Docet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOCE (DOCET)

Composition:

1 ml of concentrate contains:

active substance: docetaxel trihydrate equivalent to docetaxel 40 mg;

excipients: polysorbate 80;

1 vial of solvent contains: 13% ethanol solution.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, viscous solution of yellow to brownish-yellow color.

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01C D02.

Pharmacological Properties.

Pharmacodynamics.

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

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

In vitro clonogenic assays showed cytotoxicity of docetaxel against various murine and human tumor cell lines, as well as against freshly isolated human tumor cells. Docetaxel achieves high concentrations in the extracellular fluid and ensures prolonged cell survival. Furthermore, docetaxel exhibits activity against certain cell lines that overexpress P-glycoprotein encoded by the multidrug resistance gene. In vivo studies revealed that the effect of docetaxel is independent of the administration schedule and demonstrates a broad spectrum of antitumor activity against common tumors, including both experimental murine tumors and transplanted human tumors.

Clinical Efficacy and Safety.

Breast Cancer.

DOCET 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 study support the use of docetaxel in adjuvant therapy for patients aged 18 to 70 years with operable breast cancer with lymph node metastases and a Karnofsky performance status ≥ 80%. After stratification according to the number of involved lymph nodes (1–3, 4+), 1491 patients were randomized into two groups: one receiving 75 mg/m² docetaxel administered 1 hour after 50 mg/m² doxorubicin and 500 mg/m² cyclophosphamide (TAC group), or the other receiving 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, while all other drugs were administered as intravenous bolus injections on day 1 of each treatment cycle. Patients who developed complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection) received granulocyte colony-stimulating factor (G-CSF) for secondary prophylaxis. Patients in the TAC group received antibiotic prophylaxis with ciprofloxacin (500 mg orally twice daily for 10 days, starting on day 5 of each treatment cycle) or a similar agent. After completion of the last chemotherapy cycle, patients whose tumors expressed estrogen and/or progesterone receptors received tamoxifen 20 mg once daily for up to 5 years. Adjuvant radiotherapy was administered according to institutional guidelines and was given to 69% of patients in the TAC group and 72% in the FAC group.

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

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

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

A subgroup analysis was performed for 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)

		Disease-free survival			Overall survival
Patient subgroup	Number of patients	Hazard ratio*	95% CI [confidence interval]	p	Hazard ratio*	95% CI	p
Number of lymph nodes affected by metastases
Total	745	0.80	0.68–0.93	0.0043	0.74	0.61–0.90	0.0020
1–3	467	0.72	0.58–0.91	0.0047	0.62	0.46–0.82	0.0008
4+	278	0.87	0.70–1.09	0.2290	0.87	0.67–1.12	0.2746

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

Patients with operable node-negative breast cancer eligible for chemotherapy (GEICAM 9805 study). Data from a multicenter, open-label, randomized study support the use of docetaxel as adjuvant therapy in patients with operable node-negative breast cancer who are candidates for chemotherapy. A total of 1060 patients were randomized into two groups: to receive 75 mg/m² docetaxel as a 1-hour infusion followed by 50 mg/m² doxorubicin and 500 mg/m² cyclophosphamide (TAC group, 539 patients) or 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 grade (grade 2–3), and/or age under 35 years). Both 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"). After the last cycle of chemotherapy, patients in both groups whose tumors expressed estrogen receptors (ER+) and/or progesterone receptors (PR+) received tamoxifen 20 mg once daily for up to 5 years. According to institutional guidelines, adjuvant radiotherapy was administered to 57.3% of patients in the TAC group and 51.2% of patients 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 in all patients (median follow-up duration was 77 months). The updated data analysis was performed when all patients had completed their 10-year follow-up visits (median follow-up duration was 10 years and 5 months), except for those who had previously experienced RFS events or were lost to follow-up. The primary efficacy endpoint was recurrence-free survival (RFS); the secondary efficacy endpoint was overall survival (OS).

With a median follow-up of 77 months, recurrence-free survival in the TAC group was statistically significantly longer than in the FAC group. Patients in the TAC group had a 32% reduction in the risk of recurrence compared to patients in the FAC group (hazard ratio (HR) 0.68, 95% CI: 0.49–0.93, p = 0.01). With a median follow-up of 10 years and 5 months, patients in the TAC group had a 16.5% reduction in the risk of recurrence compared to patients in the FAC group (hazard ratio (HR) 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 was not statistically significant between the two patient groups.

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

After 8 years of follow-up, the survival rate was 93.7% in the TAC group and 91.4% in the FAC group; after 10 years of follow-up, it was 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 (based on a median follow-up of 77 months), predefined subgroups of patients receiving the TAC regimen were analyzed according to prospectively defined key prognostic factors (see Table 2).

Table 2

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

		Recurrence-free survival
Subgroup of patients	Number of patients in the TAC group	Hazard ratio*	95% CI
Total	539	0.68	0.49–0.93
Age category 1
< 50 years	260	0.67	0.43–1.05
≥ 50 years	279	0.67	0.43–1.05
Age category 2
< 35 years	42	0.31	0.11–0.89
≥ 35 years	497	0.73	0.52–1.01
Hormone receptor expression status
Negative	195	0.7	0.45–1.1
Positive	344	0.62	0.4–0.97
Tumor size
≤ 2 cm	285	0.69	0.43–1.1
> 2 cm	254	0.68	0.45–1.04
Grade of histological differentiation
Grade 1 (including unknown grade)	64	0.79	0.24–2.6
Grade 2	216	0.77	0.46–1.3
Grade 3	259	0.59	0.39–0.9
Menopausal status
Premenopausal	285	0.64	0.40–1
Postmenopausal	254	0.72	0.47–1.12

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

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

Table 3

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

Subgroups	TAC (n = 539)	FAC (n = 521)	Relative risk (TAC/FAC)	p-value
			(95 % CI)
Compliance with relative indication for chemotherapya
No	18/214 (8.4 %)	26/227 (11.5 %)	0.796 (0.434–1.459)	0.4593
Yes	48/325 (14.8 %)	69/294 (23.5 %)	0.606 (0.42–0.877)	0.0072

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, using treatment groups as reference.

