Docetaxel accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOCETAXEL ACCORD

Composition:

Active substance: docetaxel;

1 ml of concentrate for infusion solution contains 20 mg of docetaxel;

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear solution, pale yellow to brownish-yellow in color, practically free from mechanical particles.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

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

Pharmacodynamic effects

Clonogenic analysis in vitro has shown cytotoxicity of docetaxel against various murine and human tumor cell lines, as well as against freshly isolated human tumor cells. Docetaxel achieves significant concentrations in the extracellular fluid and provides high cell survival duration. Furthermore, docetaxel exhibits activity against some (although not all) cell lines expressing P-glycoprotein encoded by the multidrug resistance gene. In vivo studies have shown that the effect of docetaxel is independent of the administration schedule and demonstrates broad-spectrum antitumor activity in experimental models against both murine tumors and transplanted human tumors.

Clinical efficacy and safety

Breast cancer

Docetaxel in combination with doxorubicin and cyclophosphamide: adjuvant therapy

Patients with operable breast cancer with lymph node involvement (TAX 316)

Data from a multicenter, open-label, randomized study support the use of docetaxel in adjuvant therapy for women aged 18 to 70 years with operable breast cancer with lymph node metastases and a Karnofsky Performance Status (KPS) ≥ 80%. After stratification according to the number of involved lymph nodes (1–3, 4+), 1491 patients were randomized into two groups: 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 once every 3 weeks for 6 cycles. Docetaxel was given as a 1-hour infusion, and all other drugs were administered intravenously as bolus injections on day 1. Granulocyte colony-stimulating factor (G-CSF) was used as secondary prophylaxis in patients who experienced complicated neutropenia (febrile neutropenia, prolonged neutropenia, or infection). Patients in the TAC group received antibiotic prophylaxis with ciprofloxacin 500 mg orally twice daily for 10 days, starting on day 5 of each cycle, or an equivalent regimen. After completion of the last chemotherapy cycle, patients in both groups with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for 5 years. Adjuvant radiotherapy was administered according to institutional guidelines and was given to 69% of patients in the TAC group and 72% of patients in the FAC group.

Two interim analyses and one final analysis were conducted. The first interim analysis was planned after 3 years from the date when half of the patients were enrolled. The second interim analysis was performed after 400 events of disease-free survival (DFS) were recorded, resulting in a median follow-up period of 55 months. The final analysis was conducted when all patients reached their 10-year follow-up (unless they had a DFS event or were lost to follow-up earlier). Disease-free survival (DFS) was the primary efficacy endpoint, and overall survival (OS) was the secondary efficacy endpoint.

The final analysis was performed with an actual median follow-up of 96 months. Significantly longer DFS was demonstrated in the TAC group compared to the FAC group. The 10-year recurrence rate was reduced in patients receiving TAC compared to those receiving FAC (39% vs. 45%, respectively), representing an absolute risk reduction of 6% (p = 0.0043). Overall survival at 10 years was also significantly improved with TAC compared to FAC (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 final analysis did not fully demonstrate a favorable benefit-risk ratio of the TAC regimen in patients with metastases in 4 or more lymph nodes.

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

Subgroup analyses were performed in patients receiving TAC according to prospectively defined key prognostic factors.

Table 1

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

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

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

Patients with operable breast cancer without lymph node metastases eligible for chemotherapy (GEICAM 9805)

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

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

With a median follow-up of 77 months, recurrence-free survival (RFS) 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 (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 (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 TAC group patients compared to FAC group patients (HR 0.76, 95% CI: 0.46–1.26, p = 0.29). However, the difference in OS between the two groups was not statistically significant.

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

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

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

In the primary analysis (with median follow-up of 77 months), predefined subgroups of patients treated with 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 breast cancer without lymph node metastases treated with the TAC regimen (analysis of data from all randomized patients; Intent-to-Treat) (GEICAM 9805 study)

		Recurrence-free survival
Patient subgroup	Number of patients in TAC group	Hazard ratio (HR)*	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
Histological grade
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 use of the TAC regimen was associated with longer recurrence-free survival compared to the use of the FAC regimen.

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

Table 3

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

Subgroups	TAC (n=539)	FAC (n=521)	Relative risk (TAC/FAC) (95 % CI)	p
Compliance with relative indication for chemotherapya
Yes	18/214 (8.4 %)	26/227 (11.5 %)	0.796 (0.434 – 1.459)	0.4593
No	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 receptor.

PR = progesterone receptor.

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

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

Docetaxel as monotherapy

Two randomized, comparative phase III studies were conducted in patients with metastatic breast cancer—326 patients who had failed prior alkylating agent therapy and 392 patients who had failed prior anthracycline therapy—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 overall survival was not affected (median duration 15 months in the docetaxel group versus 14 months in the doxorubicin group, p = 0.38) nor 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). The drug was discontinued due to fluid retention in 3 patients (2%) receiving docetaxel, and in 15 patients (9%) receiving doxorubicin due to cardiotoxicity (3 cases of congestive heart failure with fatal outcome).

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

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

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

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

The incidence of grade III/IV adverse reactions was higher in the docetaxel monotherapy group (55.4%) compared to the paclitaxel group (23.0%).

Docetaxel in combination with doxorubicin

One large randomized phase III study was conducted in 429 patients with metastatic disease who had not received prior therapy, comparing doxorubicin (50 mg/m²) in combination with docetaxel (75 mg/m²) (AT group) versus doxorubicin (60 mg/m²) in combination with cyclophosphamide (600 mg/m²) (AC group). Both regimens were administered on day 1 every 3 weeks.

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

In this study, the AT group had higher incidences of severe neutropenia (90% versus 68.6%), febrile neutropenia (33.3% versus 10%), infections (8% versus 2.4%), diarrhea (7.5% versus 1.4%), asthenia (8.5% versus 2.4%), and pain (2.8% versus 0%) compared to the AC group. Conversely, the AC group had higher rates of severe anemia (15.8% versus 8.5%) and higher rates 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%). Treatment-related deaths occurred in 1 patient in the AT group (due to congestive heart failure) and in 4 patients in the AC group (1 due to septic shock, 3 due to congestive heart failure).

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

Docetaxel in combination with trastuzumab

Docetaxel in combination with trastuzumab was studied in the treatment of patients with metastatic breast cancer whose tumors 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 the patients enrolled had HER2 overexpression at IHC 3+ and/or positive FISH results. Efficacy data are summarized in Table 4.

Table 4

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

Parameter	Docetaxel plus 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‑ne)	22.12 (17.6‑28.9)

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

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

2Calculated median survival.

Docetaxel in combination with capecitabine

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

Non-small cell lung cancer

Patients previously treated with chemotherapy with or without radiotherapy

In a Phase III trial involving patients previously treated for their disease, time to disease progression (12.3 weeks vs. 7 weeks) and overall survival in patients receiving docetaxel at a dose of 75 mg/m² were statistically significantly higher than in patients 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 disease-related symptoms (p = 0.06), and radiotherapy (p < 0.01).

