Docetaxel-pharmex

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

Composition:

Active substance: docetaxel;

1 ml of concentrate contains docetaxel trihydrate equivalent to 40 mg of anhydrous docetaxel;

Excipients: polysorbate 80; citric acid monohydrate;

solvent: ethanol 96%, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties:

concentrate for solution for infusion: clear, oily solution, yellow to brownish-yellow in color;

solvent: clear, colorless solution.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Antineoplastic agents. Plant alkaloids and other natural products. Taxanes. Docetaxel. ATC code L01C D02.

Pharmacological properties.

Pharmacodynamics.

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

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

Clonogenic analysis in vitro has shown cytotoxicity of docetaxel against various murine and human tumor cell lines, as well as against cells freshly isolated from human tumors. Docetaxel achieves significant concentrations in the interstitial fluid and ensures high cellular survival duration. Furthermore, docetaxel exhibits activity against certain cell lines expressing P-glycoprotein encoded by the multidrug resistance gene. In vivo studies have shown that the effect of docetaxel is independent of the administration schedule and is manifested in a broad spectrum of antitumor activity in experimental models against both murine tumors and implanted human tumors.

Clinical efficacy and safety.

Breast cancer.

Docetaxel in combination with doxorubicin and cyclophosphamide — adjuvant therapy.

Patients with operable breast cancer with lymph node metastases (study TAX 316). Data from a multicenter, open-label, randomized trial support the use of docetaxel in adjuvant therapy for female patients aged 18 to 70 years with operable breast cancer with lymph node metastases and a Karnofsky Performance Status (KPS) ≥ 80%. After stratification according to the number of involved lymph nodes (1–3, 4+), 1491 patients were randomized into two groups: to receive 75 mg/m² docetaxel administered 1 hour after 50 mg/m² doxorubicin and 500 mg/m² cyclophosphamide (TAC group), or to receive 50 mg/m² doxorubicin followed by 500 mg/m² fluorouracil and 500 mg/m² cyclophosphamide (FAC group). Both regimens were administered every 3 weeks, for a total of 6 cycles. Docetaxel was given as a 1-hour infusion, and all other drugs were administered as intravenous 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 the last chemotherapy cycle, patients in both groups whose tumors expressed estrogen and/or progesterone receptors received tamoxifen 20 mg once daily for up to 5 years. Adjuvant radiotherapy was administered according to institutional guidelines at participating centers and was given to 69% of patients in the TAC group and 72% of patients in the FAC group.

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

The final analysis was performed with a median follow-up duration of 96 months. The 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 in the TAC group was also statistically significantly higher than in 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 either DFS or OS, the final analysis did not fully demonstrate a favorable benefit-risk profile of the TAC regimen in patients with metastases in 4 or more lymph nodes.

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

A subgroup analysis was performed for 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 with 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 trial support the use of docetaxel as adjuvant therapy in patients with operable node-negative breast cancer eligible for chemotherapy. A total of 1060 patients were randomized into two groups: to receive 75 mg/m² docetaxel as a 1-hour infusion, administered 1 hour after 50 mg/m² doxorubicin and 500 mg/m² cyclophosphamide (TAC group, 539 patients), or to receive 50 mg/m² doxorubicin followed by 500 mg/m² fluorouracil and 500 mg/m² cyclophosphamide (FAC group, 521 patients) as adjuvant therapy for patients with operable node-negative breast cancer 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 (grade 2–3), and/or age under 35 years). Both treatment regimens were administered every 3 weeks for a total of 6 cycles. Docetaxel was administered as a 1-hour infusion, and all other drugs were given intravenously on day 1 of each 3-week cycle. After randomization, primary prophylaxis with G-CSF was mandated for 230 patients in the TAC group. The incidence of grade IV neutropenia, febrile neutropenia, and neutropenic infection was lower in patients who received primary prophylaxis with G-CSF (see section "Adverse Reactions"). In both groups, after the last chemotherapy cycle, patients whose tumors expressed estrogen receptors (ER+) and/or progesterone receptors (PgR+) received tamoxifen 20 mg once daily for up to 5 years. According to the guidelines in place at the participating centers, 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 updated data analysis were performed. The primary analysis was conducted when follow-up duration exceeded 5 years for all patients (median follow-up duration was 77 months). The updated data analysis was performed when all patients had completed their 10-year follow-up visits (median follow-up duration was 10 years and 5 months), except for those who had previously experienced an event of RFS or were lost to follow-up. The primary efficacy endpoint was recurrence-free survival (RFS); the secondary efficacy endpoint was overall survival (OS).

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

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

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

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

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

In the primary analysis (with 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; ITT [Intent-to-Treat]) (GEICAM 9805 study)

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

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

Table 3

Results of exploratory subgroup analyses for 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.

a Absence 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 used as reference.

Docetaxel as monotherapy.

Two randomized comparative phase III studies were conducted in patients with metastatic breast cancer: 326 patients who had failed prior alkylating agent therapy and 392 patients who had failed prior anthracycline therapy. Patients received docetaxel at the recommended dose and schedule, i.e., 100 mg/m² every 3 weeks.