Docetaxel as monotherapy.

Two randomized phase III comparative studies were conducted involving patients with metastatic breast cancer: 326 patients who had failed prior alkylating agent therapy and 92 patients who had failed prior anthracycline therapy, who received docetaxel at the recommended dose and schedule, i.e., 100 mg/m² every 3 weeks.

In patients who had failed prior alkylating agent therapy, docetaxel was compared with doxorubicin (75 mg/m² every 3 weeks). While it did not affect overall survival (median duration was 15 months in the docetaxel group versus 14 months in the doxorubicin group, p = 0.38) or time to disease progression (27 weeks in the docetaxel group versus 23 weeks in the doxorubicin group, p = 0.54), docetaxel increased the response rate (52% versus 37%, p = 0.01) and shortened the time to response (12 weeks versus 23 weeks, p = 0.007). Treatment was discontinued due to fluid retention in 3 patients (2%) receiving docetaxel, and in 15 patients (9%) receiving doxorubicin due to cardiotoxicity (including 3 cases of congestive heart failure with fatal outcome).

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

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

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

While no significant difference was observed in the primary endpoint—overall response rate (32% versus 25%, p = 0.10)—docetaxel prolonged median time to disease progression (24.6 weeks versus 15.6 weeks; p < 0.01) and median survival (15.3 months versus 12.7 months; p = 0.03).

The docetaxel monotherapy group experienced a higher incidence of grade III/IV adverse events (55.4%) compared to the paclitaxel group (23.0%).

Docetaxel in combination with doxorubicin.

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

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

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

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

Docetaxel in combination with trastuzumab.

Docetaxel in combination with trastuzumab was studied in the treatment of patients with metastatic breast cancer whose tumors overexpressed HER2 and who had not previously received chemotherapy for metastatic disease. The study included 186 patients randomized 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. The efficacy of docetaxel in combination with trastuzumab was demonstrated regardless of prior adjuvant anthracycline therapy. The primary method for determining HER2 expression in this pivotal study was immunohistochemistry (IHC). A small subset of patients was assessed using fluorescence in situ hybridization (FISH). In this study, 87% of patients had HER2 overexpression at the IHC 3+ level, and 95% of patients enrolled had either IHC 3+ or positive FISH results. Efficacy data are summarized in Table 4.

Table 4

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

Parameter	Docetaxel + trastuzumab1 n = 92	Docetaxel1 n = 94
Response rate (95 % CI)	61 % (50–71)	34 % (25–45)
Median duration of response (months) (95 % CI)	11.4 (9.2–15.0)	5.1 (4.4–6.2)
Median PFS (months) (95 % CI)	10.6 (7.6–12.9)	5.7 (5.0–6.5)
Median survival (months) (95 % CI)	30.52 (26.8–NR)	22.12 (17.6–28.9)

PFS — progression-free survival.

NE — not estimable or not yet reached.

1 Full analysis population (ITT population).

2 Calculated median survival.

DOCET 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 patients with locally advanced or metastatic breast cancer after prior cytotoxic chemotherapy including an anthracycline. In this trial, 255 patients were randomized to receive either docetaxel (75 mg/m² as a 1-hour intravenous infusion every 3 weeks) or capecitabine (1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period). Another 256 patients were randomized to receive docetaxel monotherapy (100 mg/m² as a 1-hour intravenous infusion every 3 weeks). Survival was higher in the group receiving docetaxel in combination with capecitabine (p = 0.0126). Median survival was 442 days (docetaxel + capecitabine) compared to 352 days (docetaxel monotherapy). The overall objective response rate in the entire randomized patient population (as assessed by the investigator) was 41.6% (docetaxel + capecitabine) versus 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 previously received 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 in the docetaxel group (40%) was also statistically significantly higher than in 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.

DOCET in combination with platinum agents in chemotherapy-naïve patients.

In a phase III trial, 1218 patients with unresectable non-small cell lung cancer (NSCLC) stage IIIB or IV and a Karnofsky performance status 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 unresectable stage IIIB or IV NSCLC with docetaxel plus cisplatin (regimen TCis) versus vinorelbine plus cisplatin (regimen VCis)

Parameter	TCis n = 408	VCis n = 404	Statistical analysis
Overall survival (primary endpoint):
Median survival (months)	11.3	10.1	Hazard ratio: 1.122 [97.2 % CI: 0.937; 1.342]*
1-year survival (%)	46	41	Difference between treatment groups: 5.4 % [95 % CI: –1.1; 12.0]
2-year survival (%)	21	14	Difference between treatment groups: 6.2 % [95 % CI: 0.2; 12.3]
Median time to disease progression (weeks)	22.0	23.0	Hazard ratio: 1.032 [95 % CI: 0.876; 1.216]
Overall response rate (%)	31.6	24.5	Difference between treatment groups: 7.1 % [95 % CI: 0.7; 13.5]

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

Secondary endpoints included pain relief, overall quality of life as measured by the EuroQoL-5D questionnaire, score on the lung cancer symptom scale, and changes in overall functional status assessed by the Karnofsky Performance Index. Results for these endpoints were consistent with those observed for the primary endpoints.

It was not possible to demonstrate that the docetaxel/carboplatin combination was equivalent or at least not inferior 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 a Karnofsky Performance Status of ≥ 60 were randomized into the following treatment groups:

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

All three treatment regimens included continuous administration of prednisone or prednisolone at a dose of 5 mg twice daily.