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

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

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

	TCis (n = 408)	VCis (n = 404)	Statistical analysis
Overall survival (primary endpoint): median survival (months) 1-year survival (%) 2-year survival (%)	11.3 46 21	10.1 41 14	Hazard ratio: 1.122 [97.2 % CI: 0.937; 1.342]* Treatment group difference: 5.4 % [95 % CI: -1.1; 12.0] Treatment group difference: 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	Treatment group difference: 7.1 % [95 % CI: 0.7; 13.5]

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

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

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

Prostate cancer

Metastatic castration-resistant prostate cancer

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

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

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

Patients receiving docetaxel every 3 weeks showed a statistically significant improvement in overall survival compared to those receiving mitoxantrone. The increase in survival among patients receiving weekly docetaxel was not statistically significant compared to the control group receiving mitoxantrone. Efficacy endpoints for the docetaxel treatment groups compared to the control group are summarized in Table 6.

Table 6

Efficacy results 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) -- -- --
Response rate based on PSA level** (%) 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 = 0.0175.

**PSA – prostate-specific antigen.

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

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

Metastatic hormone-sensitive prostate cancer

STAMPEDE study

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

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

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

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

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

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

Table 7

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

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

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

bFailure-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 in level due to chemotherapy] within 24 weeks and above 4 ng/mL, confirmed by repeat testing or treatment); disease progression: local progression (lymph nodes) or detection of distant metastases; skeletal event or death from prostate cancer.

CHAARTED Study

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

• ADT + docetaxel 75 mg/m² at the start of ADT, every 3 weeks for 6 cycles.
• ADT alone.

Median overall survival was significantly longer in the docetaxel treatment group compared to the group receiving ADT as monotherapy, with median overall survival being 13.6 months longer when docetaxel was added to ADT (HR = 0.61, 95% 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 alone
Number of patients Median overall survival (months) All patients 95% CI Adjusted hazard ratio	397 57.6 49.1–72.8 0.61	393 44.0 34.4–49.1 --
95% CI	(0.47–0.80)	--
p-valuea	0.0003	--
Progression-free survival Median (months) 95% CI Adjusted hazard ratio 95% CI p-value*	19.8 16.7–22.8 0.60 0.51–0.72 p < 0.0001	11.6 10.8–14.3 -- -- --
PSA response** at 6 months, N (%) p-valuea*	127 (32.0) < 0.0001	77 (19.6) --
PSA response** at 12 months, N (%) p-valuea*	110 (27.7) < 0.0001	66 (16.8) --
Time to castration-resistant prostate cancerb
Median (months) 95% CI Adjusted hazard ratio	20.2 (17.2–23.6) 0.61	11.7 (10.8–14.7) --
95% CI	(0.51–0.72)	--
p-valuea*	< 0.0001	--
Time to clinical progressionc
Median (months)	33.0	19.8
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	--

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

*p-value for illustrative purposes.

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

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

cTime to clinical progression = time from randomization to clinical progression (i.e., worsening of bone metastasis symptoms, progression per RECIST, or clinical deterioration due to cancer as assessed by the investigator).

Gastric adenocarcinoma

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

Table 9

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

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

*Non-stratified log-rank test.

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

An updated survival analysis based on further follow-up (median follow-up duration of 41.6 months) no longer demonstrated a statistically significant difference between the two treatment groups, although it continued to indicate benefits in favor of the TCF regimen, showing a clear advantage of TCF over CF during the period between 18 and 30 months of follow-up.

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

Head and neck cancer

• Induction chemotherapy followed by radiotherapy (TAX 323 study)

The safety and efficacy of docetaxel in induction therapy for patients with squamous cell carcinoma of the head and neck (SCCHN) were evaluated in a multicenter, open-label, randomized Phase III trial (TAX 323). This study enrolled 358 patients with unresectable locally advanced SCCHN and 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, and then 5-fluorouracil (F) at 750 mg/m²/day administered as a continuous infusion over 5 days. This regimen was repeated every 3 weeks for up to 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after 2 cycles. Four to seven weeks after completion of chemotherapy, patients without 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 regimen was repeated every 3 weeks for up to 4 cycles, provided at least a minor response (≥25% reduction in tumor size in two dimensions) was observed after 2 cycles. Four to seven weeks after completion of chemotherapy, patients without 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 (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 than in the PF group; p = 0.0042 (median PFS 11.4 months versus 8.3 months, respectively), with a median follow-up duration of 33.7 months. Median overall survival (OS) was also statistically significantly longer in the TPF group compared to the PF group (median OS 18.6 months versus 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; Intent-to-Treat)

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

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

*Cox model (adjusted for primary tumor site, tumor clinical stage according to TNM T and N parameters, 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 overall health status scale compared to patients treated with the PF regimen (p = 0.01, using the EORTC QLQ-C30 scale).

Clinical benefit measures

Assessment of functional status (using Head and Neck Patient Satisfaction Scale (PSS-HN), developed to evaluate patients' speech intelligibility, ability to eat in public, and dietary normality) demonstrated a statistically significant advantage of the TPF regimen over the PF regimen.

The median time to first deterioration in WHO performance status was statistically significantly longer in the TPF group than in the PF group. In both groups, pain intensity improved during treatment, indicating adequate pain control.

• Induction chemotherapy followed by chemoradiotherapy (TAX 324 study)

The safety and efficacy of docetaxel 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 323). This study included 501 patients with locally advanced SCCHN and a WHO performance status of 0 or 1, who were randomized into two groups. The study population included patients with technically unresectable tumors, those with a low likelihood of benefit from surgery, and those for whom an organ-preserving strategy was chosen. Efficacy and safety were assessed solely based on survival outcomes, with organ preservation success not formally evaluated. Patients in the docetaxel group received 75 mg/m² docetaxel (T) as a 1-hour intravenous infusion on day 1, followed by 100 mg/m² cisplatin (P) as an intravenous infusion lasting 30 minutes to 3 hours, then 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from day 1 to day 4. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received subsequent chemoradiotherapy (CRT) per protocol (TPF/CRT regimen). Patients in the control group received 100 mg/m² cisplatin (P) as an intravenous infusion lasting 30 minutes to 3 hours on day 1, followed by 5-fluorouracil (F) at 1000 mg/m²/day as a continuous intravenous infusion from day 1 to day 5. These cycles were repeated every 3 weeks for a total of 3 cycles. All patients without disease progression received subsequent chemoradiotherapy (CRT) per protocol (PF/CRT regimen).

Within no less than 3 weeks and no more than 8 weeks after the start of the last induction chemotherapy cycle (days 22–56 of the last cycle), patients in both groups underwent a 7-week course of CRT. During radiotherapy, carboplatin (AUC 1.5) was administered weekly as a 1-hour intravenous infusion, up to a maximum of 7 doses. Radiation was delivered using megavoltage equipment at 2 Gy per fraction, once daily, 5 days per week for 7 weeks, to a total cumulative dose of 70–72 Gy. Surgical intervention at the primary tumor site and/or neck region could be recommended at any time after completion of CRT. All patients in the docetaxel group received prophylactic antibiotics. The primary endpoint used to assess efficacy in this study was overall survival (OS), which was statistically significantly longer in the docetaxel group compared to the PF group (log-rank test, p = 0.0058), with a median OS of 70.6 months versus 30.1 months, respectively, representing a 30% reduction in the risk of death in the TPF group compared to the PF group (HR 0.70; 95% CI: 0.54–0.90), with a median follow-up duration of 41.9 months. 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 versus 13.1 months in the PF group). This difference was also statistically significant (HR 0.71; 95% CI: 0.56–0.90; log-rank test, p = 0.004). Efficacy results are presented in Table 11.