In patients who had failed prior alkylating agent therapy, docetaxel was compared with doxorubicin (75 mg/m² every 3 weeks). While overall survival (15 months in the docetaxel group vs. 14 months in the doxorubicin group, p = 0.38) and time to disease progression (27 weeks in the docetaxel group vs. 23 weeks in the doxorubicin group, p = 0.54) were not significantly affected, docetaxel increased the response rate (52% vs. 37%, p = 0.01) and shortened the time to response (12 weeks vs. 23 weeks, p = 0.007). Treatment was discontinued due to fluid retention in 3 patients (2%) receiving docetaxel, 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, the efficacy of docetaxel was compared with that of combination therapy with mitomycin C and vinblastine (12 mg/m² every 6 weeks and 6 mg/m² every 3 weeks). Docetaxel improved the response rate (33% vs. 12%, p < 0.0001), prolonged time to disease progression (19 weeks vs. 11 weeks, p = 0.0004), and prolonged overall survival (11 months vs. 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 monotherapy with docetaxel versus paclitaxel in patients with advanced breast cancer who had previously received anthracycline-based therapy. A total of 449 patients were randomized into two groups: to receive monotherapy with docetaxel at a dose of 100 mg/m² as a 1-hour infusion or monotherapy with paclitaxel at a dose of 175 mg/m² as a 3-hour infusion. Both drugs were administered every 3 weeks.

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

In the docetaxel monotherapy group, more grade III/IV adverse events were observed (55.4%) compared to the paclitaxel treatment group (23.0%).

Docetaxel in combination with doxorubicin.

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

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

In this study, the AT group experienced higher rates of severe neutropenia (90% vs. 68.6%), febrile neutropenia (33.3% vs. 10%), infection (8% vs. 2.4%), diarrhea (7.5% vs. 1.4%), asthenia (8.5% vs. 2.4%), and pain (2.8% vs. 0%) compared to the AC group. Conversely, the AC group had higher rates of severe anemia (15.8% vs. 8.5%) and higher rates of severe cardiotoxic reactions: congestive heart failure (3.8% vs. 2.8%), absolute decrease in left ventricular ejection fraction (LVEF) by ≥20% (13.1% vs. 6.1%), and absolute decrease in LVEF by ≥30% (6.2% vs. 1.1%). Drug-related toxicities led to fatal outcomes 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 the treatment period and throughout follow-up.

Docetaxel in combination with trastuzumab.

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

Table 4

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

PFS — time to disease progression.

NE — value not estimable or not yet reached.

1 Full analysis population (ITT population).

2 Calculated median survival.

Docetaxel in combination with capecitabine.

Data from one multicenter, randomized, controlled phase III clinical trial support the use of docetaxel in combination with capecitabine for the treatment of women 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 population (as assessed by the investigator) was 41.6% (docetaxel + capecitabine) compared to 29.7% (docetaxel monotherapy); p = 0.0058. Time to disease progression was longer in the group receiving docetaxel in combination with capecitabine (p < 0.0001). Median time to disease progression was 186 days (docetaxel + capecitabine) compared to 128 days (docetaxel monotherapy).

Non-small cell lung cancer.

Patients previously treated with chemotherapy with or without radiotherapy.

In a phase III trial involving patients who had prior treatment for their disease, time to disease progression (12.3 weeks vs. 7 weeks) and overall survival were statistically significantly higher in patients receiving docetaxel at a dose of 75 mg/m² compared to those receiving best supportive care (BSC). The 1-year survival rate was also statistically significantly higher in the docetaxel group (40%) compared to the BSC group (16%).

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

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

Docetaxel in combination with platinum agents in patients who have not previously received chemotherapy.

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

Data on survival, median time to disease progression, and response rate 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), and presented for the entire evaluable patient population.

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

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

Prostate cancer.

Metastatic castration-resistant prostate cancer.

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

• Docetaxel 75 mg/m² every 3 weeks; a total of 10 cycles.
• Docetaxel 30 mg/m² 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 three weeks showed a statistically significant improvement in overall survival compared to those receiving mitoxantrone. The increase in survival among patients receiving weekly docetaxel was not statistically significant compared to the control group receiving mitoxantrone. Efficacy endpoints for the docetaxel treatment groups compared to the control group are summarized in Table 6.

Table 6

Efficacy outcomes in patients with hormone-refractory metastatic prostate cancer treated 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: 0.0175.

**PSA – prostate-specific antigen.

Since the safety profile of docetaxel administered weekly was somewhat better than that of docetaxel given every 3 weeks, certain patients may derive greater benefit from weekly docetaxel administration.

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 concomitantly with standard of care (androgen deprivation therapy – ADT) in patients with locally advanced or metastatic hormone-sensitive prostate cancer at high risk were evaluated in a randomized, multi-center, multi-arm, multi-stage (MAMS) trial with continuous transition between phases II/III (STAMPEDE – MRC PR08). Overall, 1776 male patients were randomized into the treatment groups:

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

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

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

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

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

Table 7

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

a p-value calculated based on the likelihood ratio test, adjusted for all stratification factors (except central 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 above nadir [maximum decline 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-related events; or death from prostate cancer.

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

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

Median overall survival was significantly longer in the docetaxel treatment group compared to the group receiving ADT alone, with 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).

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

Table 8

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

a Time-to-event variables: stratified log-rank test. Categorical response variables: Fisher’s exact test.

* p-value for descriptive purposes.