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

Table 6

Efficacy outcomes in 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

Endpoint	Docetaxel every 3 weeks	Docetaxel weekly	Mitoxantrone every 3 weeks
Number of patients Median survival (months) 95 % CI Hazard ratio 95 % CI p-value†*	335 18.9 (17.0–21.2) 0.761 (0.619–0.936) 0.0094	334 17.4 (15.7–19.0) 0.912 (0.747–1.113) 0.3624	337 16.5 (14.4–18.6) -- -- --
Number of patients PSA response rate (%) 95 % CI p-value*	291 45.4 (39.5–51.3) 0.0005	282 47.9 (41.9–53.9) < 0.0001	300 31.7 (26.4–37.3) --
Number of patients Pain response rate (%) 95 % CI p-value*	153 34.6 (27.1–42.7) 0.0107	154 31.2 (24.0–39.1) 0.0798	157 21.7 (15.5–28.9) --
Number of patients Tumor response rate (%) 95 % CI p-value*	141 12.1 (7.2–18.6) 0.1112	134 8.2 (4.2–14.2) 0.5853	137 6.6 (3.0–12.1) --

† Stratified log-rank test.
* Statistical significance threshold of 0.0175.

** PSA — prostate-specific antigen.

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

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

Metastatic hormone-sensitive prostate cancer

STAMPEDE study

The safety and efficacy of docetaxel administered concurrently with standard of care (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 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 group compared to the monotherapy standard of care group, with a median overall survival 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)

Endpoint	Docetaxel + standard of care	Standard of care as monotherapy
Number of patients with metastatic prostate cancer	362	724
Median overall survival (months)	62	43
95% CI	51–73	40–48
Adjusted hazard ratio	0.76
95% CI	(0.62–0.92)
p-valuea	0.005
Failure-free survivalb	20.4	12
Median (months)
95% CI	16.8–25.2	9.6–12
Adjusted hazard ratio	0.66
95% CI	(0.57–0.76)
p-valuea	<0.001

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

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

CHAARTED Study

The safety and efficacy of docetaxel administered at the 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 median overall survival being 13.6 months longer when docetaxel was added to ADT (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.47–0.80, p = 0.0003).

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

Table 8

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

Endpoint	Docetaxel + ADT	ADT as monotherapy
Number of patients	397	393
Median overall survival (months)
All patients	57.6	44.0
95% CI Adjusted hazard ratio	49.1–72.8	34.4–49.1
	0.61	--
95% CI	(0.47–0.80)	--
p-valuea	0.0003	--
Progression-free survival	19.8	11.6
Median (months)
95% CI	16.7–22.8	10.8–14.3
Adjusted hazard ratio	0.60	--
95% CI	0.51–0.72	--
p-value*	P<0.0001	--
PSA response** at 6 months, N (%)	127 (32.0)	77 (19.6)
p-valuea*	<0.0001	--
PSA response** at 12 months, N (%)	110 (27.7)	66 (16.8)
p-valuea*	<0.0001	--
Time to castration-resistant prostate cancerb	20.2	11.7
Median (months)
95% CI	(17.2–23.6)	(10.8–14.7)
Adjusted hazard ratio	0.61	--
95% CI	(0.51–0.72)	--
p-valuea*	<0.0001	--
Time to clinical progressionc	33.0	19.8
Median (months)
95% CI	(27.3–41.2)	(17.9–22.8)
Adjusted hazard ratio	0.61	--
95% CI	(0.50–0.75)	--
p-valuea*	<0.0001	--

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

* p-value for illustrative purposes.

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

b Time to castration-resistant prostate cancer is defined as the time from randomization to PSA progression 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 occurs first.

c Time to clinical progression is defined as the 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 trial was conducted. A total of 445 patients with a Karnofsky performance status > 70 were randomized into two groups: one receiving either docetaxel (T) (75 mg/m² on day 1) in combination with cisplatin (C) (75 mg/m² on day 1) and 5-fluorouracil (F) (750 mg/m²/day for 5 days), or cisplatin (100 mg/m² on day 1) and 5-fluorouracil (1000 mg/m²/day for 5 days). The treatment cycle duration was 3 weeks in the TCF group and 4 weeks in the CF group. The median number of cycles per patient was 6 (range: 1–16) in the TCF group compared to 4 (range: 1–12) in the CF group. Time to disease progression (TTP) was the primary endpoint. 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 data are summarized in Table 9.

Table 9

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

Endpoint	TCF n = 221	CF n = 224
Median PFS (months)	5.6	3.7
(95% CI)	(4.86–5.91)	(3.45–4.47)
Hazard ratio	1.473
(95% CI)	(1.189–1.825)
* p-value	0.0004
Median survival (months)	9.2	8.6
(95% CI)	(8.38–10.58)	(7.16–9.46)
Estimated 2-year survival rate (%)	18.4	8.8
Hazard ratio	1.293
(95% CI)	(1.041–1.606)
* p-value	0.0201
Overall response rate (complete response + partial response) (%)	36.7	25.4
p-value	0.0106
Disease progression as best overall response (%)	16.7	25.9

* Unstratified log-rank test.

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

A refined analysis of survival based on further follow-up (median follow-up duration of 41.6 months) no longer demonstrated a statistically significant difference between the two study groups, although it continued to indicate advantages for the TCF regimen. The analysis showed that the benefit of TCF over CF was clearly evident during the period between 18 and 30 months of follow-up.