Table 11

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

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

A risk ratio of less than 1 indicates in favor of using 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.

NR – not relevant.

Pediatric patient population

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

Pharmacokinetics.

Absorption. The pharmacokinetics of docetaxel were studied in phase I trials in cancer patients after administration of 20–115 mg/m² of the drug. The pharmacokinetic profile of docetaxel is dose-independent and corresponds to a three-compartment pharmacokinetic model with half-life periods for the α-, β-, and γ-phases of 4 min, 36 min, 11.1 hours, and 17.5 hours, respectively, when samples are collected up to 24 hours. In an additional study evaluating the pharmacokinetics of docetaxel at similar doses (75–100 mg/m²) in patients but over a longer time interval (over 22 days), a longer mean terminal half-life ranging from 91 to 120 hours was observed. This duration in the final phase is partially due to relatively slow efflux from the peripheral compartment.

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

Elimination. A study using radiolabeled 14C-docetaxel was conducted in three cancer patients. After oxidative metabolism of the tert-butyl ether 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 radioactivity. Approximately 80% of the isotope present in feces was excreted within the first 48 hours as one major inactive metabolite, three minor metabolites, and a very small amount of unchanged drug.

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

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

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

Combination therapy

Doxorubicin

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

Capecitabine

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

Cisplatin

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

Cisplatin and 5-fluorouracil

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

Prednisone and dexamethasone

The effect of prednisone on the pharmacokinetics of docetaxel after standard premedication with dexamethasone was studied in 42 patients.

Prednisone

No effect of prednisone on the pharmacokinetics of docetaxel was observed.

Preclinical safety data

The carcinogenic potential of docetaxel has not been studied.

Docetaxel has been shown to be genotoxic via an aneugenic mechanism in the in vitro micronucleus and chromosomal aberration tests in CHO-K1 cells and in the in vivo micronucleus test in mice. However, it did not induce mutagenicity in the Ames test or in the CHO/HGPRT gene mutation assay.

These results are consistent with the pharmacological activity of docetaxel.

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

Clinical characteristics.

Indications.

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

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

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

Docetaxel Accord 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.

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

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

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

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

Docetaxel in combination with cisplatin is indicated for the treatment of patients with inoperable, locally advanced or metastatic non-small cell lung cancer if prior chemotherapy for this condition has not been administered.

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

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

Head and neck cancer. Docetaxel Accord 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 of the medicinal product. Baseline neutrophil count < 1500 cells/mm³. Severe hepatic impairment (see sections "Special warnings and precautions for use" and "Dosage and administration").

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

Interaction with other medicinal products and other forms of interaction.

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

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

When used in combination with CYP3A4 inhibitors, the frequency of docetaxel adverse reactions may increase due to reduced metabolism. If co-administration of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) cannot be avoided, careful clinical monitoring and dose adjustment of docetaxel during treatment with strong CYP3A4 inhibitors are recommended (see section "Special warnings and precautions for use"). 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 in the presence 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 the binding of docetaxel to plasma proteins. In addition, dexamethasone does not impair the binding of docetaxel to plasma proteins. Docetaxel does not affect the plasma protein binding of digoxin.

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

Special precautions for use.

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

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

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

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

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

Gastrointestinal reactions. Caution is recommended in patients with neutropenia, particularly those at increased risk of gastrointestinal complications. Although most cases occurred during the first or second chemotherapy cycle with docetaxel, enterocolitis may develop at any time and may be fatal within the first 24 hours of onset. Patients should be carefully monitored for early signs of serious gastrointestinal toxicities (see sections "Special precautions for use", "Dosage and administration", and "Adverse reactions").

Hypersensitivity reactions. Patients should be carefully monitored for possible hypersensitivity reactions, particularly during the first and second infusions. Hypersensitivity reactions may occur within minutes after the start of docetaxel infusion; therefore, appropriate measures for treating hypotension and bronchospasm should be readily available. Mild hypersensitivity reactions, such as flushing or localized skin reactions, do not require interruption of therapy. However, severe reactions such as marked hypotension, bronchospasm, or generalized rash/erythema, and very rarely anaphylaxis with fatal outcome, require immediate discontinuation of docetaxel and initiation of appropriate treatment. Re-administration of docetaxel is contraindicated in patients who have experienced a severe hypersensitivity reaction. Patients with a prior history of hypersensitivity reaction to paclitaxel may have an increased risk of hypersensitivity reaction to docetaxel, including more severe reactions. These patients should be closely monitored at the beginning of docetaxel therapy.

Skin reactions. Cases of localized erythema of the skin of the extremities (on palms and soles), accompanied by edema and subsequent desquamation of the epithelium, have been observed. Severe symptoms, such as widespread skin rashes with subsequent desquamation of the epithelium, have also been reported, necessitating interruption or permanent discontinuation of docetaxel therapy.

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

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

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

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

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

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

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

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

Neurotoxicity. The occurrence of severe peripheral neurotoxic effects requires dose reduction of the drug (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 prior chemotherapy regimen. This heart failure may be moderate or severe and is associated with a high risk of fatal outcome. If docetaxel is to be used in combination with trastuzumab, cardiac function should be evaluated before initiation of therapy. Cardiac function should be monitored regularly during treatment (e.g., every 3 months) to identify patients who may develop cardiac dysfunction. Further information is provided in the "General characteristics" section of trastuzumab.

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

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

Secondary malignancies. Secondary malignancies have been reported with docetaxel in combination with other antineoplastic agents known to cause secondary malignancies. Secondary malignancies (including acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma) may develop several months or years after discontinuation of therapy including docetaxel. Patients should be carefully monitored for secondary malignancies (see section "Adverse reactions").

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

Other warnings. Women of reproductive age should use contraception during treatment and for 2 months after discontinuation of docetaxel therapy. Men should use contraception during treatment and for 4 months after discontinuation of docetaxel therapy (see section "Use during pregnancy or breastfeeding").

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

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

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

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

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

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

Elderly patients

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

Warnings for use in adjuvant therapy of breast cancer

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

Warnings for use in castration-resistant prostate cancer

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

Warnings for use in hormone-sensitive prostate cancer

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

Warnings for use in gastric adenocarcinoma

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

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

Warnings regarding excipients

The medicinal product Docetaxel Accord 20 mg/1 ml concentrate contains 50% of the total concentrate volume as anhydrous ethanol (alcohol), i.e., up to 395 mg of anhydrous ethanol per vial, equivalent to 10 ml of beer or 4 ml of wine.

The medicinal product Docetaxel Accord 80 mg/4 ml concentrate contains 50% of the total concentrate volume as anhydrous ethanol (alcohol), i.e., up to 1.58 g of anhydrous ethanol per vial, equivalent to 40 ml of beer or 16 ml of wine.

The medicinal product Docetaxel Accord 160 mg/8 ml concentrate contains 50% of the total concentrate volume as anhydrous ethanol (alcohol), i.e., up to 3.16 g of anhydrous ethanol per vial, equivalent to 79 ml of beer or 32 ml of wine.

The product is harmful for patients suffering from alcoholism.

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

The potential impact of the product on the central nervous system should be taken into account.

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

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

Preparation of solution for intravenous administration. Do not use other docetaxel products containing two vials (concentrate and solvent) with this product (Docetaxel Accord, 20 mg/ml concentrate for preparation of infusion solution, containing only one vial).