** PSA response: PSA level < 0.2 ng/mL confirmed by two consecutive measurements at least 4 weeks apart.

b Time to castration-resistant prostate cancer = time from randomization to increase in PSA level or clinical progression (i.e., worsening of symptomatic bone metastases, progression by 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 by 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) in combination with cisplatin (C) (75 mg/m² on day 1) and 5-fluorouracil (F) (750 mg/m²/day for 5 days), and the other receiving 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. The primary endpoint was time to disease progression (TTP). A 32.1% reduction in the risk of progression was observed in the TCF group, 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 results 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 alone (CF regimen) in patients with gastric adenocarcinoma

* Unstratified log-rank test.

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

A refined 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 study groups, although it continued to indicate benefits in favor of the TCF regimen and showed that the advantage of TCF over CF was particularly evident between 18 and 30 months of follow-up.

Overall, the results of 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 75 mg/m² of docetaxel (T), followed by 75 mg/m² of cisplatin (P), and then 5-fluorouracil (F) at a dose of 750 mg/m²/day administered as a continuous infusion over 5 days. This regimen was repeated every 3 weeks for up to 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after two cycles. Four to seven 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 100 mg/m² of cisplatin (P), followed by 5-fluorouracil (F) at a dose of 1000 mg/m²/day for 5 days. This regimen was repeated every 3 weeks for up to 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after two cycles. Four to seven 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 (either 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 (OS) 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 data from all randomized patients; Intent-to-Treat)

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

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

** Log-rank test.

*** χ2 (chi-square) test.

Quality of life outcomes. Patients treated with the TPF regimen showed a statistically significant less 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. Outcomes assessed using the Performance Status Scale (PSS-HN), including subscales developed to evaluate patients' speech intelligibility, ability to eat in public, and dietary normalcy, 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 than in 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 in induction therapy for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) were evaluated in a randomized, multicenter, open-label phase III trial (TAX 324). A total of 501 patients with locally advanced HNSCC and 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 low likelihood of benefit from surgery, and those for whom an organ-preserving strategy was chosen. Efficacy and safety were assessed solely based on survival outcomes; organ preservation success was not formally evaluated. Patients in the docetaxel group received 75 mg/m² docetaxel (T) as a 1-hour intravenous infusion on day 1, followed by 100 mg/m² cisplatin (P) as an intravenous infusion lasting 30 minutes to 3 hours, then 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from day 1 to day 4. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received subsequent chemoradiotherapy (CRT) per protocol (treatment regimen TPF/CRT). Patients in the control group received 100 mg/m² cisplatin (P) as an intravenous infusion lasting 30 minutes to 3 hours on day 1, followed by 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from day 1 to day 5. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received subsequent chemoradiotherapy (CRT) per protocol (treatment regimen PF/CRT).

Beginning no earlier than 3 weeks and no later than 8 weeks after initiation of the last induction chemotherapy cycle (days 22 to 56 of 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, up to a maximum of 7 doses. Radiation was delivered using megavoltage equipment at 2 Gy fractions once daily, 5 days per week for 7 weeks, to a total cumulative dose of 70–72 Gy. Surgical intervention at the primary tumor site and/or neck region could be recommended at any time after completion of CRT. All patients in the docetaxel group received prophylactic antibiotics.

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

Table 11

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

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

* Unadjusted log-rank test.

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

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

NA — not applicable.

Pediatric population.

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

Pharmacokinetics.

Absorption. The pharmacokinetics of docetaxel were studied in phase I clinical trials in cancer patients following administration of 20–115 mg/m² of the drug. 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 duration of the last 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 area under the concentration-time curve (AUC) of 4.6 µg/mL/h. Mean values for total clearance and volume of distribution at steady state were 21 L/m²/h and 113 L, respectively.

Inter-subject variability in total clearance of docetaxel reached approximately 50%. Docetaxel is more than 95% bound to plasma proteins.

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

Special patient groups.

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

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

Fluid retention. Docetaxel clearance was not altered in patients with mild or moderate fluid retention; data on docetaxel clearance in patients with severe fluid retention are not available.

Combination therapy. When used in combination with other drugs, docetaxel did not affect the clearance of doxorubicin or plasma levels of doxorubicin (and its metabolites). The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide were not altered when administered concomitantly.

A phase I clinical study evaluating the effect of capecitabine on 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’-DFUR (5'-deoxy-5-fluorouridine).

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

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

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

Preclinical safety data.

The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be genotoxic—via an aneugenic mechanism in the in vitro micronucleus and chromosomal aberration tests in CHO-K1 cells and in the in vivo micronucleus test in mice.

However, it did not induce mutagenicity in the Ames test or in the CHO/HGPRT gene mutation assay.

These results are consistent with the pharmacological activity of docetaxel.

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

Clinical characteristics.

Indications.

Breast cancer.

Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for adjuvant therapy in patients with:

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

Adjuvant therapy should be administered to patients with operable breast cancer without lymph node involvement if they are candidates for chemotherapy according to established international guidelines for primary treatment of early-stage breast cancer.

Docetaxel 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 condition.

Docetaxel as monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after prior cytotoxic therapy that included an anthracycline or an alkylating agent has failed.

Docetaxel in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer with HER2 overexpression in tumor cells who have not previously received chemotherapy for metastatic disease.