Overall, results of quality-of-life and clinical efficacy assessments consistently indicated improvement in the TCF group. In patients treated with the TCF regimen, there was a longer time to definitive deterioration in overall health status by 5% according to the QLQ-C30 questionnaire (p = 0.0121) and a longer time to definitive deterioration in functional status according to the Karnofsky Performance 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 for induction therapy in patients with squamous cell carcinoma of the head and neck (SCCHN) were evaluated in a multicenter, open-label, randomized Phase III trial (TAX 323). This study included 358 patients with unresectable locally advanced SCCHN and a WHO performance status of 0 or 1, who were randomized into two groups. Patients in the docetaxel treatment group received docetaxel (T) at 75 mg/m², followed by cisplatin (P) at 75 mg/m², followed by 5-fluorouracil (F) at 750 mg/m²/day as a continuous infusion over 5 days. This treatment regimen was administered every 3 weeks for 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after two cycles. Starting no less than 4 weeks and no more than 7 weeks after completion of chemotherapy, patients without evidence of disease progression received radiotherapy (RT) over 7 weeks according to institutional standards (treatment regimen TPF/RT). Patients in the control group received cisplatin (P) at 100 mg/m², followed by 5-fluorouracil (F) at 1000 mg/m²/day for 5 days. This treatment regimen was administered every 3 weeks for 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after two cycles. Starting no less than 4 weeks and no more than 7 weeks after completion of chemotherapy, patients without evidence of disease progression received radiotherapy (RT) over 7 weeks according to institutional standards (treatment regimen PF/RT). Locoregional radiotherapy was delivered using either standard fractionation (1.8–2.0 Gy once daily, 5 days per week, to a total dose of 66–70 Gy) or accelerated fractionation/hyperfractionation (twice daily with a minimum interval of 6 hours between fractions, 5 days per week). For accelerated fractionation, the recommended total dose was 70 Gy; for hyperfractionation, it was 74 Gy. Surgical resection of the tumor was permitted after chemotherapy (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 overall follow-up duration of 33.7 months. Median overall survival was also statistically significantly longer in the TPF group compared to the PF group (median OS 18.6 months vs. 14.5 months, respectively), with a 28% reduction in the 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; ITT)

Endpoint	Docetaxel + cisplatin + 5-fluorouracil n = 177	Cisplatin + 5-fluorouracil n = 181
Median progression-free survival (months) (95% CI)	11.4 (10.1–14.0)	8.3 (7.4–9.1)
Adjusted hazard ratio (95% CI) *p-value	0.70 (0.55–0.89) 0.0042
Median survival (months) (95% CI)	18.6 (15.7–24.0)	14.5 (11.6–18.7)
Hazard ratio (95% CI) **p-value	0.72 (0.56–0.93) 0.0128
Best overall response to chemotherapy (%) (95% CI)	67.8 (60.4–74.6)	53.6 (46.0–61.0)
***p-value	0.006
Best overall response to investigational treatment [chemotherapy ± radiotherapy] (%) (95% CI)	72.3 (65.1–78.8)	58.6 (51.0–65.8)
***p-value	0.006
Median duration of response to chemotherapy ± radiotherapy (months) (95% CI)	n = 128 15.7 (13.4–24.6)	n = 106 11.7 (10.2–17.4)
Hazard ratio (95% CI) **p-value	0.72 (0.52–0.99) 0.0457

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 classification parameters T and N, and WHO performance status).

** Log-rank test.

*** χ² (chi-squared) test.

Quality of life measures.

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

Clinical benefit measures.

Assessment scores for functional status (using Head and Neck-specific subscales (PSS-HN), developed to evaluate a patient's ability to be understood when speaking, ability to eat in public, and normalcy of diet) 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 satisfactory pain control.

Induction chemotherapy followed by chemoradiotherapy (TAX 324 study).

The safety and efficacy of docetaxel for induction therapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were evaluated in a randomized, multicenter, open-label Phase III trial (TAX 324). A total of 501 patients with locally advanced SCCHN and 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 surgical success, and those for whom an organ-preserving strategy was chosen. Efficacy and safety were assessed solely based on survival outcomes; organ preservation success was not formally evaluated. Patients in the docetaxel group received 75 mg/m² docetaxel (T) as a 1-hour intravenous infusion on Day 1, followed by 100 mg/m² cisplatin (P) as an intravenous infusion lasting from 30 minutes to 3 hours, then 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from Day 1 to Day 4. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received subsequent chemoradiotherapy (CRT) per protocol (TPF/CRT regimen). Patients in the control group received 100 mg/m² cisplatin (P) as an intravenous infusion lasting from 30 minutes to 3 hours on Day 1, followed by 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from Day 1 to Day 5. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received CRT per protocol (PF/CRT regimen).

Beginning no earlier than 3 weeks and no later than 8 weeks after the start of the last induction chemotherapy cycle (i.e., between Day 22 and Day 56 of the last cycle), patients in both groups were to undergo a 7-week course of CRT. During radiotherapy, carboplatin (AUC 1.5) was administered weekly as a 1-hour intravenous infusion, up to a maximum of 7 doses. Radiotherapy 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 in the neck could be recommended at any time after completion of CRT. All patients in the docetaxel group received prophylactic antibiotics.

The primary endpoint used to assess efficacy 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 30% reduction in the risk of death in the TPF group versus the PF group (hazard ratio (HR) 0.70; 95% confidence interval (CI): 0.54–0.90), based on a median follow-up time of 41.9 months (median OS: 70.6 months in the TPF group vs. 30.1 months in the PF group). Results for 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 vs. 13.1 months in the PF group). This difference was also statistically significant (HR 0.71; 95% CI: 0.56–0.90; log-rank test, p = 0.004). Efficacy results are presented in Table 11.

Table 11

Efficacy of docetaxel in induction therapy in patients with locally advanced SCCHN (analysis of all randomized patients; ITT)

Endpoint	Docetaxel + cisplatin + 5-fluorouracil n = 255	Cisplatin + 5-fluorouracil n = 246
Median overall survival (months) (95 % CI)	70.6 (49.0–NR)	30.1 (20.9–51.5)
Hazard ratio (95 % CI) *p-value	0.70 (0.54–0.90) 0.0058
Median PFS (months) (95 % CI)	35.5 (19.3–NR)	13.1 (10.6–20.2)
Hazard ratio (95 % CI) **p-value	0.71 (0.56–0.90) 0.004
Best overall response (complete response + partial response) to chemotherapy (%) (95 % CI)	71.8 (65.8–77.2)	64.2 (57.9–70.2)
***p-value	0.070
Best overall response (complete response + partial response) to investigational treatment [chemotherapy ± chemoradiotherapy] (%) (95 % CI)	76.5 (70.8–81.5)	71.5 (65.5–77.1)
***p-value	0.209

A risk ratio of less than 1 indicates a benefit in favor 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 the medicinal product DOCET for all subgroups of pediatric patients with breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma, and head and neck cancer, except for poorly differentiated nasopharyngeal carcinoma types II and III (data on use of the drug in children are provided in section "Children").