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

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

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

The vial of Docetaxel Accord, 20 mg/ml, contains docetaxel at a concentration of 20 mg/ml. The required amount of Docetaxel Accord concentrate should be added to a 250 ml bag or infusion vial containing 5% glucose solution or 0.9% sodium chloride solution (9 mg/ml) for injection.

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

The bag or vial containing the infusion solution should be gently shaken to ensure thorough mixing with the added concentrate.

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

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

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

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

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

Use during pregnancy or breastfeeding.

Women of reproductive age/contraception in men and women

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

Due to the genotoxic risk of docetaxel (see section "Preclinical safety data"), women of reproductive age should use effective contraception during treatment and for 2 months after discontinuation of docetaxel therapy. Men should use effective contraception 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. Like other cytotoxic medicinal products, docetaxel may cause harm to the fetus if administered during pregnancy. Therefore, docetaxel should not be administered during pregnancy, except when there is a compelling need.

Breastfeeding period

Docetaxel is a lipophilic substance, but it is unknown whether it penetrates into breast milk. Considering the risk of adverse reactions 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"). Therefore, men receiving docetaxel should seek consultation regarding sperm cryopreservation before initiation of therapy.

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

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

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

Administration and Dosage

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

Dosing Regimen. For the treatment of breast cancer, non-small cell lung cancer, gastric cancer, and head and neck cancer, premedication with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days may be used (if not contraindicated); the first dose should be taken one day before the first administration of docetaxel (see section "Special Instructions"). To reduce the risk of hematological toxicity associated with docetaxel, prophylactic administration of granulocyte colony-stimulating factor (G-CSF) may be considered.

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

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

To reduce the risk of hematological toxicity associated with docetaxel, prophylactic administration of G-CSF may be considered.

Docetaxel is administered intravenously over one hour every 3 weeks.

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

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

In combination with trastuzumab (administered weekly), docetaxel is given at the recommended dose of 100 mg/m² every 3 weeks. In the pivotal clinical trial of docetaxel, the first infusion of the drug was administered the day after the first dose of trastuzumab. Subsequently, doses of docetaxel were given immediately after completion of trastuzumab infusion, provided the patient tolerated the most recently administered trastuzumab well. Specific dosing and administration instructions for trastuzumab are provided in the "Summary of Product Characteristics" for trastuzumab.

In combination with capecitabine, docetaxel is administered at the recommended dose of 75 mg/m² every 3 weeks; capecitabine is administered at a dose of 1250 mg/m² twice daily (no later than 30 minutes after food) for 2 weeks followed by a 1-week break. Specific instructions for dose calculation of capecitabine according to body surface area are provided in the "Summary of Product Characteristics" for capecitabine.

Non-Small Cell Lung Cancer. For the treatment of patients with non-small cell lung cancer who have not previously received chemotherapy, docetaxel is recommended at a dose of 75 mg/m², followed immediately by cisplatin 75 mg/m² administered over 30–60 minutes. For the treatment of patients who have previously received platinum-based chemotherapy that proved ineffective, 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. Concurrently, prednisone or prednisolone should be administered continuously at 5 mg orally twice daily (see section "Pharmacodynamics").

Metastatic Hormone-Sensitive Prostate Cancer

The recommended dose of docetaxel is 75 mg/m² every 3 weeks for 6 cycles. Prednisone or prednisolone may be administered 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, a 5-fluorouracil infusion (750 mg/m²/day) is initiated and continued continuously for 5 days. This cycle is repeated every 3 weeks. Patients should receive premedication with antiemetic agents and appropriate hydration (adequate fluid intake) during cisplatin administration. To reduce the risk of hematological toxicity associated with chemotherapy, prophylactic administration of G-CSF is required (see also subsection "Dose Adjustment During Treatment").

Head and Neck Cancer. Patients should receive premedication with antiemetic agents and appropriate hydration (before and after cisplatin administration). To reduce the risk of hematological toxicity associated with chemotherapy, prophylactic administration of G-CSF may be considered. All patients enrolled in clinical trials TAX 323 and TAX 324 who received docetaxel were administered 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, a 5-fluorouracil infusion (750 mg/m²/day) is initiated and continued continuously 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 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, a 5-fluorouracil infusion (1000 mg/m²/day) is initiated and continued continuously for 4 days. This regimen is repeated every 3 weeks for 5 cycles. After chemotherapy, patients should receive chemoradiotherapy.

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

Dose Adjustment During Treatment

General Principles. Docetaxel should be administered only if the neutrophil count is ≥1500 cells/mm³. If febrile neutropenia develops during docetaxel therapy, or if the neutrophil count is <500 cells/mm³ for more than one week, or if severe acute or progressively worsening cumulative skin reactions occur, or if 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 III or IV stomatitis should have the docetaxel dose reduced to 60 mg/m².

In Combination with Cisplatin. For patients in whom, during the previous cycle of docetaxel 75 mg/m² in combination with cisplatin, the nadir leukocyte count was <25,000 cells/mm³, for patients who developed febrile neutropenia during docetaxel therapy, and for patients who experienced serious non-hematological toxicities, the dose of docetaxel should be reduced to 65 mg/m² in subsequent cycles. Specific dose adjustments for cisplatin are described in the "Summary of Product Characteristics" for cisplatin.

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

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

Specific dose adjustments for trastuzumab are described in the "Summary of Product Characteristics" for trastuzumab.

In Combination with Cisplatin and 5-Fluorouracil. If a patient develops an episode of febrile neutropenia, prolonged neutropenia, or infection during neutropenia despite G-CSF administration, the dose of docetaxel should be reduced from 75 to 60 mg/m². If episodes of complicated neutropenia recur, the dose should be further reduced from 60 to 45 mg/m². If a patient develops grade IV thrombocytopenia, the dose of docetaxel 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 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 Adjustment Measures for Chemotherapy Agents in Patients Receiving the Combination of Docetaxel, Cisplatin, and 5-Fluorouracil

Toxicity manifestations	Dose adjustments
Grade 3 diarrhea	First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: reduce the dose of docetaxel by 20%.
Grade 4 diarrhea	First episode: reduce the doses of docetaxel and 5-fluorouracil by 20%. Second episode: discontinue therapy.
Grade 3 mucositis or other inflammatory mucosal processes	First episode: reduce the dose of 5-fluorouracil by 20%. Second episode: discontinue 5-fluorouracil for all subsequent treatment cycles. Third episode: reduce the dose of docetaxel by 20%.
Grade 4 mucositis or other inflammatory mucosal processes	First episode: discontinue 5-fluorouracil for all subsequent treatment cycles. Second episode: reduce the dose of docetaxel by 20%.

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

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

Special patient groups

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

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

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

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

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

Children.

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

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

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

There is a lack of substantial evidence on the use of the drug in children for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma, and cancers of the head and neck, except for poorly differentiated nasopharyngeal carcinoma types II and III.

Overdose.

There have been several reports of docetaxel overdose. There is currently no specific antidote for docetaxel. In case of overdose, the patient should be hospitalized in a specialized unit and closely monitored for vital functions. An exacerbation of the drug's adverse reactions should be expected. In particular, bone marrow suppression, peripheral neurotoxicity, and mucosal inflammation are anticipated. After confirmation of overdose, therapeutic doses of G-CSF should be administered to the patient as soon as possible. Symptomatic supportive measures should be implemented as needed.