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

Non-small cell lung cancer.

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

Docetaxel 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.

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

Gastric adenocarcinoma.

Docetaxel 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.

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients. Baseline neutrophil count < 1500 cells/mm³. Severe hepatic impairment (see sections "Method of administration and dosage" and "Special precautions").

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

Interaction with other medicinal products and other forms of interaction.

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

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

When used in combination with CYP3A4 inhibitors, the frequency of docetaxel adverse reactions may increase due to reduced metabolism of docetaxel. 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 precautions").

In a pharmacokinetic study in patients receiving ketoconazole and docetaxel concomitantly, administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole resulted in a 49% reduction in docetaxel clearance. This may lead to worsened tolerability of docetaxel even at lower doses.

The pharmacokinetics of docetaxel when administered concomitantly with prednisone were 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 potential interactions of this drug with other medicinal products have not been formally studied in vivo, in vitro data indicate that drugs with high plasma protein binding (such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate) did not impair the binding of docetaxel to plasma proteins. Furthermore, dexamethasone does not impair the binding of docetaxel to plasma proteins. Docetaxel does not affect the plasma protein binding of digoxin.

The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide were not altered when these drugs were administered concomitantly. Limited data from one uncontrolled study suggest a possible interaction between docetaxel and carboplatin. When these agents were used in combination, the clearance of carboplatin 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 per day (e.g., 8 mg twice daily) for 3 days, starting 1 day before administration of docetaxel, may reduce the frequency and severity of fluid retention and hypersensitivity reactions. In patients with prostate cancer, premedication should be performed with oral dexamethasone 8 mg administered 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion.

Hematological changes during treatment with the drug

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 cycles of antineoplastic therapy. All patients receiving docetaxel require careful monitoring of peripheral blood counts. Docetaxel may be re-administered in a new chemotherapy cycle only after neutrophil counts have recovered to ≥1500 cells/mm³ following completion of the previous cycle.

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

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

Gastrointestinal reactions.

Caution is advised in patients with neutropenia, particularly those at increased risk of gastrointestinal complications. Although most cases occurred during the first or second chemotherapy cycle with docetaxel-containing regimens, enterocolitis may develop at any time and can be fatal on the day of onset. Patients should be carefully monitored for early signs of serious gastrointestinal toxicity (see sections "Dosage and administration," "Special precautions for use," and "Adverse reactions").

Hypersensitivity reactions.

Patients must be carefully monitored for possible hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within minutes after the start of docetaxel infusion; therefore, all necessary measures for treatment of hypotension and bronchospasm should be readily available. Mild hypersensitivity reactions, such as flushing or localized skin reactions, do not require interruption of therapy. However, severe reactions such as severe hypotension, bronchospasm, generalized rash/erythema, or very rarely anaphylaxis, which may be fatal, require immediate discontinuation of docetaxel infusion and initiation of appropriate therapy. 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 are at increased risk of hypersensitivity reaction to docetaxel, including more severe reactions. These patients should be closely monitored at the beginning of docetaxel therapy.

Skin reactions.

Cases of localized erythema of the skin of the extremities (on palms and soles), associated with edema and subsequent epidermal desquamation, have been observed. Cases of severe symptoms, such as widespread skin rash with subsequent desquamation, requiring interruption or permanent discontinuation of docetaxel therapy, have also been reported.

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 receiving concomitant radiotherapy.

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

Patients with hepatic impairment.

Patients with elevated transaminase levels (ALT and/or AST) >1.5 times the ULN and alkaline phosphatase >2.5 times the ULN during monotherapy with docetaxel 100 mg/m² are at higher risk of severe adverse reactions, including fatal outcomes due to drug toxicity (e.g., sepsis, gastrointestinal bleeding), febrile neutropenia, infections, thrombocytopenia, stomatitis, and asthenia. Therefore, the recommended dose of docetaxel in patients with elevated liver enzymes is 75 mg/m²; liver enzyme levels should be assessed before initiation of treatment and prior to 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, and docetaxel should not be administered unless there is a compelling need.

In a pivotal clinical trial of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated ALT and/or AST >1.5 times ULN, alkaline phosphatase >2.5 times ULN, and bilirubin >ULN were among the exclusion criteria; therefore, dose reduction of docetaxel cannot be recommended, and the drug should not be administered to such patients unless there is a compelling need. Data on the use of docetaxel in combination therapy in 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 (see section "Dosage and administration").

Cardiotoxicity.

In patients receiving docetaxel in combination with trastuzumab, particularly after prior anthracycline-based chemotherapy (doxorubicin or epirubicin), cases of heart failure have been observed. This heart failure may be moderate or severe and is associated with a high risk of fatal outcome. If combination therapy with docetaxel and trastuzumab is necessary, cardiac function should be evaluated before initiation of therapy. Regular cardiac monitoring (e.g., every 3 months) during treatment is recommended to detect patients who may develop cardiac dysfunction. Further information is available in the trastuzumab product information.

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

Ocular disorders.