Pharmacokinetics.

Absorption. The pharmacokinetics of docetaxel were studied in phase I 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 of 4 min, 36 min, and 11.1 hours, respectively. This prolonged terminal phase half-life is partly due to relatively slow efflux from the peripheral compartment.

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

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

Special patient populations.

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

Hepatic dysfunction. In a small number of patients (n = 23) with mild to moderate liver function abnormalities based on biochemical blood tests (ALT [alanine aminotransferase] and AST [aspartate aminotransferase] 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 agents, docetaxel did not affect the clearance of doxorubicin or plasma levels of doxorubicin (and its metabolites). The pharmacokinetics of docetaxel, doxorubicin, and cyclophosphamide were not altered when administered concomitantly.

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

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

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

Preclinical safety data.

The carcinogenic potential of docetaxel has not been studied.

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

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

These results are consistent with the pharmacological activity of docetaxel.

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

Clinical characteristics.

Indications.

Breast cancer. Docet in combination with doxorubicin and cyclophosphamide is indicated for adjuvant therapy in patients with:

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

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

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

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

Docet in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer with tumor cell overexpression of HER-2 who have not previously received chemotherapy for metastases.

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

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

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

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

Gastric adenocarcinoma. Docet 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 metastases.

Head and neck cancer. Docet 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 "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 types of interactions.

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

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

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

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

Docetaxel is highly bound to plasma proteins (>95%). Although potential interactions of this drug with other medicinal products have not been formally studied in vivo, in vitro data indicate that drugs with high plasma protein binding (such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylates, sulfamethoxazole, and sodium valproate) do not impair docetaxel binding to plasma proteins. Additionally, dexamethasone does not impair docetaxel binding to plasma proteins. Docetaxel does not affect the plasma protein binding of digoxin.

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

Special precautions for use.

In patients with breast cancer or non-small cell lung cancer, in the absence of contraindications, premedication with oral corticosteroids such as dexamethasone at a dose of 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 is performed with oral dexamethasone at a dose of 8 mg 12 hours, 3 hours, and 1 hour before the start of docetaxel infusion.

Hematological changes during treatment with the medicinal product. The most common adverse reaction during docetaxel treatment 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 had previously received multiple courses 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 (see section "Dosage and administration").

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

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 must 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 administered. 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 must be closely monitored (see sections "Dosage and administration" and "Adverse reactions").

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

Hypersensitivity reactions. Patients must be carefully monitored for possible hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may develop within minutes after the start of docetaxel infusion; therefore, all necessary measures for treatment of arterial hypotension and bronchospasm should be readily available. A mild hypersensitivity reaction with minor symptoms such as flushing or localized skin reactions does not require interruption of therapy. However, severe reactions such as marked arterial hypotension, bronchospasm, or generalized rash/erythema, or in very rare cases potentially fatal anaphylaxis, require immediate discontinuation of docetaxel infusion and appropriate treatment. Re-administration of docetaxel is contraindicated in patients who have experienced a severe hypersensitivity reaction. Patients with a previous history of hypersensitivity reaction to paclitaxel may have an increased risk of hypersensitivity reaction to docetaxel, including more severe reactions. These patients should be closely monitored at the beginning of docetaxel therapy.

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

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

Fluid retention. Patients with significant fluid retention, such as pleural effusion, pericardial effusion, or ascites, should be carefully monitored.

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

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

Patients with impaired liver function. Patients with elevated transaminase levels (ALT and/or AST) more than 1.5 times the upper limit of normal (ULN) and alkaline phosphatase more than 2.5 times ULN during docetaxel monotherapy at 100 mg/m² have a higher risk of severe adverse reactions, including fatal outcomes due to toxic effects of the drug, such as sepsis and gastrointestinal bleeding, as well as febrile neutropenia, infections, thrombocytopenia, stomatitis, and asthenia. Therefore, the recommended dose of docetaxel for patients with elevated liver enzymes is 75 mg/m²; liver enzyme levels should be determined before initiation of treatment and before each new chemotherapy cycle (see section "Dosage and administration").

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

In a pivotal clinical study of docetaxel in combination with cisplatin and 5-fluorouracil in patients with gastric adenocarcinoma, elevated levels of ALT and/or AST more than 1.5 times ULN, alkaline phosphatase more than 2.5 times ULN, and bilirubin above ULN were among the exclusion criteria; therefore, dose reduction of docetaxel cannot be recommended for such patients. The medicinal product should 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 impaired liver function.

Patients with impaired renal function. There are no data on treatment with docetaxel in patients with severe renal impairment.

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

Cardiotoxicity. Cases of heart failure have been observed in patients receiving docetaxel in combination with trastuzumab, particularly if anthracyclines (doxorubicin or epirubicin) were administered in a previous chemotherapy course. This heart failure could be moderate or severe and was associated with a high risk of death (see section "Adverse reactions"). If docetaxel is to be used in combination with trastuzumab, cardiac function should be evaluated before initiation of therapy. Cardiac function should be regularly monitored during treatment with these agents (e.g., every 3 months) to identify patients who may develop cardiac dysfunction.

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

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

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

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

Other warnings. Women of childbearing potential must use contraception during treatment and for 2 months after discontinuation of docetaxel therapy. Men must use contraception during treatment and for 4 months after discontinuation of docetaxel therapy (see section "Pregnancy and breastfeeding").