Adverse Reactions

Summary of safety profile data for all indications. Data on adverse reactions considered likely related to docetaxel administration were obtained from studies involving the following patients:

• 1312 and 121 patients receiving docetaxel as monotherapy at doses of 100 mg/m² and 75 mg/m², respectively;
• 258 patients receiving docetaxel in combination with doxorubicin;
• 406 patients receiving docetaxel in combination with cisplatin;
• 92 patients receiving docetaxel in combination with trastuzumab;
• 255 patients receiving docetaxel in combination with capecitabine;
• 332 patients (TAX 327) receiving docetaxel in combination with prednisone or prednisolone (clinically significant treatment-related adverse reactions are 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 (Grade 3 = G3; Grade 3–4 = G3/4; Grade 4 = G4), Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART), and Medical Dictionary for Regulatory Activities (MedDRA) terminology.

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

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

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

When docetaxel was used in combination with trastuzumab, adverse reactions (of any grade) were observed in ≥ 10% of patients. Compared to docetaxel monotherapy, this combination increased the frequency of serious adverse reactions (40% vs. 31%) and Grade IV adverse reactions (34% vs. 23%).

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

For the combination with ADT and prednisone or prednisolone (STAMPEDE study), adverse reactions 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 usually 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), sensation of chest tightness, back pain, dyspnea, fever, or chills. Severe reactions manifested as 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 "Adverse reactions"). Mild to moderate neurosensory reactions included paresthesia, dysesthesia, or pain, 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, particularly localized on palms and soles (including severe palmar-plantar erythrodysesthesia), as well as on arms, face, or chest, often accompanied by pruritus. Rash most commonly appeared within one week after docetaxel infusion. Less frequently, severe manifestations occurred, such as rash followed by desquamation of epithelium, sometimes necessitating treatment interruption or complete discontinuation of docetaxel (see sections "Special precautions" and "Dosage and administration"). 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, dryness of the skin, phlebitis, hemorrhage, and swelling of the vein used for infusion.

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

Table 13

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

System organ classes according to MedDRA	Very common	Common	Uncommon
Infections and infestations	Infections (G3/4: 5.7%, including sepsis and pneumonia, fatal in 1.7% of cases)	Infections associated with G4 neutropenia (G3/4: 4.6%)
Blood and lymphatic system disorders	Neutropenia (G4: 76.4%); anemia (G3/4: 8.9%); febrile neutropenia	Thrombocytopenia (G4: 0.2%)
Immune system disorders	Hypersensitivity reactions (G3/4: 5.3%)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3: 4.1%); peripheral motor neuropathy (G3/4: 4%); dysgeusia (severe: 0.07%)
Cardiac disorders		Arrhythmia (G3/4: 0.7%)	Heart failure
Vascular disorders		Arterial hypotension; arterial hypertension; hemorrhagic complications
Respiratory, thoracic and mediastinal disorders	Dyspnea (severe: 2.7%)
Gastrointestinal disorders	Stomatitis (G3/4: 5.3%); diarrhea (G3/4: 4%); nausea (G3/4: 4%); vomiting (G3/4: 3%)	Constipation (severe: 0.2%); abdominal pain (severe: 1%); gastrointestinal hemorrhage (severe: 0.3%)	Esophagitis (severe: 0.4%)
Skin and subcutaneous tissue disorders	Alopecia; skin reactions (G3/4: 5.9%); nail disorders (severe: 2.6%)
Musculoskeletal and connective tissue disorders	Myalgia (severe: 1.4%)	Arthralgia
General disorders and administration site conditions	Fluid retention (severe: 6.5%); asthenia (severe: 11.2%); pain	Local reactions after drug administration; non-cardiac chest pain (severe: 0.4%)
Investigations		G3/4 increased blood bilirubin levels (< 5%); G3/4 increased alkaline phosphatase levels (< 4%); G3/4 increased AST levels (< 3%); G3/4 increased ALT levels (< 2%)

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

Blood and lymphatic system disorders. Rare: bleeding or hemorrhage occurring on the background of grade III/IV thrombocytopenia.

Nervous system disorders. Data are available on reversibility of nervous system impairment in 35.3% of patients in whom it developed after monotherapy with docetaxel at a dose of 100 mg/m². These disorders spontaneously resolved within 3 months.

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

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

Table 14

Adverse reactions recorded in patients with non-small cell lung cancer receiving docetaxel as monotherapy at a dose of 75 mg/m²

MedDRA System Organ Classes	Very common	Common
Infections and infestations	Infections (G3/4: 5%)
Blood and lymphatic system disorders	Neutropenia (G4: 54.2%); anemia (G3/4: 10.8%); thrombocytopenia (G4: 1.7%)	Febrile neutropenia
Immune system disorders		Hypersensitivity reactions (no severe cases)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 0.8%)	Peripheral motor neuropathy (G3/4: 2.5%)
Cardiac disorders		Arrhythmia (no severe cases)
Vascular disorders		Arterial hypotension
Gastrointestinal disorders	Nausea (G3/4: 3.3%); stomatitis (G3/4: 1.7%); vomiting (G3/4: 0.8%); diarrhea (G3/4: 1.7%)	Constipation
Skin and subcutaneous tissue disorders	Alopecia; skin reactions (G3/4: 0.8%)	Nail disorders (severe: 0.8%)
Musculoskeletal and connective tissue disorders		Myalgia
General disorders and administration site conditions	Asthenia (severe: 12.4%); fluid retention (severe: 0.8%); pain
Investigations		G3/4 increased blood bilirubin (< 2%)

Table 15

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

MedDRA System Organ Classes	Very common	Common	Uncommon
Infections and infestations	Infections (G3/4: 7.8%)
Blood and lymphatic system disorders	Neutropenia (G4: 91.7%); anemia (G3/4: 9.4%); febrile neutropenia; thrombocytopenia (G4: 0.8%)
Immune system disorders		Hypersensitivity reactions (G3/4: 1.2%)
Metabolism and nutrition disorders		Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3: 0.4%)	Peripheral motor neuropathy (G3/4: 0.4%)
Cardiac disorders		Heart failure; arrhythmia (no severe cases)
Vascular disorders			Arterial hypotension
Gastrointestinal disorders	Nausea (G3/4: 5%); stomatitis (G3/4: 7.8%); diarrhea (G3/4: 6.2%); vomiting (G3/4: 5%); constipation
Skin and subcutaneous tissue disorders	Alopecia; nail disorders (severe: 0.4%); skin reactions (no severe cases)
Musculoskeletal and connective tissue disorders		Myalgia
General disorders and administration site conditions	Asthenia (severe: 8.1%); fluid retention (severe: 1.2%); pain	Local reactions after drug administration
Investigations		G3/4 Increased blood bilirubin (< 2.5%); G3/4 increased alkaline phosphatase (< 2.5%)	G3/4 Increased AST (< 1%); G3/4 increased ALT (< 1%)