Cases of cystoid macular edema (CME) have been observed in patients receiving docetaxel. In the event of visual disturbances, an urgent and complete ophthalmological examination is required. 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 associated with the development of second primary malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma) may occur months or years after 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 after the first or second cycle of docetaxel therapy (see section "Adverse reactions"). Patients at risk of tumor lysis syndrome (e.g., those with renal impairment, hyperuricemia, bulky tumors, or rapid progression) should be closely monitored. Correction of dehydration and high uric acid levels is recommended before initiation of therapy.

Other warnings.

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

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

Additional warnings for use of docetaxel in adjuvant therapy of breast cancer.

Complicated neutropenia.

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

Gastrointestinal tract reactions.

Symptoms such as early abdominal pain, tenderness, and 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 observed in patients receiving TAC therapy for node-positive breast cancer during the first year after treatment (see sections "Adverse reactions" and "Pharmacodynamics").

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 for these patients was not fully demonstrated in the final analysis (see section "Pharmacodynamics").

Elderly patients.

Safety data analysis in patients aged 60 years and older receiving docetaxel in combination with capecitabine showed increased incidence of grade 3–4 adverse events, serious adverse events, and early discontinuation due to adverse events compared to patients under 60 years of age.

Warnings for use in adjuvant therapy of breast cancer.

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

Warnings for use in castration-resistant prostate cancer.

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

Warnings for use in hormone-sensitive prostate cancer.

Of 545 patients who received docetaxel every 3 weeks in the hormone-sensitive prostate cancer study (STAMPEDE [Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy]), 296 were over 65 years of age and 48 were 75 years or older. In the docetaxel group, patients over 65 years of age experienced higher rates of hypersensitivity reactions, neutropenia, anemia, fluid retention, dyspnea, and nail changes. However, the increase in frequency of any of these reactions did not reach 10% compared to patients under 65 years. In patients aged ≥75 years, neutropenia, anemia, diarrhea, dyspnea, and upper respiratory tract infections were reported more frequently (at least 10% higher) compared to younger patients.

Warnings for use in gastric adenocarcinoma.

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

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

Warnings regarding excipients.

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

The product is harmful for patients suffering from alcoholism.

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

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

Safety measures for handling the medicinal product.

Docetaxel-Farmex belongs to antineoplastic agents and, like any other potentially toxic agent, requires adherence to safety measures during handling, particularly during solution preparation. Medical gloves should be worn when handling docetaxel. If the concentrate, intermediate solution, or infusion solution comes into contact with the skin, the area should be immediately and thoroughly washed with soap and water. If the concentrate, intermediate solution, or infusion solution contacts mucous membranes, the affected area should be immediately and thoroughly rinsed with water.

Preparation of the intermediate solution.

1. Take the required number of vials of Docetaxel-Farmex (allow vials to reach room temperature for 5 minutes if stored in a refrigerator).
2. Using a syringe, aseptically withdraw all solvent from the solvent vial included in the same package as the Docetaxel-Farmex concentrate.

Inject all the solvent into the vial containing the Docetaxel-Farmex concentrate.

1. After removing the syringe with needle from the vial, mix the resulting mixture of solvent and concentrate for 45 seconds by gently inverting the vial.

DO NOT SHAKE! The intermediate solution of Docetaxel-Farmex has been prepared.

1. Leave the vial with the intermediate solution at room temperature for 5 minutes, then check the homogeneity and clarity of the solution (the presence of foam even after 5 minutes is normal due to the presence of polysorbate 80 in the formulation).

The intermediate solution containing 10 mg/mL of docetaxel should be used immediately after preparation. However, the chemical and physical stability of the ready-to-use solution is maintained for 8 hours if stored at +2 to +8°C or at room temperature.

Preparation of the ready-to-use infusion solution.

1. When preparing the infusion solution, remember that 1 mL of the intermediate solution contains 10 mg of docetaxel.
2. Draw the required volume of intermediate solution into a syringe and inject it into a vial containing 250 mL of 0.9% sodium chloride or 5% glucose solution. If the required dose of Docetaxel-Farmex exceeds 200 mg, a larger volume of infusion fluid should be used so that the concentration of docetaxel does not exceed 0.74 mg/mL.
3. Mix the contents of the infusion vial by gentle swirling.
4. The Docetaxel-Farmex solution for injection should be used within the next 4 hours and administered as a 1-hour infusion under aseptic conditions, under normal room lighting and at room temperature.
5. If precipitates [sediment or any particles (inclusions)] are observed upon inspection of the intermediate solution or infusion solution, the solution must not be administered and should be discarded.

Waste disposal.

Unused medicinal product or waste materials must be destroyed according to established procedures.

Use during pregnancy or breastfeeding.

Contraception in men and women. Women of childbearing potential and men receiving docetaxel should be advised to avoid conception. Women should immediately inform their physician if pregnancy occurs.

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

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

Lactation. 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 treatment with docetaxel.

Fertility. Animal studies have shown that docetaxel may affect male fertility (see section "Preclinical safety data"). Therefore, men should be advised to consult on sperm cryopreservation before starting docetaxel therapy.

Ability to influence 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 or operate machinery (see sections "Special precautions for use" and "Adverse reactions"). Therefore, patients should be warned about the possible effects of the alcohol content and adverse effects of this drug on their ability to drive vehicles or operate machinery and advised not to drive or operate machinery if such adverse effects occur during treatment.