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

Additional warnings for 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 (see section "Dosage and administration").

Gastrointestinal 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 symptoms of congestive heart failure during treatment and follow-up. An increased risk of CHF has been demonstrated in patients receiving TAC therapy for metastatic breast cancer during the first year after treatment (see sections "Adverse reactions" and "Pharmacodynamic properties").

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

Elderly patients.

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

Warnings for use in adjuvant therapy of breast cancer

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

Warnings for use in castration-resistant prostate cancer

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

Warnings for use in hormone-sensitive prostate cancer

Of 545 patients who received docetaxel every 3 weeks in a hormone-sensitive prostate cancer study (STAMPEDE [Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy]), 296 patients were over 65 years of age, and 48 patients were 75 years of age or older. In the majority of patients over 65 years of age in the docetaxel group, hypersensitivity reaction, neutropenia, anemia, fluid retention, dyspnea, and nail changes were reported compared to patients under 65 years of age. None of these increases in frequency reached a 10% difference compared to the control group. In patients aged 75 years or older compared to younger patients, neutropenia, anemia, diarrhea, dyspnea, and upper respiratory tract infection were reported more frequently (at least 10% more frequently).

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 a gastric cancer study, 74 patients were 65 years of age or older, and 4 patients were 75 years of age or older. The frequency of serious adverse effects was higher in elderly patients than in younger patients. In patients aged 65 years or older, adverse effects (all grades) such as 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, with a quantity of 50% of the total volume of the concentrate, i.e., up to 0.395 g (0.5 ml) per vial; in terms of alcohol content, this is equivalent to 10 ml of beer or 4 ml of wine.

The product is harmful for patients suffering from alcoholism.

The alcohol content of the medicinal product should be taken into account when prescribing it 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 product on the central nervous system should be considered.

Handling and administration of the product (special precautions for disposal of unused medicinal products or their waste). Docet belongs to antineoplastic agents and, like any other potentially toxic agent, requires adherence to safety measures when handling during solution preparation. The use of protective gloves is recommended when handling the product.

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

Preparation of solution for intravenous administration. Do not use other docetaxel medicinal products whose packaging contains 2 vials (concentrate and solvent) with this medicinal product (Docet, 20 mg/ml concentrate for infusion solution, containing only 1 vial).

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

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

If vials have been stored in a refrigerator, the required number of packages of Docet concentrate for infusion solution should be kept at room temperature up to 25°C for 5 minutes before use.

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

The concentration of docetaxel in the Docet medicinal product vial is 20 mg/ml. The required amount of Docet concentrate for infusion solution should be added as a single injection (one puncture) into a 250 ml infusion bag or vial containing 5% glucose solution or 0.9% (9 mg/ml) sodium chloride solution for injection.

If the patient requires a docetaxel dose greater than 190 mg, a larger volume of infusion solution should be used to avoid exceeding a docetaxel concentration of 0.74 mg/ml.

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

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

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

Before administration, the infusion solution of the medicinal product Docet, like all parenteral preparations, should be carefully inspected; solutions containing precipitate must not be used.

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

Unused medicinal product or waste materials must be destroyed in accordance with current regulations.

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 inform their physician immediately if pregnancy occurs.

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

Pregnancy. There are no data on the use of docetaxel in pregnant women. In animal studies, docetaxel showed embryotoxic and fetotoxic effects; in addition, the use of the drug in animals led to reduced fertility. Like other cytotoxic medicinal products, docetaxel may have harmful effects on the fetus if administered to pregnant women. Therefore, docetaxel must not be administered during pregnancy, except when there is an urgent need.

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

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

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

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

The alcohol content in this medicinal product and adverse effects 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 effect of the medicinal product on their ability to drive vehicles or operate machinery and advised not to engage in such activities if they experience the mentioned adverse effects during treatment.

Method of Administration and Dosage

The use of docetaxel should be restricted to departments specialized in cytotoxic chemotherapy. Docetaxel must be administered exclusively under the supervision of a physician experienced in anticancer chemotherapy.

Recommended Doses. For the treatment of breast cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer, premedication with oral corticosteroids such as dexamethasone at a dose of 16 mg per day (e.g., 8 mg twice daily) for 3 days may be used (unless contraindicated); the first dose should be taken one day before the first administration of docetaxel (see section "Special Instructions"). To reduce the risk of hematological toxicity associated with docetaxel, prophylactic use of granulocyte colony-stimulating factor (G-CSF) may be considered.

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

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

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

Docetaxel is administered intravenously over one hour every 3 weeks.

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

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

In combination with trastuzumab (administered weekly), docetaxel is given at the recommended dose of 100 mg/m² every 3 weeks. In the pivotal clinical trial with docetaxel, the first infusion of the drug was administered the day after the first dose of trastuzumab. Subsequently, docetaxel doses were administered immediately after completion of trastuzumab infusions, provided the patient tolerated the most recently administered trastuzumab well.

In combination with capecitabine, docetaxel is administered at the recommended dose of 75 mg/m² every 3 weeks; capecitabine is given at a dose of 1250 mg/m² twice daily (no later than 30 minutes after food intake) for 2 weeks followed by a 1-week break.

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

Prostate Cancer .

Metastatic Castration-Resistant Prostate Cancer

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

Metastatic Hormone-Sensitive Prostate Cancer

The recommended dose of docetaxel is 75 mg/m² every 3 weeks for 6 cycles. Prednisone or prednisolone may be taken continuously at 5 mg orally twice daily.

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

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

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

Dose Modifications During Treatment .

