxel at 100 mg/m². These disorders spontaneously resolved 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 resolved within 21 days.

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

Adverse reactions observed in patients with non-small cell lung cancer treated with TAxOTER® as 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 reported).

Metabolic and nutritional disorders. Common: anorexia.

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

Cardiac disorders. Common: arrhythmia (no severe cases reported).

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 reactions. Very common: asthenia (severe: 12.4%); fluid retention (severe: 0.8%); pain.

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

Adverse reactions observed in patients with breast cancer treated with TAxOTER® 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%).

Metabolic and nutritional disorders. Common: anorexia.

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

Cardiac disorders. Common: heart failure; arrhythmia (no severe cases reported).

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 reported).

Musculoskeletal and connective tissue disorders. Common: myalgia.

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

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

Adverse reactions observed in patients with non-small cell lung cancer treated with TAxOTER® 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%).

Metabolic and nutritional disorders. Very common: anorexia.

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

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

Vascular disorders. Common: 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 reactions. Very common: asthenia (severe: 9.9%); fluid retention (severe: 0.7%); fever (G3/4: 1.2%). Common: local reactions after drug administration; pain.

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

Adverse reactions observed in patients with breast cancer treated with TAxOTER® at a dose of 100 mg/m² in combination with trastuzumab

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

Metabolic and nutritional disorders. Very common: anorexia.

Psychiatric disorders. Very common: insomnia.

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

Cardiac disorders. Common: heart failure.

Eye disorders. Very common: 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 reactions. 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 TAxOTER® at a dose of 100 mg/m² in combination with trastuzumab.

Blood and lymphatic system disorders. Very common: hematological toxicity of combined therapy with trastuzumab and docetaxel increased compared to docetaxel monotherapy (32% of Grade III/IV neutropenia vs. 22% using NCI-CTC criteria [National Cancer Institute – Common Toxicity Criteria]). It should be noted that the frequency of this adverse 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 docetaxel monotherapy).

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

Adverse reactions observed in patients with breast cancer treated with TAxOTER® 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%).

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

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

Eye disorders. Very common: 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: palmar-plantar 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 reactions. 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 levels (G3/4: 9%).

Adverse reactions observed in patients with prostate cancer treated with TAxOTER® 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%).

Metabolic and nutritional disorders. Very common: anorexia (G3/4: 0.6%).

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

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

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

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

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

Skin and subcutaneous tissue disorders. Very common: alopecia; nail disorders (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 reactions. Very common: increased fatigue (G3/4: 3.9%); fluid retention (severe: 0.6%).

Description of adverse reactions observed in patients with locally advanced (or metastatic hormone-sensitive prostate cancer at high risk) treated with TAxOTER® 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 reactions. 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 TAxOTER® at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with breast cancer with (TAX 316) or without (GEICAM 9805) lymph node metastases – 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: NA).

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

Metabolic and nutritional disorders. Very common: anorexia (G3/4: 1.5%).

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

Eye disorders. Very common: conjunctivitis (G3/4: < 0.1%). Common: 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 reactions. Very common: asthenia (G3/4: 10%); fever (G3/4: NA); peripheral edema (G3/4: 0.2%).

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

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

Description of individual adverse reactions observed with TAxOTER® at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with breast cancer with (TAX 316) or without (GEICAM 9805) lymph node metastases.

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

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

Cardiac disorders. In the TAX 316 study, congestive heart failure (CHF) developed in 26 patients (3.5%) in the TAC group and in 17 patients (2.3%) in the FAC group. In all patients except one in each group, CHF was diagnosed more than 30 days after the start of treatment. 2 patients in the TAC group and 4 patients in the FAC group died due to heart failure.

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

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

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

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

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

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

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

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

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

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

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

In the GEICAM 9805 study, peripheral edema that began during the treatment period persisted during follow-up in 4 patients (0.8%) in the TAC group and in 2 patients (0.4%) in the FAC group. At the end of the follow-up period (median follow-up duration was 10 years and 5 months), no patients (0%) in the TAC group had peripheral edema, while in the FAC group, peripheral edema persisted in 1 patient (0.2%). Lymphatic edema that began during the treatment period persisted during follow-up in 5 patients (0.9%) in the TAC group and in 2 patients (0.4%) in the FAC group. At the end of the follow-up period, lymphatic edema persisted in 4 patients (0.8%) in the TAC group and in 1 patient (0.2%) in the FAC group.