Method of Administration and Dosage

Administration of docetaxel should be carried out in departments specialized in cytotoxic chemotherapy. Docetaxel must be administered exclusively under the supervision of a physician experienced in antineoplastic chemotherapy.

Recommended Doses

For the treatment of breast cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer, in the absence of contraindications, premedication with oral corticosteroids such as dexamethasone 16 mg/day (e.g., 8 mg twice daily) for 3 days is recommended, with the first dose administered one day prior to docetaxel administration (see section "Special Precautions"). To reduce the risk of hematotoxicity, prophylactic administration of granulocyte colony-stimulating factor (G-CSF) may be considered.

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

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

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

Docetaxel is administered intravenously over one hour every 3 weeks.

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

For the treatment of patients with locally advanced or metastatic breast cancer, the recommended monotherapy dose of docetaxel is 100 mg/m².

In combination with doxorubicin (at a dose of 50 mg/m²), docetaxel should be administered at a dose of 75 mg/m² as first-line therapy.

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

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

Non-Small Cell Lung Cancer. For treatment of patients with previously untreated non-small cell lung cancer, docetaxel is recommended at a dose of 75 mg/m², followed immediately by cisplatin 75 mg/m² administered intravenously over 30–60 minutes. For patients who have previously failed platinum-based chemotherapy, monotherapy with docetaxel at 75 mg/m² is recommended.

Prostate Cancer.

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

Metastatic Hormone-Sensitive Prostate Cancer. The recommended dose of docetaxel is 75 mg/m² every 3 weeks for 6 cycles. Prednisone or prednisolone may be administered 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 administered as an intravenous infusion over 1–3 hours (both drugs administered only on day 1 of the cycle). Immediately after completion of cisplatin infusion, a continuous 5-day infusion of 5-fluorouracil at 750 mg/m²/day should be initiated. 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, prophylactic administration of G-CSF is required (see also subsection "Dose Adjustment During Treatment" below).

Head and Neck Cancer. Premedication with antiemetics and appropriate hydration (before and after cisplatin administration) is required. Prophylactic administration of G-CSF may be considered to reduce the risk of hematological toxicity. All patients in the docetaxel groups of studies TAX 323 and TAX 324 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 infusion, immediately followed on day 1 of the cycle by cisplatin 75 mg/m² administered as an infusion over 1–3 hours; immediately after completion of cisplatin infusion, a continuous 5-day infusion of 5-fluorouracil (750 mg/m²/day) should be initiated. This regimen is repeated every 3 weeks for 4 cycles. After chemotherapy, patients should receive radiotherapy.
• Induction chemotherapy followed by chemoradiotherapy (based on data from study TAX 324). For induction chemotherapy of locally advanced SCCHN (technically unresectable, with low probability of surgical intervention or requiring an organ-sparing approach), the recommended dose of docetaxel is 75 mg/m² administered as a 1-hour infusion, immediately followed on day 1 of the cycle by cisplatin 100 mg/m² administered as an infusion over 0.5–3 hours; immediately after completion of cisplatin infusion, a continuous 4-day infusion of 5-fluorouracil (1000 mg/m²/day) should be initiated. This regimen is repeated every 3 weeks for 5 cycles. After chemotherapy, patients should receive chemoradiotherapy.

Specifics of dose adjustment for cisplatin and 5-fluorouracil are described in the respective product characteristics.

Dose Adjustment During Treatment

General Principles. Docetaxel should be administered only to patients with an absolute neutrophil count (ANC) greater than 1500/mm³. If febrile neutropenia develops during docetaxel therapy, or if neutrophil count remains below 500/mm³ for more than 1 week, or if severe acute skin reactions or cumulative skin reactions occur, or if peripheral neuropathy is significantly pronounced, the docetaxel dose should be reduced from 100 mg/m² to 75 mg/m² and/or from 75 mg/m² to 60 mg/m². If such reactions persist at the 60 mg/m² dose level, docetaxel 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 Precautions" and "Adverse Reactions"). Patients who develop grade 3 or 4 stomatitis should have the docetaxel dose reduced to 60 mg/m².

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

In Combination with Capecitabine. Dose adjustment specifics for capecitabine are described in the capecitabine prescribing information.

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

Dose adjustment specifics for trastuzumab are described in the trastuzumab product characteristics.

In Combination with Cisplatin and 5-Fluorouracil. If, despite G-CSF administration, a patient experiences an episode of febrile neutropenia, prolonged neutropenia, or neutropenia-associated infection, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m². If complicated neutropenia episodes recur, the dose should be further reduced from 60 mg/m² to 45 mg/m². If a patient develops grade IV thrombocytopenia, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m². Subsequent treatment cycles 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 Precautions").

Table 12

Recommended Dose Adjustment Measures for Chemotherapy Agents in Patients Receiving Combination Docetaxel, Cisplatin, and 5-Fluorouracil

Dosage adjustments for cisplatin and 5-fluorouracil are described in the respective instructions for medical use.

In the pivotal clinical study of docetaxel, patients who developed complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infectious diseases) during SCTC therapy 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 hepatic impairment. According to pharmacokinetic data from monotherapy studies with docetaxel at a dose of 100 mg/m², the recommended dose of docetaxel for patients with elevated transaminase levels (ALT and/or AST) greater than 1.5 times the upper limit of normal (ULN), as well as alkaline phosphatase levels greater than 2.5 times ULN, is 75 mg/m². For patients with increased serum bilirubin levels (>ULN) and/or increased ALT and AST levels greater than 3.5 times UL 2N accompanied by elevated alkaline phosphatase levels greater than 6 times ULN, dose reduction is not recommended; however, docetaxel should generally not be administered unless there is an urgent need.