General Principles. Docetaxel should be administered only if the neutrophil count is ≥1500 cells/mm³. If febrile neutropenia develops during docetaxel therapy, or if the neutrophil count is <500 cells/mm³ for more than one week, or if severe acute or progressively worsening cumulative skin reactions occur, or if severe peripheral neuropathy develops, the dose of docetaxel should be reduced from 100 to 75 mg/m² and/or from 75 to 60 mg/m². If such reactions occur even at the 60 mg/m² dose, the drug should be discontinued.

Adjuvant Therapy of Breast Cancer. For patients receiving adjuvant therapy with docetaxel, doxorubicin, and cyclophosphamide (TAC regimen), primary prophylaxis with G-CSF should be considered. Patients who develop febrile neutropenia and/or neutropenic infection should have the docetaxel dose reduced to 60 mg/m² in all subsequent treatment cycles (see sections "Special Instructions" and "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 course of docetaxel 75 mg/m² in combination with cisplatin, experienced a nadir platelet count <25,000 cells/mm³, for patients who developed febrile neutropenia during docetaxel therapy, and for patients who experienced severe non-hematological toxicities, the docetaxel dose should be reduced to 65 mg/m² in subsequent cycles.

In Combination with Capecitabine.

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

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

Table 12

Recommended Dose Modification Measures for Patients Receiving the Combination of Docetaxel, Cisplatin, and 5-Fluorouracil

Toxicity manifestations	Dose adjustments
Grade III diarrhea	First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: reduce the dose of docetaxel by 20%.
Grade IV diarrhea	First episode: reduce the doses of docetaxel and 5-fluorouracil by 20%. Second episode: discontinue treatment.
Stomatitis or other mucosal inflammation of Grade III severity	First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: discontinue 5-fluorouracil in all subsequent treatment cycles. Third episode: reduce the dose of docetaxel by 20%.
Stomatitis or other mucosal inflammation of Grade IV severity	First episode: discontinue 5-fluorouracil in all subsequent treatment cycles. Second episode: reduce the dose of docetaxel by 20%.

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

Special patient groups.

Patients with hepatic impairment. According to pharmacokinetic data from monotherapy studies with docetaxel at a dose of 100 mg/m², the recommended dose of docetaxel for patients with elevated levels of transaminases (ALT and/or AST) >1.5 times the upper limit of normal (ULN) and alkaline phosphatase >2.5 times ULN is 75 mg/m². For patients with increased serum bilirubin (>ULN) and/or ALT and AST >3.5 times ULN, accompanied by elevated alkaline phosphatase >6 times ULN, dose reduction is not recommended; however, docetaxel should not be administered at all unless there is an urgent clinical need.

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

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

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

When docetaxel is used in combination with capecitabine, a reduction of the initial capecitabine dose to 75% is recommended for patients aged 60 years and older.

Children.

Docet 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 the medicinal product Docet in pediatric patients have not been obtained.

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

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

Overdose. There have been several reports of cases of overdose with the medicinal product. There is currently no specific antidote for docetaxel. In the event of overdose, the patient should be hospitalized in a specialized unit and closely monitored for vital functions. An exacerbation of the drug's adverse effects should be expected. Primarily, complications such as bone marrow suppression, peripheral neurotoxicity, and mucosal inflammation are anticipated. As soon as an overdose is confirmed, therapeutic doses of G-CSF should be administered to the patient as soon as possible. Other necessary symptomatic measures should be applied if needed.

Adverse Reactions

Summary of safety profile data across all indications. Data on adverse reactions considered probably 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 from 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), COSTART (Coding Symbols for Thesaurus of Adverse Reaction Terms), and MedDRA (Medical Dictionary for Regulatory Activities) terminology.

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

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

The most common adverse reactions observed with docetaxel monotherapy include neutropenia (reversible and noncumulative; median time to nadir of neutrophil count is 7 days; median duration of severe neutropenia [< 500 cells/mm³] is 7 days), anemia, alopecia, nausea, vomiting, stomatitis, diarrhea, and asthenia. The severity of adverse effects may increase when docetaxel 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 previously treated with anthracyclines are detailed in the "General Characteristics" section of the capecitabine product information.

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

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

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

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

Skin and subcutaneous tissue disorders. Reversible skin reactions, usually mild or moderate in severity, were observed. These 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. Rarely, severe manifestations occurred, such as rash with subsequent epithelial desquamation, sometimes necessitating interruption or complete discontinuation of docetaxel (see sections "Dosage and administration" and "Special precautions"). Severe nail disorders included hypo- or hyperpigmentation, and in some cases pain and onycholysis.

General disorders and administration site conditions. Infusion site reactions were predominantly mild and included hyperpigmentation, inflammation, erythema, skin dryness, phlebitis, extravasation, and venous swelling at the infusion site.

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

Adverse reactions observed in patients with breast cancer treated with Docect® as monotherapy at a dose of 100 mg/m²

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

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

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

Metabolic and nutritional disorders. Very common: anorexia.

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

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

Vascular disorders. Common: 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 (G3/4: < 5%); increased alkaline phosphatase (G3/4: < 4%); increased AST (G3/4: < 3%); increased ALT (G3/4: < 2%).

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

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

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

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

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

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

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

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

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

Metabolic and nutritional disorders. Common: anorexia.

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

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

Vascular disorders. Common: arterial hypotension.

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

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

Musculoskeletal and connective tissue disorders. Common: myalgia.

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

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

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

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

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

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

Metabolic and nutritional disorders. Common: anorexia.

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

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

Vascular disorders. Uncommon: 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 (G3/4: < 2.5%); increased alkaline phosphatase (G3/4: < 2.5%). Uncommon: increased AST (G3/4: < 1%); increased ALT (G3/4: < 1%).

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

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

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

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

Metabolic and nutritional disorders. Very common: anorexia.

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

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

Vascular disorders. Common: 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 (G3/4: 2.1%); increased ALT (G3/4: 1.3%). Uncommon: increased AST (G3/4: 0.5%); increased alkaline phosphatase (G3/4: 0.3%).

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

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

Metabolic and nutritional disorders. Very common: anorexia.