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

Acute leukemia/myelodysplastic syndrome. Over 10 years of follow-up in the TAX 316 study, acute leukemia was detected in 3 of 744 patients (0.4%) in the TAC group and in 1 of 736 patients (0.1%) in the FAC group. During the follow-up period (median follow-up duration was 8 years), 1 patient (0.1%) in the TAC group and 1 patient (0.1%) in the FAC group died from acute myeloid leukemia. Myelodysplastic syndrome was diagnosed in 2 of 744 patients (0.3%) in the TAC group and in 1 of 736 patients (0.1%) in the FAC group.

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

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

Neutropenic complications. Table 13 shows that the incidence of Grade IV neutropenia, febrile neutropenia, and neutropenic infection decreased in patients receiving primary prophylaxis with G-CSF after such prophylaxis became mandatory in the TAC group of the GEICAM study.

Table 13

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

Adverse reactions observed in patients with gastric adenocarcinoma treated with Taxotere® at a dose of 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%).

Aural and vestibular 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 desquamation of skin epithelium (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 selected adverse reactions observed in patients with gastric adenocarcinoma treated with Taxotere® at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil

Blood and lymphatic system disorders. Febrile neutropenia and neutropenic infections occurred in 17.2% and 13.5% of patients, respectively, regardless of whether G-CSF was administered. G-CSF was 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 who did not receive G-CSF prophylaxis (see section "Dosage and administration").

Adverse reactions observed in patients with head and neck cancer treated with Taxotere® at a dose of 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 neoplasm (G3/4: 0.6%).

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

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

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

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

Eye disorders. Common: increased lacrimation, conjunctivitis.

Aural and vestibular disorders. Common: hearing impairment.

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

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

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

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

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

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

Investigations. Common: weight gain.

Induction chemotherapy followed by (study TAX 324)

Infectious and parasitic diseases. Very common: infectious diseases (G3/4: 3.6%). Common: neutropenic infections.

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

Blood and lymphatic system disorders. Very common: neutropenia (G3/4: 83.5%), anemia (G3/4: 12.4%), thrombocytopenia (G3/4: 4.0%), febrile neutropenia.

Immune system disorders. Uncommon: hypersensitivity reactions.

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

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

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

Aural and vestibular disorders. Very common: hearing impairment (G3/4: 1.2%).

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

Vascular disorders. Uncommon: venous complications.

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

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

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

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

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

Post-marketing surveillance data.

Benign, malignant and unspecified neoplasms (including cysts and polyps). Administration of docetaxel in combination with other antineoplastic agents known to be associated with development of a second primary malignancy has been linked to cases of second primary malignancies (frequency unknown), including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma. In pivotal clinical trials in breast cancer patients treated with the TAC regimen, cases of acute myeloid leukemia and myelodysplastic syndrome were observed (frequency unknown).

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

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

Nervous system disorders. Administration of docetaxel has been associated with rare cases of seizures or transient loss of consciousness, sometimes occurring during infusion.

Eye disorders. Very rare cases of transient visual disturbances (flashes, flickering lights, scotomata), typically occurring during infusion and often associated with hypersensitivity reactions, have been reported. These disturbances resolved spontaneously after discontinuation of infusion. Rare cases of increased lacrimation, with or without associated conjunctivitis, due to obstruction of the lacrimal duct, have been reported. Cases of cystoid macular edema (CME) have been observed in patients receiving docetaxel.

Aural and vestibular disorders. Rare cases of ototoxicity, hearing impairment or loss have been reported.

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

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

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

Gastrointestinal disorders. Rare cases of enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, with potentially fatal outcomes (frequency unknown), have been reported. Rare cases of dehydration resulting from gastrointestinal disorders, including enterocolitis and gastrointestinal perforation, have been reported. Rare cases of intestinal obstruction and bowel obstruction have also been reported.

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

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

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

General disorders and administration site conditions. Rare cases of radiation recall phenomenon (acute radiation reactions during chemotherapy, occurring weeks, months, or years after radiotherapy) have been reported. Cases of recurrent injection site reaction (recurrence of skin reaction at a site of prior extravasation after administration of docetaxel at another site) have been reported (frequency unknown). Fluid retention was not associated with acute episodes of oliguria or arterial hypotension. Rare cases of dehydration and pulmonary edema have been reported.

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

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

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

Shelf life.

For 1 ml (20 mg) pack – 2 years.

For 4 ml (80 mg) pack – 3 years.

Storage conditions. Keep out of the reach of children. Store in the original packaging at temperatures not exceeding 25 °C.

The infusion solution should be used within 6 hours at temperatures below 25 °C, including 1 hour of infusion.

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

Packaging.

No. 1: 4 ml (80 mg) in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Sanofi-Aventis Deutschland GmbH.

Manufacturer's address and place of business. Bruningstrasse 50, Industriepark Höchst, 65926 Frankfurt am Main, Germany.

Marketing authorization holder. LLC "Sanofi-Aventis Ukraine", Ukraine.