Table 16

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

MedDRA System Organ Classes	Very common	Common	Uncommon
Infections and infestations	Infections (G3/4: 5.7%)
Blood and lymphatic system disorders	Neutropenia (G4: 51.5%); anaemia (G3/4: 6.9%); thrombocytopenia (G4: 0.5%)	Febrile neutropenia
Immune system disorders	Hypersensitivity reactions (G3/4: 2.5%)
Metabolism and nutrition disorders	Anorexia
Nervous system disorders	Peripheral sensory neuropathy (G3: 3.7%); peripheral motor neuropathy (G3/4: 2%)
Cardiac disorders		Arrhythmia (G3/4: 0.7%)	Heart failure
Vascular disorders		Arterial hypotension (G3/4: 0.7%)
Gastrointestinal disorders	Nausea (G3/4: 9.6%); vomiting (G3/4: 7.6%); diarrhoea (G3/4: 6.4%); stomatitis (G3/4: 2%)	Constipation
Skin and subcutaneous tissue disorders	Alopecia; nail disorders (severe: 0.7%); skin reactions (G3/4: 0.2%)
Musculoskeletal and connective tissue disorders	Myalgia (severe: 0.5%)
General disorders and administration site conditions	Asthenia (severe: 9.9%); fluid retention (severe: 0.7%); pyrexia (G3/4: 1.2%)	Local reactions after drug administration; pain
Investigations		G3/4 increased blood bilirubin (2.1%); G3/4 increased ALT (1.3%)	G3/4 increased AST (0.5%); G3/4 increased alkaline phosphatase (0.3%)

Table 17

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

MedDRA system organ classes	Very common	Common
Blood and lymphatic system disorders	Neutropenia (G3/4: 32%); febrile neutropenia (including neutropenia associated with fever and antibiotic use) or neutropenic sepsis
Metabolism and nutrition disorders	Anorexia
Psychiatric disorders	Insomnia
Nervous system disorders	Paresthesia; headache; dysgeusia; hypoesthesia
Cardiac disorders		Heart failure
Eye disorders	Increased lacrimation; conjunctivitis
Vascular disorders	Lymphedema
Respiratory, thoracic and mediastinal disorders	Nosebleeds; pharyngolaryngeal pain; nasopharyngitis; dyspnea; cough; rhinorrhea
Gastrointestinal disorders	Nausea; diarrhea; vomiting; constipation; stomatitis; dyspepsia; abdominal pain
Skin and subcutaneous tissue disorders	Alopecia; erythema; rash; nail disorders
Musculoskeletal and connective tissue disorders	Myalgia; arthralgia; limb pain; bone pain; back pain
General disorders and administration site conditions	Asthenia; peripheral edema; fever; increased fatigue; mucosal inflammation; pain; acute respiratory illness; chest pain; chills	Lethargy
Investigations	Weight increased

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

Blood and lymphatic system disorders. Very common: hematologic toxicity of combined therapy with trastuzumab and docetaxel increased compared to docetaxel monotherapy (32% of cases of grade III/IV neutropenia versus 22%, using NCI-CTC criteria [National Cancer Institute – Common Toxicity Criteria]). It should be noted that the incidence of this adverse effect in this patient population may be underestimated, as even with docetaxel monotherapy at a dose of 100 mg/m², neutropenia occurs in 97% of patients, with 76% experiencing 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% versus 17% compared to patients receiving docetaxel as monotherapy).

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

Table 18

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

MedDRA system organ classes	Very common	Common
Infections and infestations		Oral mucosal candidiasis (G3/4: < 1 %)
Blood and lymphatic system disorders	Neutropenia (G3/4: 63 %); anemia (G3/4: 10 %)	Thrombocytopenia (G3/4: 3 %)
Metabolism and nutrition disorders	Anorexia (G3/4: 1 %); decreased appetite	Dehydration (G3/4: 2 %)
Nervous system disorders	Dysgeusia (G3/4: < 1 %); paraesthesia (G3/4: < 1 %)	Dizziness; headache (G3/4: < 1 %); peripheral neuropathy
Eye disorders	Increased lacrimation
Respiratory, thoracic and mediastinal disorders	Pharyngolaryngeal pain (G3/4: 2 %)	Dyspnea (G3/4: 1 %); cough (G3/4: < 1 %); epistaxis (G3/4: < 1 %)
Gastrointestinal disorders	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	Upper abdominal pain; dry mouth
Skin and subcutaneous tissue disorders	Palmar-plantar erythrodysesthesia syndrome (G3/4: 24 %); alopecia (G3/4: 6 %); nail disorders (G3/4: 2 %)	Dermatitis; erythematous rash (G3/4: < 1 %); nail discoloration; onycholysis (G3/4: 1 %)
Musculoskeletal and connective tissue disorders	Myalgia (G3/4: 2 %); arthralgia (G3/4: 1 %)	Limb pain (G3/4: < 1 %); back pain (G3/4: 1 %)
General disorders and administration site conditions	Asthenia (G3/4: 3 %); pyrexia (G3/4: 1 %); fatigue/ general weakness (G3/4: 5 %); peripheral edema (G3/4: 1 %)	Lethargy; pain
Investigations		Weight decreased; increased blood bilirubin (G3/4: 9 %)

Table 19

Adverse reactions recorded in patients with metastatic castration-resistant prostate cancer treated with docetaxel 75 mg/m² in combination with prednisone or prednisolone

MedDRA System Organ Classes	Very common	Common
Infections and infestations	Infections (G3/4: 3.3%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 32%); anemia (G3/4: 4.9%)	Thrombocytopenia (G3/4: 0.6%); febrile neutropenia
Immune system disorders		Hypersensitivity reactions (G3/4: 0.6%)
Metabolism and nutrition disorders	Anorexia (G3/4: 0.6%)
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 1.2%); dysgeusia (G3/4: 0%)	Peripheral motor neuropathy (G3/4: 0%)
Eye disorders		Increased lacrimation (G3/4: 0.6%)
Cardiac disorders		Worsening of left ventricular function (G3/4: 0.3%)
Respiratory, thoracic and mediastinal disorders		Nosebleeds (G3/4: 0%); dyspnea (G3/4: 0.6%); cough (G3/4: 0%)
Gastrointestinal disorders	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	Alopecia; nail disorders (no severe cases)	Exfoliative rash (G3/4: 0.3%)
Musculoskeletal and connective tissue disorders		Arthralgia (G3/4: 0.3%); myalgia (G3/4: 0.3%)
General disorders and administration site conditions	Increased fatigue (G3/4: 3.9%); fluid retention (severe: 0.6%)

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

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

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

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

Metabolism and nutrition disorders. Common: loss of appetite.

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

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

Eye disorders. Common: blurred vision.

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

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

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

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

Musculoskeletal and connective tissue disorders. Very common: myalgia.

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

aAccording to data from the GETUG AFU15 study.