Psychiatric disorders. Very common: insomnia.

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

Cardiac disorders. Common: heart failure.

Eye disorders. Very common: increased lacrimation; conjunctivitis.

Vascular disorders. Very common: lymphedema.

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

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

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

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

General disorders and administration site 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 observed in patients with breast cancer treated with Docect® at a dose of 100 mg/m² in combination with trastuzumab.

Blood and lymphatic system disorders. Very common: hematologic toxicity of combination therapy with trastuzumab and docetaxel increased compared to docetaxel monotherapy (32% incidence 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 incidence of febrile neutropenia or neutropenic sepsis also increases in patients receiving the combination of trastuzumab and docetaxel (23% vs. 17% compared to docetaxel monotherapy).

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

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

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

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

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

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

Eye disorders. Very common: increased lacrimation.

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

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

Skin and subcutaneous tissue disorders. Very common: 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/general weakness (G3/4: 5%); peripheral edema (G3/4: 1%). Common: lethargy; pain.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Description of adverse reactions observed in patients with locally advanced or metastatic hormone-sensitive prostate cancer at high risk treated with Docect® 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%), headache. Common: dizziness.

Eye disorders. Common: blurred vision.

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

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

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

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

Musculoskeletal and connective tissue disorders. Very common: myalgia.

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

Adverse reactions observed with Docect® at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with breast cancer with or without lymph node metastases (TAX 316 and GEICAM 9805 studies) — pooled data

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

Blood and lymphatic system disorders. Very common: anemia (G3/4: 3%); neutropenia (G3/4: 59.2%); thrombocytopenia (G3/4: 1.6%); febrile neutropenia (G3/4: NC).

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

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

Nervous system disorders. Very common: dysgeusia (G3/4: 0.6%); peripheral sensory neuropathy (G3/4: < 0.1%). Common: peripheral motor neuropathy (G3/4: 0%). Uncommon: syncope (G3/4: 0%); neurotoxicity 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: NC); peripheral edema (G3/4: 0.2%).

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

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

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

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

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

Cardiac disorders. In the 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, during the follow-up period, congestive heart failure developed 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 treatment and persisted during follow-up was observed in 49 patients (9.2%) in the TAC group and in 35 patients (6.7%) in the FAC group. Alopecia related to 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%)

Complications	Without primary prophylaxis with G-CSF (n = 111) n (%)	With primary prophylaxis with G-CSF (n = 421) n (%)
Neutropenia (Grade IV)	104 (93.7)	135 (32.1)
Febrile neutropenia	28 (25.2)	23 (5.5)
Neutropenic infection	14 (12.6)	21 (5.0)
Neutropenic infection (Grade III–IV)	2 (1.8)	5 (1.2)

Adverse reactions observed in patients with gastric adenocarcinoma treated with docetaxel 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 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 granulocyte colony-stimulating factor (G-CSF) was administered. G-CSF was used for secondary prophylaxis in 19.3% of patients (10.7% of all chemotherapy cycles). Febrile neutropenia and neutropenic infections occurred in 12.1% and 3.4% of patients receiving G-CSF, and in 15.6% and 12.9% of patients who did not receive G-CSF prophylaxis (see section "Dosage and administration").

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

Induction chemotherapy followed by radiotherapy (TAX 323 study)

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

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

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

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

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 (TAX 324 study)

Infections and parasitic diseases. Very common: infections (G3/4: 3.6%). Common: neutropenic infections. Benign, malignant and unspecified neoplasms (including cysts and polyps). Common: pain due to malignant tumor (G3/4: 1.2%).

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

Immune system disorders. Uncommon: hypersensitivity reactions.

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

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

Immune system disorders. Several cases of anaphylactic shock, sometimes fatal, have been reported. 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 were sometimes observed during infusion.

Eye disorders. Very rare transient visual disturbances (flashes, flickering lights, scotomata) have been reported, typically occurring during infusion and often associated with hypersensitivity reactions. These disorders resolved spontaneously after discontinuation of infusion. Rare cases of conjunctivitis, with or without associated lacrimal duct obstruction leading to increased lacrimation, have been reported.

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

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

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

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

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

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

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

Rare cases of dehydration secondary to gastrointestinal disorders, including enterocolitis and gastrointestinal perforation, have been reported. Rare cases of intestinal obstruction and bowel obstruction have also been reported.

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

Renal and urinary disorders. Cases of renal dysfunction and renal failure have been reported. In approximately 20% of these cases, no risk factors for acute renal failure (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 following docetaxel administration. In some cases, these adverse events may have been influenced by concomitant factors. Cases of scleroderma-like skin lesions, typically preceded by peripheral lymphedema, have also been reported. Cases of persistent alopecia (frequency unknown) have been reported.

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

Cases of recurrent injection site reaction (recurrence of skin reaction at a site of previous 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 have been reported. Hyponatremia, mainly associated with dehydration, vomiting, and pneumonia, has been reported. Hypokalemia, hypomagnesemia, and hypocalcemia were observed, typically in the context of gastrointestinal disorders, especially diarrhea. Tumor lysis syndrome, potentially fatal (frequency unknown), has been reported.

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

Reporting of adverse reactions.

Reporting of adverse reactions after marketing 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 2–8 °C. Keep out of the reach of children.

Incompatibilities. Do not use with other solutions except those specified in the section "Dosage and administration".

Packaging. 0.5 mL of concentrate in a vial and 1.5 mL of solvent in a vial, packed in a cardboard box; 2 mL of concentrate in a vial and 6 mL of solvent in a vial, packed in a cardboard box; 3 mL of concentrate in a vial and 9 mL of solvent in a vial, packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Venus Remedies Limited.

Manufacturer's address and site of operations. Hill Top Industrial Estate, Jarmajri, EPIP Phase-I (Ext.), Baddi, Solan District, Himachal Pradesh 173205, India.