In the pivotal clinical study of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated levels of ALT and/or AST greater than 1.5 times ULN, alkaline phosphatase greater than 2.5 times ULN, and bilirubin greater than ULN were among the exclusion criteria; therefore, dose reduction of docetaxel cannot be recommended for such patients. The drug should generally not be administered to this patient group unless there is an urgent need.

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

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

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

Children.

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

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

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

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

Overdose.

There have been several reports of docetaxel overdose. There is currently 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 intensification of the drug's adverse effects should be expected. Primarily, such disorders as bone marrow suppression, peripheral neurotoxic effects, and mucosal inflammation are anticipated. After confirming overdose, therapeutic doses of G-CSF should be administered to the patient as soon as possible. If necessary, other appropriate symptomatic measures should be taken.

Adverse Reactions.

Integrated 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 presented);
• 1276 patients (744 and 532 patients in studies TAX 316 and GEICAM 9805, respectively) receiving docetaxel in combination with doxorubicin and cyclophosphamide (clinically significant treatment-related adverse reactions are presented);
• 300 patients with 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 presented);
• 174 and 251 patients with head and neck cancer receiving docetaxel in combination with cisplatin and 5-fluorouracil (clinically significant treatment-related adverse reactions are presented);
• 545 patients [STAMPEDE study] receiving docetaxel in combination with prednisone or prednisolone and androgen deprivation therapy (ADT).

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

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 category, adverse effects are listed in order of decreasing severity.

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

When docetaxel was 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 described in 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 frequently 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 commonly reported symptoms included skin flushing, rash (with or without pruritus), chest tightness, back pain, dyspnea, fever, or chills. Severe adverse reactions manifested as hypotension and/or bronchospasm, or generalized rash/erythema (see section "Special warnings and precautions for use").

Nervous system disorders

Severe peripheral neurotoxic reactions require dose reduction of the medicinal product (see sections "Dosage and administration" and "Adverse reactions"). 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 were observed, which were generally mild or moderate in severity. These reactions included rash, often localized on palms and soles (including severe hand-foot syndrome), as well as on 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 desquamation of epithelium, sometimes necessitating interruption or complete discontinuation of docetaxel (see sections "Dosage and administration" and "Special warnings and precautions for use"). 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 hemorrhage, and swelling of the vein used for infusion.

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

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

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

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

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

Metabolism and nutrition disorders. Very common: anorexia.

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

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

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

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

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

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

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

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

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

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

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

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

Skin and subcutaneous tissue disorders. Very rare: one case of irreversible alopecia has been reported. Skin reactions were reversible and resolved within 21 days.

General disorders and administration site conditions. The median cumulative dose at drug discontinuation was greater than 1000 mg/m², and the median time to reversible development of fluid retention was 16.4 weeks (range 0 to 42 weeks). Development of moderate to severe fluid retention occurred later in patients who received premedication (median cumulative dose: 818.9 mg/m²) compared to those who did not 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 docetaxel at a dose of 75 mg/m².

Infections and parasitic diseases. Very common: infections (G3/4: 5%).

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

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

Metabolism and nutrition disorders. Common: anorexia.

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

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

Vascular disorders. Common: arterial hypotension.

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

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

Musculoskeletal and connective tissue disorders. Common: myalgia.

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

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

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

Infections and parasitic diseases. Very common: infections (G3/4: 7.8%).

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

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

Metabolism and nutrition disorders. Common: anorexia.

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

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

Vascular disorders. Uncommon: arterial hypotension.

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

Skin and subcutaneous tissue disorders. Very common: alopecia; nail disorders (severe: 0.4%); skin reactions (no severe cases reported).

Musculoskeletal and connective tissue disorders. Common: myalgia.

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

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

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

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

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

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

Metabolism and nutrition disorders. Very common: anorexia.

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

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

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

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

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

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

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

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

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

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

Metabolism and nutrition disorders. Very common: anorexia.

Psychiatric disorders. Very common: insomnia.

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

Cardiac disorders. Common: heart failure.

Eye disorders. Very common: increased lacrimation, conjunctivitis.

Vascular disorders. Very common: lymphedema.

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

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

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

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

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

Investigations. Very common: weight gain.

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

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

Cardiac disorders. Symptomatic heart failure was observed in patients receiving the combination of trastuzumab and docetaxel compared to those receiving 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 docetaxel monotherapy group.

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

Infections and parasitic diseases. Common: oral candidiasis (G3/4: <1%).

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

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

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

Eye disorders. Very common: increased lacrimation.

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

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

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

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

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

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

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

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

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

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

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

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

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

Cardiac disorders. Common: left ventricular dysfunction (G3/4: 0.3%).

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

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

Skin and subcutaneous tissue disorders. Very common: alopecia; nail disorders (no severe cases). Common: desquamative rash (G3/4: 0.3%).

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

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

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

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

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

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

Metabolism and nutrition disorders. Common: loss of appetite.