Table 20

Adverse reactions recorded with administration of docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with lymph node metastatic breast cancer (study TAX 316) and without (study GEICAM 9805) – pooled data

MedDRA system organ classes	Very common	Common	Uncommon
Infections and infestations	Infections (G3/4: 2.4%); neutropenic infections (G3/4: 2.6%);
Blood and lymphatic system disorders	Anemia (G3/4: 3%); neutropenia (G3/4: 59.2%); thrombocytopenia (G3/4: 1.6%); febrile neutropenia (G3/4: NC)
Immune system disorders		Hypersensitivity reactions (G3/4: 0.6%)
Metabolism and nutrition disorders	Anorexia (G3/4: 1.5%)
Nervous system disorders	Dysgeusia (G3/4: 0.6%); peripheral sensory neuropathy (G3/4: < 0.1%);	Peripheral motor neuropathy (G3/4: 0%);	Syncope (G3/4: 0%); neurotoxicity symptoms (G3/4: 0%); drowsiness (G3/4: 0%)
Eye disorders	Conjunctivitis (G3/4: < 0.1%);	Increased lacrimation (G3/4: < 0.1%)
Cardiac disorders		Arrhythmia (G3/4: 0.2%);
Vascular disorders	Hot flushes (G3/4: 0.5%)	Arterial hypotension (G3/4: 0%); phlebitis (G3/4: 0%)	Lymphedema (G3/4: 0%)
Respiratory, thoracic and mediastinal disorders		Cough (G3/4: 0%)
Gastrointestinal disorders	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%)	Abdominal pain (G3/4: 0.4%)
Skin and subcutaneous tissue disorders	Alopecia (persistent: < 3%); skin toxicity manifestations (G3/4: 0.6%); nail disorders (G3/4: 0.4%)
Musculoskeletal and connective tissue disorders	Myalgia (G3/4: 0.7%); arthralgia (G3/4: 0.2%)
General disorders and administration site conditions	Asthenia (G3/4: 10%); pyrexia (G3/4: NC); peripheral edema (G3/4: 0.2%)
Reproductive system and breast disorders	Amenorrhea (G3/4: NC)
Investigations		Increased body weight (G3/4: 0%); decreased body weight (G3/4: 0.2%)

Description of individual adverse reactions recorded during the use of docetaxel at a dose of 75 mg/m² in combination with doxorubicin and cyclophosphamide as adjuvant therapy in patients with lymph node metastatic breast cancer (study TAX 316) and without metastases (study GEICAM 9805)

Nervous system. In study TAX 316, peripheral sensory neuropathy began during the treatment period and persisted during follow-up in 84 patients (11.3%) in the TAC regimen group and in 15 patients (2%) in the FAC regimen group. At the end of the follow-up period (median follow-up duration was 8 years), peripheral sensory neuropathy persisted in 10 patients (1.3%) in the TAC regimen group and in 2 patients (0.3%) in the FAC regimen group.

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

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

In study GEICAM 9805, congestive heart failure developed during the follow-up period in 3 patients (0.6%) in the TAC regimen group and in 3 patients (0.6%) in the FAC regimen group. At the end of the follow-up period (actual median follow-up duration was 10 years and 5 months), no patient in the TAC regimen group had congestive heart failure, and one patient in the TAC regimen group died due to dilated cardiomyopathy, while in the FAC regimen group, congestive heart failure persisted in 1 patient (0.2%).

Skin and subcutaneous tissue disorders. In study TAX 316, alopecia that persisted after completion of chemotherapy and throughout the follow-up period was recorded in 687 out of 744 patients (92.3%) in the TAC regimen group and in 645 out of 736 patients (87.6%) in the FAC regimen group.

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

In study GEICAM 9805, alopecia that persisted after completion of chemotherapy and throughout the follow-up period was documented in 49 patients (9.2%) in the TAC regimen group and in 35 patients (6.7%) in the FAC regimen group.

Alopecia related to the investigational drug began or worsened during the follow-up period in 42 patients (7.9%) in the TAC regimen group and in 30 patients (5.8%) in the FAC regimen group. At the end of the follow-up period (median follow-up duration was 10 years and 5 months), alopecia persisted in 3 patients (0.6%) in the TAC regimen group and in 1 patient (0.2%) in the FAC regimen group.

Reproductive system and breast disorders. In study TAX 316, amenorrhea that began during the treatment period and persisted during follow-up after completion of chemotherapy was observed in 202 out of 744 patients (27.2%) in the TAC regimen group and in 125 out of 736 patients (17.0%) in the FAC regimen group. At the end of the follow-up period (median follow-up duration was 8 years), amenorrhea persisted in 121 out of 744 patients (16.3%) in the TAC regimen group and in 86 patients (11.7%) in the FAC regimen group.

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

General disorders and administration site conditions. In study TAX 316, peripheral edema that began during the treatment period and persisted during follow-up after completion of chemotherapy was observed in 119 out of 744 patients (16.0%) in the TAC regimen group and in 23 out of 736 patients (3.1%) in the FAC regimen group. At the end of the follow-up period (actual median follow-up duration was 8 years), peripheral edema persisted in 19 patients (2.6%) in the TAC regimen group and in 4 patients (0.5%) in the FAC regimen group.

In study TAX 316, lymphedema that began during the treatment period and persisted during follow-up after completion of chemotherapy was observed in 11 out of 744 patients (1.5%) in the TAC regimen group and in 1 out of 736 patients (0.1%) in the FAC regimen group. At the end of the follow-up period (actual median follow-up duration was 8 years), lymphedema persisted in 6 patients (0.8%) in the TAC regimen group and in 1 patient (0.1%) in the FAC regimen group.

In study TAX 316, asthenia that began during the treatment period and persisted during follow-up after completion of chemotherapy was observed in 236 out of 744 patients (31.7%) in the TAC regimen group and in 180 out of 736 patients (24.5%) in the FAC regimen group. At the end of the follow-up period (actual median follow-up duration was 8 years), asthenia persisted in 29 patients (3.9%) in the TAC regimen group and in 16 patients (2.2%) in the FAC regimen group.

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

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

Acute leukemia/myelodysplastic syndrome. During 10 years of follow-up in study TAX 316, acute leukemia was detected in 3 out of 744 patients (0.4%) in the TAC regimen group and in 1 out of 736 patients (0.1%) in the FAC regimen group. During the follow-up period (median follow-up duration was 8 years), 1 patient (0.1%) in the TAC regimen group and 1 patient (0.1%) in the FAC regimen group died from acute myeloid leukemia. Myelodysplastic syndrome was diagnosed in 2 out of 744 patients (0.3%) in the TAC regimen group and in 1 out of 736 patients (0.1%) in the FAC regimen group. After 10 years of follow-up in study GEICAM 9805, acute leukemia occurred in 1 out of 532 patients (0.2%) in the TAC regimen group. No cases were observed in the FAC regimen group.

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

Neutropenic complications. Table 21 shows that the incidence of Grade IV neutropenia, febrile neutropenia, and neutropenic infection in patients receiving primary prophylaxis with G-CSF decreased after such prophylaxis became mandatory in the TAC arm of the GEICAM study.

Table 21

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

	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)

Table 22

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

MedDRA System Organ Classes	Very common	Common
Infections and infestations	Neutropenic infections; infectious disorders (G3/4: 11.7%)
Blood and lymphatic system disorders	Anemia (G3/4: 20.9%); neutropenia (G3/4: 83.2%); thrombocytopenia (G3/4: 8.8%); febrile neutropenia
Immune system disorders	Hypersensitivity reactions (G3/4: 1.7%)
Metabolism and nutrition disorders	Anorexia (G3/4: 11.7%)
Nervous system disorders	Peripheral sensory neuropathy (G3/4: 8.7%)	Dizziness (G3/4: 2.3%); peripheral motor neuropathy (G3/4: 1.3%)
Eye disorders		Increased lacrimation (G3/4: 0%)
Ear and labyrinth disorders		Hearing impairment (G3/4: 0%)
Cardiac disorders		Arrhythmia (G3/4: 1.0%)
Gastrointestinal disorders	Diarrhea (G3/4: 19.7%); nausea (G3/4: 16%); stomatitis (G3/4: 23.7%); vomiting (G3/4: 14.3%)	Constipation (G3/4: 1.0%); abdominal pain (G3/4: 1.0%); esophagitis/dysphagia/odynophagia (G3/4: 0.7%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 4.0%)	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	Lethargy (G3/4: 19.0%); pyrexia (G3/4: 2.3%); fluid retention (severe/life-threatening: 1%)

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

Blood and lymphatic system disorders

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

Table 23

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

Induction chemotherapy followed by radiotherapy

(TAX 323 study)

System organ classes according to MedDRA	Very common	Common	Uncommon
Infections and infestations	Infections (G3/4: 6.3%); neutropenic infections
Benign, malignant and unspecified neoplasms (including cysts and polyps)		Pain due to malignant tumor (G3/4: 0.6%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 76.3%); anaemia (G3/4: 9.2%); thrombocytopenia (G3/4: 5.2%)	Febrile neutropenia
Immune system disorders		Hypersensitivity reactions (no severe cases)
Metabolism and nutrition disorders	Anorexia (G3/4: 0.6%)
Nervous system disorders	Dysgeusia/parosmia; peripheral sensory neuropathy (G3/4: 0.6%)	Dizziness
Eye disorders		Increased lacrimation; conjunctivitis
Ear and labyrinth disorders		Hearing impairment
Cardiac disorders		Myocardial ischaemia (G3/4: 1.7%)	Arrhythmia (G3/4: 0.6%)
Vascular disorders		Venous disorders (G3/4: 0.6%)
Gastrointestinal disorders	Nausea (G3/4: 0.6%); stomatitis (G3/4: 4.0%); diarrhoea (G3/4: 2.9%); vomiting (G3/4: 0.6%)	Constipation; oesophagitis/dysphagia/odynophagia (G3/4: 0.6%); abdominal pain; dyspepsia; gastrointestinal haemorrhage (G3/4: 0.6%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 10.9%)	Rash with pruritus; increased skin dryness; increased skin desquamation (G3/4: 0.6%)
Musculoskeletal and connective tissue disorders		Myalgia (G3/4: 0.6%)
General disorders and administration site conditions	Lethargy (G3/4: 3.4%); fever (G3/4: 0.6%); fluid retention; oedema
Investigations		Weight increased

Induction chemotherapy followed by chemoradiotherapy

(TAX 324 study)

Infections and infestations	Infections (G3/4: 3.6%)	Neutropenic infections
Benign, malignant and unspecified neoplasms (including cysts and polyps)		Pain due to malignant tumor (G3/4: 1.2%)
Blood and lymphatic system disorders	Neutropenia (G3/4: 83.5%); anemia (G3/4: 12.4%); thrombocytopenia (G3/4: 4.0%); febrile neutropenia
Immune system disorders			Hypersensitivity reactions
Metabolism and nutrition disorders	Anorexia (G3/4: 12.0%)
Nervous system disorders	Dysgeusia/parosmia (G3/4: 0.4%); peripheral sensory neuropathy (G3/4: 1.2%)	Dizziness (G3/4: 2.0%); peripheral motor neuropathy (G3/4: 0.4%)
Eye disorders		Increased lacrimation	Conjunctivitis
Ear and labyrinth disorders	Impaired hearing (G3/4: 1.2%)
Cardiac disorders		Arrhythmia (G3/4: 2.0%)	Myocardial ischemia
Vascular disorders			Venous disorders
Gastrointestinal disorders	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%)	Dyspepsia (G3/4: 0.8%); abdominal pain (G3/4: 1.2%); gastrointestinal hemorrhage (G3/4: 0.4%)
Skin and subcutaneous tissue disorders	Alopecia (G3/4: 4.0%); pruritic rash	Increased skin dryness; increased desquamation of skin epithelium
Musculoskeletal and connective tissue disorders		Myalgia (G3/4: 0.4%)
General disorders and administration site conditions	Lethargy (G3/4: 4.0%); fever (G3/4: 3.6%); fluid retention (G3/4: 1.2%); edema (G3/4: 1.2%)
Investigations	Decreased body weight		Increased body weight

Post-marketing data

Benign, malignant and unspecified neoplasms (including cysts and polyps). Administration of docetaxel in combination with other antineoplastic agents known to cause secondary malignancies has been associated with the development of secondary malignancies (frequency unknown), including non-Hodgkin's lymphoma.

In pivotal studies in breast cancer patients receiving the TAC regimen, cases of acute myeloid leukaemia and myelodysplastic syndrome have also been reported (frequency unknown).

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

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

Nervous system disorders. Administration of docetaxel has been associated with rare cases of seizures or transient loss of consciousness. These reactions sometimes occurred during drug infusion.

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

Cases of crystalline macular oedema have been observed in patients receiving docetaxel.

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

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

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

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

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

Rare cases of dehydration resulting from gastrointestinal disorders, including enterocolitis and gastrointestinal perforation, have been reported. There have also been reports of rare cases of intestinal obstruction and bowel obstruction.

Hepatobiliary disorders. Very rare cases of hepatitis, sometimes fatal (predominantly in patients who had pre-existing hepatic dysfunction prior to initiation of chemotherapy), have been reported.

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

Skin and subcutaneous tissue disorders. Very rare cases of systemic lupus erythematosus, bullous eruptions such as erythema multiforme, and severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported with docetaxel use. Cases of scleroderma-like skin lesions, often preceded by peripheral lymphoedema, have also been reported. Cases of persistent alopecia (frequency unknown) have been observed.

General disorders and administration site conditions. Rare cases of radiation recall reaction (acute radiation-like skin reactions occurring during chemotherapy administered weeks, months or even years after radiotherapy) have been reported. Cases of recurrent injection site reaction (recurrence of skin reaction at a site where extravasation had previously occurred, after administration of docetaxel at another site) have also been reported (frequency unknown).

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

Rare cases of dehydration and pulmonary oedema have been reported.

Metabolism and nutrition disorders. Cases of electrolyte imbalance have been reported. Hyponatraemia has been observed, primarily associated with dehydration, vomiting and pneumonia.

Hypokalaemia, hypomagnesaemia and hypocalcaemia have also been observed, usually in association with gastrointestinal disorders, particularly diarrhoea.

Tumour lysis syndrome, potentially fatal (frequency unknown), has been reported.

Musculoskeletal and connective tissue disorders. Myositis associated with the use of docetaxel has been reported (frequency unknown).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any 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, protected from light, at a temperature not exceeding 25 °C. Keep out of the reach of children.

After dilution into an infusion bag according to the recommendations, the docetaxel infusion solution is stable for 6 hours when stored at temperatures below 25 °C. It should be used within 6 hours (including 1 hour of intravenous infusion). The infusion solution should not remain in the infusion system for more than 8 hours at 25 °C.

Additionally, physical and chemical stability of the infusion solution prepared according to the recommendations has been maintained in non-PVC bags for up to 48 hours when stored at 2–8 °C.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section “Special precautions for administration”.

Packaging.

1 ml (20 mg), 4 ml (80 mg), or 8 ml (160 mg) of concentrate for solution for infusion in a clear type I glass vial stoppered with a polymer-fluorotec plus coated rubber stopper and sealed with an aluminium flip-off cap; 1 vial per carton.

Prescription status. Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and location of operations.

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorisation Holder. Accord Healthcare S.L.U.

Inquiries regarding product quality, safety concerns, improper use of the medicine, or complaints are accepted 24/7 by phone at +380993100335 or by email at: [email protected].

Marketing Authorisation Holder's address. World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.