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

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

Eye disorders. Common: blurred vision.

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

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

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

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

Musculoskeletal and connective tissue disorders. Very common: myalgia.

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

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

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

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

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

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

Nervous system disorders. Very common: dysgeusia (G3/4: 0.6%); peripheral sensory neuropathy (G3/4: <0.1%). Common: peripheral motor neuropathy (G3/4: 0%). Uncommon: syncope (G3/4: 0%); neurotoxicity manifestations (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: arterial hypotension (G3/4: 0%); phlebitis (G3/4: 0%). Uncommon: lymphedema (G3/4: 0%).

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

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

Skin and subcutaneous tissue disorders. Very common: alopecia (persistent: <3%); skin toxicity manifestations (G3/4: 0.6%); nail disorders (G3/4: 0.4%).

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

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

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

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

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

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

In the GEICAM 9805 study, peripheral sensory neuropathy that began during 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 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. Two patients in the TAC group and four patients in the FAC group died due to heart failure.

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

At the end of the follow-up period (actual median follow-up duration 10 years and 5 months), no patient in the TAC group had congestive heart failure, and one patient in the TAC group died due to dilated cardiomyopathy, while in the FAC group, congestive heart failure persisted in one 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 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 related to study drug use began or worsened during follow-up in 42 patients (7.9%) in the TAC group and in 30 patients (5.8%) in the FAC group.

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

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

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

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

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

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

In the GEICAM 9805 study, peripheral edema that began during 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 10 years and 5 months), no patient (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 diagnosed in 3 of 744 patients (0.4%) in the TAC group and in 1 of 736 patients (0.1%) in the FAC group. During the follow-up period (median follow-up duration 8 years), 1 patient (0.1%) in the TAC group and 1 patient (0.1%) in the FAC group died from acute myeloid leukemia. Myelodysplastic syndrome was diagnosed in 2 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 arm 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 docetaxel at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil.

Infections 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%).

Metabolic and nutritional disorders. Very common: anorexia (G3/4: 11.7%).

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

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

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

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

Gastrointestinal disorders. Very common: diarrhea (G3/4: 19.7%), nausea (G3/4: 16%), stomatitis (G3/4: 23.7%), vomiting (G3/4: 14.3%). Common: constipation (G3/4: 1.0%), abdominal pain (G3/4: 1.0%), esophagitis/dysphagia/odynophagia (G3/4: 0.7%).

Skin and subcutaneous tissue disorders. Very common: alopecia (G3/4: 4.0%). Common: rash with pruritus (G3/4: 0.7%), nail disorders (G3/4: 0.7%), increased skin desquamation (G3/4: 0%).

General disorders and administration site conditions. Very common: lethargy (G3/4: 19.0%), fever (G3/4: 2.3%), fluid retention (severe/life-threatening: 1%).

Description of selected adverse reactions observed in patients with gastric adenocarcinoma treated with docetaxel at a dose of 75 mg/m² in combination with cisplatin and 5-fluorouracil.

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

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

Induction chemotherapy followed by radiotherapy (TAX 323 study).

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

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

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

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

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

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

Eye disorders. Common: increased lacrimation, conjunctivitis.

Ear and labyrinth disorders. Common: hearing impairment.

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

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

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

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

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

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

Investigations. Common: weight gain.

Induction chemotherapy followed by chemoradiotherapy (TAX 324 study).

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

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

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

Immune system disorders. Uncommon: hypersensitivity reactions.

Metabolic and nutritional disorders. Very common: anorexia (G3/4: 12.0%).

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

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

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

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

Vascular disorders. Uncommon: venous disorders.

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

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

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

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

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

Post-marketing surveillance data.

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

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

Immune system disorders. Isolated 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. These reactions sometimes occurred during infusion.

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

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

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

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

Ventricular arrhythmias, including ventricular tachycardia (frequency unknown), sometimes fatal, have occurred in patients receiving docetaxel in combination regimens with doxorubicin, 5-fluorouracil and/or cyclophosphamide.

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

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

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

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

Hepatobiliary disorders. Very 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 (e.g., 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 reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, have been reported during docetaxel treatment. 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 (recurrent skin reaction at a site previously affected by extravasation after docetaxel administration at another site) have been reported (frequency unknown).

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

Rare cases of dehydration and pulmonary edema have been reported.

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

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

Reporting suspected adverse reactions.

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

Do not use with other solutions except those specified in the "Special precautions for disposal and handling" section.

Packaging.

Docetaxel-Farmex, 20 mg / 0.5 ml

0.5 ml (20 mg) concentrate in a glass vial, 1 concentrate vial (20 mg / 0.5 ml) and 1 solvent vial (1.5 ml) in a blister pack, 1 blister pack in a cardboard box.

Docetaxel-Farmex, 80 mg / 2 ml

2 ml (80 mg) concentrate in a glass vial, 1 concentrate vial (80 mg / 2 ml) and 1 solvent vial (6 ml) in a blister pack, 1 blister pack in a cardboard box.

Docetaxel-Farmex, 120 mg / 3 ml

3 ml (120 mg) concentrate in a glass vial, 1 concentrate vial (120 mg / 3 ml) and 1 solvent vial (9 ml) in a blister pack, 1 blister pack in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's location and address of business activity.

100, Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine.