Cabazitaxel accord

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CABAZITAXEL ACCORD (CABAZITAXEL ACCORD)

Composition:

Active substance: cabazitaxel;

1 ml of concentrate contains 20 mg of cabazitaxel;

3 ml vial contains 60 mg of cabazitaxel;

Excipients: ethanol anhydrous, polysorbate 80A-LQ (MH), containing: polysorbate 80, citric acid.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear solution, colorless to pale yellow or brownish-yellow. Practically free from particles.

Pharmacotherapeutic group. Antineoplastic agents. ATC code L01C D04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Cabazitaxel is an antineoplastic agent that acts by disrupting the microtubule system in cells. Cabazitaxel binds to tubulin and promotes the aggregation of tubulin into microtubules, while simultaneously inhibiting their depolymerization. This leads to stabilization of microtubules, resulting in inhibition of cellular functions during mitosis and interphase.

Pharmacodynamic effect. Cabazitaxel demonstrated a broad spectrum of antitumor activity against human tumor xenografts in mice at advanced stages. Cabazitaxel is active against tumors sensitive to docetaxel. In addition, cabazitaxel has shown activity against tumor models resistant to chemotherapy, including docetaxel.

Clinical efficacy and safety. The efficacy and safety of cabazitaxel in combination with prednisone or prednisolone were evaluated in a randomized, open-label, international, multicenter Phase III study involving patients with hormone-refractory metastatic prostate cancer who had previously received docetaxel-containing therapy.

Overall survival (OS) was the primary efficacy endpoint in this study. Secondary endpoints included progression-free survival (PFS) (defined as the time from randomization to tumor progression, prostate-specific antigen [PSA] progression, pain progression, or death from any cause, whichever occurred first), tumor response rate based on Response Evaluation Criteria in Solid Tumors [RECIST], PSA progression (defined as an increase of 25% or more in patients who had previously responded to treatment in terms of PSA levels, or an increase of 50% or more in patients who did not respond to treatment in terms of PSA levels), PSA response (defined as a reduction in serum PSA level by at least 50%), pain progression (assessed using the Pain Rating Intensity [PRI] scale from the McGill-Melzack questionnaire and the Analgesic Score [AS]), and pain response (defined as a decrease in median PRI score of at least 2 points compared to baseline without a concomitant increase in AS, or a reduction in analgesic use by 50% or more compared to the mean AS at baseline without a concomitant increase in pain intensity).

A total of 755 patients were randomized to receive either cabazitaxel 25 mg/m² administered intravenously every 3 weeks for up to 10 cycles in combination with oral prednisone or prednisolone 10 mg/day (n = 378), or mitoxantrone 12 mg/m² administered intravenously every 3 weeks for up to 10 cycles in combination with oral prednisone or prednisolone 10 mg/day (n = 377).

Patients included in this study were aged 18 years and older, with hormone-refractory metastatic prostate cancer that was either measurable according to RECIST criteria or non-measurable by RECIST but characterized by rising PSA levels or appearance of new tumor lesions, and with an Eastern Cooperative Oncology Group [ECOG] performance status of 0 to 2. Patients were required to have an absolute neutrophil count > 1500/mm³, platelets > 100,000/mm³, hemoglobin > 10 g/dL, creatinine < 1.5 × ULN (upper limit of normal), total bilirubin < 1 × ULN, and AST (aspartate aminotransferase) and ALT (alanine aminotransferase) < 1.5 × ULN.

Patients with a history of congestive heart failure or myocardial infarction within the previous 6 months, as well as those with uncontrolled cardiac arrhythmias, angina, and/or arterial hypertension, were excluded from this study.

Demographic characteristics, including age, race, and ECOG performance status (0 to 2), were balanced between the two treatment groups. In the cabazitaxel group, the median patient age was 68 years (range: 46 to 92 years), and the racial distribution was as follows: 83.9% of patients were Caucasian, 6.9% Asian/Eastern populations, 5.3% Black, and 4% other racial groups.

The median number of treatment cycles was 6 in the cabazitaxel group and 4 in the mitoxantrone group. The proportion of patients who completed the full course of treatment in the study (10 cycles) was 29.4% in the cabazitaxel group and 13.5% in the comparator group.

Overall survival was statistically significantly longer in the cabazitaxel group compared to the mitoxantrone group (15.1 months vs. 12.7 months, respectively), with a 30% reduction in the risk of death compared to the mitoxantrone group (see Table 1 and Figure 1).

A subgroup of 59 patients had previously received docetaxel at a cumulative dose of < 225 mg/m² (29 patients in the cabazitaxel group, 30 patients in the mitoxantrone group). In this subgroup, there was no statistically significant difference in overall survival (hazard ratio [95% CI]: 0.96 [0.49–1.86]).

Table 1

Efficacy of cabazitaxel in the treatment of patients with hormone-refractory metastatic prostate cancer

Parameter	Docetaxel + prednisone (n = 378)	Mitoxantrone + prednisone (n = 377)
Overall survival
Number of patients who died (%)	234 (61.9%)	279 (74%)
Median survival (months) [95% CI]	15.1 [14.1–16.3]	12.7 [11.6–13.7]
Hazard ratio (HR)1 [95% CI]	0.70 [0.59–0.83]
p-value	< 0.0001

1HR was determined using the Cox model; HR less than 1 favors cabazitaxel.

Figure 1. Kaplan-Meier overall survival curves

A significant improvement in PFS was observed in the cabazitaxel group compared to the mitoxantrone group: 2.8 (2.4–3.0) months versus 1.4 (1.4–1.7) months, respectively; HR (95% CI) 0.74 (0.64–0.86), p < 0.0001.

A statistically significantly higher tumor response rate was observed in the cabazitaxel group—14.4% (95% CI: 9.6–19.3)—compared to 4.4% (95% CI: 1.6–7.2) in the mitoxantrone group, p = 0.0005.

Secondary endpoints related to PSA were positive in the cabazitaxel group. Median time to PSA progression was 6.4 months (95% CI: 5.1–7.3) in the cabazitaxel group versus 3.1 months (95% CI: 2.2–4.4) in the mitoxantrone group, HR 0.75 (95% CI: 0.63–0.90), p = 0.0010. PSA response was observed in 39.2% of the cabazitaxel group (95% CI: 33.9–44.5) and in 17.8% of the mitoxantrone group (95% CI: 13.7–22.0), p = 0.0002.

There was no statistically significant difference between the two treatment groups in terms of pain progression and pain response.

In a multicenter, multinational, randomized, open-label phase III study (study EPC 11785), 1200 patients with hormone-refractory metastatic prostate cancer previously treated with a regimen containing docetaxel were randomized to receive cabazitaxel at a dose of 25 mg/m² (n = 602) or 20 mg/m² (n = 598). OS was the primary efficacy endpoint.

The study achieved its primary objective—demonstrating non-inferior efficacy of cabazitaxel at 20 mg/m² compared to 25 mg/m² (see Table 2). A statistically significantly higher proportion (p < 0.001) of patients achieved PSA response in the 25 mg/m² group (42.9%) compared to the 20 mg/m² group (29.5%). A significantly higher risk of PSA progression was observed in the 20 mg/m² group compared to patients receiving 25 mg/m² (HR 1.195; 95% CI: 1.025, 1.393). There were no statistical differences in other secondary endpoints (PFS, tumor response and pain response, tumor and pain progression, and the four EORTC QLQ-C30 subscales).

Table 2

Overall survival in study EPC 11785, cabazitaxel 25 mg/m² versus cabazitaxel 20 mg/m² (per-protocol population)—primary efficacy endpoint

	CBZ20 + PRED (n = 598)	CBZ25 + PRED (n = 602)
Overall survival
Number of deaths, n (%)	497 (83.1 %)	501 (83.2 %)
Median survival (95 % CI) (in months)	13.4 (12.19–14.88)	14.5 (13.47–15.28)
Hazard ratio
Compared to CBZ25 + PRED	1.024	-
One-sided 98.89 % UCI	1.184	-
One-sided 95 % LCI	0.922	-

CBZ20 – cabazitaxel 20 mg/m², CBZ25 – cabazitaxel 25 mg/m², PRED – prednisone/prednisolone, CI – confidence interval, LCI – lower confidence interval, UCI – upper confidence interval.

a Relative risk is estimated using Cox proportional hazards regression model. A hazard ratio < 1 indicates a lower risk for cabazitaxel 20 mg/m² compared to 25 mg/m².

The safety profile of cabazitaxel at a dose of 25 mg/m² observed in study EFC11785 was qualitatively and quantitatively similar to the profile observed in study EEC6193. Study EFC11785 demonstrated a better safety profile for cabazitaxel at a dose of 20 mg/m².

Table 3

Summary of safety data for the cabazitaxel 25 mg/m² group
compared to the cabazitaxel 20 mg/m² group, study EFC11785

	CBZ20 + PRED (n = 580)	CBZ25 + PRED (n = 595)
Mean number of cycles/ mean duration of treatment	6/18 weeks	7/21 week
Number of patients with dose reduction, n (%)	from 20 to 15 mg/m2: 58 (10.0%) from 15 to 12 mg/m2: 9 (1.6%)	from 25 to 20 mg/m2: 128 (21.5%) from 20 to 15 mg/m2: 19 (3.2%) from 15 to 12 mg/m2: 1 (0.2%)

Adverse reactions of all grades (%)

Diarrhea	30.7	39.8
Nausea	24.5	32.1
Increased fatigue	24.7	27.1
Hematuria	14.1	20.8
Asthenia	15.3	19.7
Decreased appetite	13.1	18.5
Vomiting	14.5	18.2
Constipation	17.6	18.0
Back pain	11.0	13.9
Clinically evident neutropenia	3.1	10.9
Urinary tract infection	6.9	10.8
Peripheral sensory neuropathy	6.6	10.6
Dysgeusia	7.1	10.6

Adverse reactions > grade 3 (%)

Clinically significant neutropenia	2.4	9.6
Febrile neutropenia	2.1	9.2

Hematological abnormalities (%)

Neutropenia > grade 3	41.8	73.3
Anemia > grade 3	9.9	13.7
Thrombocytopenia > grade 3	2.6	4.2

CBZ20 – cabazitaxel 20 mg/m², CBZ25 – cabazitaxel 25 mg/m², PRED – prednisone/prednisolone.

a Adverse reactions of all grades with frequency greater than 10%.

b Adverse reactions ≥ grade 3 with frequency greater than 5%.

c According to laboratory parameters.

In a prospective, multinational, randomized, open-label phase IV study (study LPS14201/CARD), 255 patients with hormone-resistant metastatic prostate cancer who had previously received prior treatment in any sequence with a regimen including docetaxel and androgen receptor (AR)-targeted agents (abiraterone or enzalutamide), with disease progression within 12 months after initiation of treatment, were randomized to receive either cabazitaxel 25 mg/m² every 3 weeks plus prednisone/prednisolone 10 mg daily (n = 129) or AR-targeted agents (abiraterone 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily) (n = 126). The primary endpoint was radiographic progression-free survival (rPFS), as defined by the Prostate Cancer Working Group 2 (PCWG2). Secondary endpoints included overall survival (OS), time to initiation of new anticancer therapy (TNT), PSA response, and tumor response.

Demographic and disease characteristics were balanced between treatment groups. At baseline, the median age was 70 years, 95% of patients had an ECOG performance status of 0–1, and the median Gleason score was 8. A proportion of patients (61%) had previously received AR-targeted agent treatment following prior docetaxel therapy.

The study met its primary endpoint: rPFS was significantly longer in the cabazitaxel group compared to the AR-targeted agent group (8 months versus 3.7 months, respectively), representing a 46% reduction in the risk of radiographic disease progression compared with AR-targeted agents (see Table 4 and Figure 2).

Table 4

Efficacy of cabazitaxel in the CARD study in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) (per-protocol population analysis – "as-treated" population) – rPFS

Parameter	cabazitaxel + prednisone/prednisolone + G-CSF (n = 129)	AR-targeted agent: abiraterone + prednisone/prednisolone or enzalutamide (n = 126)
Number of events at data cutoff date (%)	95 (73.6%)	101 (80.2%)
Median rPFS (months) (95% CI)	8.0 (5.7–9.2)	3.7 (2.8–5.1)
HR (95% CI)	0.54 (0.40–0.73)
p-value1	< 0.0001

2 Granulocyte colony-stimulating factor.

1 Stratified log-rank test, significance threshold – 0.05.

Figure 2. Primary endpoint: Kaplan-Meier curve of radiographic progression-free survival (per-protocol population).

Pre-planned subgroup analysis for rPFS by stratification factors at randomization showed HR 0.61 (95% CI: 0.39–0.96) in patients who previously received an AR-targeted agent before docetaxel, and HR 0.48 (95% CI: 0.32–0.70) in patients who previously received an AR-targeted agent after docetaxel.

Cabazitaxel was statistically more effective than the comparator AR-targeted agents for each of the alpha-protected key secondary endpoints, including OS (13.6 months in the cabazitaxel treatment group versus 11 months in the AR-targeted agent treatment group, HR 0.64, 95% CI: 0.46–0.89; p = 0.008), rPFS (4.4 months in the cabazitaxel treatment group versus 2.7 months in the AR-targeted agent treatment group, HR 0.52; 95% CI: 0.40–0.68), confirmed PSA response (36.3% in the cabazitaxel treatment group versus 14.3% in the AR-targeted agent treatment group, p = 0.0003), and best tumor response (36.5% in the cabazitaxel treatment group versus 11.5% in the AR-targeted agent treatment group, p = 0.004).

The safety profile of cabazitaxel 25 mg/m² observed in the CARD study was generally consistent with that observed in the TROPIC and PROSELICA studies (see section "Adverse Reactions"). The incidence of adverse reactions ≥ grade 3 was 53.2% in the cabazitaxel group compared to 46.0% in the AR-targeted agent treatment group. The incidence of serious adverse reactions ≥ grade 3 was 31.7% in the cabazitaxel group versus 37.1% in the AR-targeted agent treatment group. The proportion of patients who permanently discontinued study treatment due to adverse reactions was 19.8% in the cabazitaxel group versus 8.1% in the AR-targeted agent treatment group. The incidence of adverse reactions leading to death was 5.6% in the cabazitaxel group versus 10.5% in the AR-targeted agent treatment group.

Children and adolescents

The European Medicines Agency has waived the obligation for the manufacturer to submit results of studies on the use of cabazitaxel for the treatment of prostate cancer in all pediatric subpopulations.

Cabazitaxel was evaluated in an open-label, multicenter, phase 1–2 study involving a total of 39 pediatric patients (aged 4 to 18 years during phase 1 and aged 3 to 16 years during phase 2). Phase 2 did not demonstrate efficacy of cabazitaxel at a dose of 30 mg/m² when administered as monotherapy to pediatric patients with recurrent or refractory diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG).

Pharmacokinetics.

Population pharmacokinetic analysis was performed in 170 patients, including patients with advanced solid tumors (n = 69), metastatic breast cancer (n = 34), and metastatic prostate cancer (n = 67). These patients received cabazitaxel at doses ranging from 10 to 30 mg/m² once weekly or once every 3 weeks.

Absorption. After 1-hour intravenous infusion of 25 mg/m² cabazitaxel in patients with hormone-refractory metastatic prostate cancer (n = 67), the maximum concentration (Cmax) was 226 ng/mL (coefficient of variation (CV): 107%) and was reached at the end of the 1-hour infusion (Tmax). The mean area under the pharmacokinetic concentration-time curve (AUC) was 991 ng·h/mL (CV: 34%).

No significant deviations from dose proportionality were observed over the dose range of 10 to 30 mg/m² in patients with advanced solid tumors (n = 126).

Distribution. The volume of distribution at steady state (Vss) was 4870 L (2640 L/m² for patients with a median body surface area of 1.84 m²).

In vitro, binding of cabazitaxel to human plasma proteins ranged from 89–92% and was not saturated at concentrations up to 50,000 ng/mL, which encompasses the maximum concentration observed in clinical studies. Cabazitaxel binds predominantly to human serum albumin (82.0%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). In vitro, the blood-to-plasma concentration ratio ranged from 0.9 to 0.99, indicating that cabazitaxel was evenly distributed between blood and plasma.

Metabolism. Cabazitaxel is extensively metabolized in the liver (>95%), primarily by the CYP3A isoenzyme (80–90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites (including three active metabolites formed via O-demethylation) were detected in plasma, one of which is the major metabolite, accounting for 5% of the administered parent drug. Approximately 20 metabolites of cabazitaxel are excreted in urine and feces.

Based on in vitro data, cabazitaxel at clinically relevant concentrations may potentially inhibit drugs that are primarily substrates of CYP3A. However, one clinical study showed that cabazitaxel (single dose of 25 mg/m² administered as a 1-hour infusion) did not affect plasma levels of midazolam, a marker substrate of CYP3A. Therefore, no clinically relevant interaction is expected when CYP3A substrates are co-administered with cabazitaxel at therapeutic doses. There is no potential risk of inhibition of drugs that are substrates of other CYP enzymes (1A2, 2B6, 2C9, 2C8, 2C19, 2E1, and 2D6), nor is there a potential risk of induction by cabazitaxel of drugs that are substrates of CYP1A, CYP2C9, or CYP3A. In vitro, cabazitaxel did not inhibit the main biotransformation pathway of warfarin to 7-hydroxywarfarin, which is mediated by CYP2C9. Thus, no pharmacokinetic interaction between cabazitaxel and warfarin is expected in vivo.

In vitro, cabazitaxel did not inhibit Multidrug Resistance Proteins (MRP) MRP1 and MRP2 or Organic Cation Transporter (OCT1). Cabazitaxel inhibited P-glycoprotein (P-gp) (digoxin, vinblastine), Breast Cancer Resistance Proteins (BCRP) (methotrexate), and Organic Anion Transporting Polypeptide OATP1B3 (CCB8) at concentrations at least 15 times higher than those used clinically; however, it inhibited OATP1B1 (estradiol-17β-glucuronide) transport at concentrations only 5 times higher than clinically used. Thus, the risk of in vivo interaction with substrates of MRP, OCT1, P-gp, BCRP, and OATP1B3 is unlikely at the 25 mg/m² dose. The risk of interaction with the OATP1B1 transporter protein is possible, particularly during infusion (lasting 1 hour) and within 20 minutes after the end of infusion (see section "Interaction with other medicinal products and other forms of interaction").

Elimination. After a 1-hour intravenous infusion of 25 mg/m² [14C]-cabazitaxel, approximately 80% of the administered dose was excreted within 2 weeks. Cabazitaxel is primarily excreted in feces as numerous metabolites (76% of dose); renal excretion of cabazitaxel and its metabolites accounts for less than 4% of the dose (2.3% of unchanged drug in urine).

Cabazitaxel has a high plasma clearance of 48.5 L/h (26.4 L/h/m² for patients with a median body surface area of 1.84 m²) and a prolonged terminal half-life of 95 hours.

Special populations

Elderly. In the pharmacokinetic analysis population of 70 patients aged 65 years and older (57 patients aged 65–75 years and 13 patients aged ≥75 years), no effect of age on cabazitaxel pharmacokinetics was observed.

Children. The safety and efficacy of Cabazitaxel Accord in children and adolescents (under 18 years of age) have not been established.

Hepatic impairment. Cabazitaxel is primarily eliminated via hepatic metabolism.

A dedicated study in 43 oncology patients with hepatic dysfunction showed no effect of mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) or moderate (total bilirubin >1.5 to ≤3.0 × ULN) hepatic dysfunction on cabazitaxel pharmacokinetics. The maximum tolerated dose (MTD) in these patients was 20 mg/m² and 15 mg/m², respectively.

In three patients with severe hepatic dysfunction (total bilirubin >3 × ULN), a 39% reduction in drug clearance was observed compared to patients with mild hepatic dysfunction, indicating some effect of severe hepatic dysfunction on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severe hepatic dysfunction has not been established.

Based on safety and tolerability data, the cabazitaxel dose should be reduced in patients with mild hepatic dysfunction (see sections "Special warnings and precautions for use" and "Dosage and administration"). Cabazitaxel Accord is contraindicated in patients with severe hepatic dysfunction (see section "Contraindications").

Renal impairment. Cabazitaxel is minimally excreted by the kidneys (2.3% of the administered dose). Population pharmacokinetic analysis in 170 patients, including 14 patients with moderate renal impairment (creatinine clearance 30–50 mL/min) and 59 patients with mild renal impairment (creatinine clearance 50–80 mL/min), showed that mild and moderate renal impairment had no significant effect on cabazitaxel pharmacokinetics. This was confirmed by a dedicated comparative pharmacokinetic study in patients with solid malignancies who had normal renal function (8 patients), moderate renal dysfunction (8 patients), or severe renal dysfunction (9 patients), and who received multiple cycles of cabazitaxel as single intravenous infusions at doses up to 25 mg/m².

Environmental risk assessment

Environmental risk assessment studies indicated that the use of cabazitaxel will not pose a significant risk to the aquatic environment (see section "Special warnings and precautions for use" regarding disposal of unused medicinal product).

Clinical characteristics.

Indications.

In combination with prednisone or prednisolone, the medicinal product Cabazitaxel Accord is indicated for the treatment of adult patients with hormone-refractory metastatic prostate cancer who have previously been treated with a docetaxel-containing regimen (see section "Pharmacodynamics").

Contraindications.

Hypersensitivity reactions to cabazitaxel and to other taxanes, polysorbate 80 or to any of the excipients of the medicinal product in medical history.

Neutrophil count less than 1500/mm³.

Severe hepatic impairment (total bilirubin > 3 × ULN).

Concomitant vaccination with yellow fever vaccine (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

In vitro studies have shown that cabazitaxel is metabolized predominantly by CYP3A (80–90%) (see section "Pharmacokinetics").

CYP3A inhibitors. Repeated concomitant administration of cabazitaxel with ketoconazole (dose of the latter 400 mg daily), a potent CYP3A inhibitor, results in a 20% reduction in cabazitaxel clearance and a corresponding 25% increase in AUC. Concomitant administration of the drug with potent CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) will lead to increased cabazitaxel concentrations. Therefore, concomitant administration of cabazitaxel with potent CYP3A inhibitors should be avoided (see sections "Special precautions for use" and "Method of administration and dosage").

Concomitant administration of the drug with aprepitant, a moderate CYP3A inhibitor, does not affect cabazitaxel clearance.

CYP3A inducers. Repeated concomitant administration of cabazitaxel with rifampicin (dose of the latter 600 mg daily), a potent CYP3A inducer, results in a 21% increase in cabazitaxel clearance and a corresponding 17% decrease in AUC. Concomitant administration of the drug with potent CYP3A inducers (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) will lead to decreased cabazitaxel concentrations. Therefore, concomitant administration of cabazitaxel with potent CYP3A inducers should be avoided (see sections "Special precautions for use" and "Method of administration and dosage"). In addition, patients should also refrain from taking preparations containing St. John's wort.

OATP1B1. In vitro studies have also demonstrated that cabazitaxel inhibits organic anion transporting polypeptides OATP1B1. There is a risk of interaction with OATP1B1 substrates (e.g., statins, valsartan, repaglinide), particularly during infusion (lasting 1 hour) and for 20 minutes after completion of infusion. It is recommended to maintain a 12-hour interval before infusion and at least 3 hours after completion of infusion before administering OATP1B1 substrates.

Vaccinations. Administration of live or live attenuated vaccines to patients whose immune system is weakened by chemotherapy may result in severe or fatal infections. Patients receiving cabazitaxel should refrain from vaccination with live attenuated vaccines. Inactivated or killed vaccines may be administered, but the immune response to such vaccines may be diminished.

Special precautions.

Hypersensitivity reactions. All patients should be premedicated prior to the start of infusion with Cabazitaxel Accord (see section "Dosage and administration").

Patients should be closely monitored for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within minutes after the start of Cabazitaxel Accord infusion; therefore, medications and equipment for the treatment of hypotension and bronchospasm should be readily available. Severe reactions may include generalized rash/erythema, hypotension, and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of Cabazitaxel Accord and appropriate therapy. Patients experiencing hypersensitivity reactions must discontinue treatment with Cabazitaxel Accord (see section "Contraindications").

Myelosuppression. Myelosuppression manifests as neutropenia, anemia, thrombocytopenia, and pancytopenia (see subsections "Neutropenia" and "Anemia" below).

Neutropenia. Patients receiving Cabazitaxel Accord may be given prophylactic G-CSF according to recommendations of the American Society of Clinical Oncology (ASCO) and/or current institutional guidelines to reduce the risk of neutropenic complications (febrile neutropenia, prolonged neutropenia, or neutropenic infection) or for their treatment.

Primary prophylaxis with G-CSF should be considered for patients with clinical characteristics placing them at high risk (age ≥65 years, poor performance status, prior episodes of febrile neutropenia, history of extensive radiation fields, poor nutritional status, or other serious comorbidities) and increased susceptibility to complications from prolonged neutropenia. The use of G-CSF has been shown to reduce the frequency and severity of neutropenia.

Neutropenia is the most common adverse reaction associated with Cabazitaxel Accord (see section "Adverse reactions"). Complete blood counts should be monitored weekly during the first cycle and before each subsequent treatment cycle. Dose adjustments may be necessary. Dose reduction is required in cases of febrile neutropenia or prolonged neutropenia despite appropriate management (see section "Dosage and administration"). Treatment should only be resumed once neutrophil counts have recovered to ≥1500/mm³ (see section "Contraindications").

Gastrointestinal disorders. Symptoms such as abdominal pain, tenderness on palpation, fever, persistent constipation, and diarrhea—both with and without neutropenia—may be early signs of serious gastrointestinal toxicity and should be promptly recognized and treated. Temporary delay or discontinuation of cabazitaxel therapy may be necessary.

Risk of diarrhea, nausea, vomiting, dehydration. If diarrhea develops after administration of Cabazitaxel Accord, standard anti-diarrheal agents may be used. Appropriate measures for rehydration should also be implemented. Diarrhea may occur more frequently in patients previously treated with abdominal-pelvic irradiation. Dehydration is more commonly observed in patients aged ≥65 years. Adequate rehydration measures should be taken, along with monitoring and correction of serum electrolyte levels, particularly potassium.

Treatment delay or dose reduction of the medicinal product may be necessary in case of ≥Grade III diarrhea (see section "Dosage and administration"). If nausea or vomiting occurs, standard antiemetic agents may be administered.

Risk of serious gastrointestinal reactions. Cases of gastrointestinal bleeding and perforation, intestinal obstruction, and colitis—including fatal outcomes—have been reported in patients treated with cabazitaxel (see section "Adverse reactions"). Caution is recommended when treating patients at highest risk of gastrointestinal complications: those with neutropenia, elderly patients, patients receiving concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, or anticoagulants, and those with a history of pelvic radiotherapy or prior gastrointestinal disorders such as ulcers or gastrointestinal bleeding.

Peripheral neuropathy. Peripheral neuropathy—including peripheral sensory neuropathy (e.g., paresthesia, dysesthesia) and peripheral motor neuropathy—has been observed in patients receiving cabazitaxel. Patients experiencing neuropathic symptoms such as pain, burning sensation, tingling, numbness, or weakness should inform their physician before continuing treatment. Physicians should assess patients for signs or worsening of neuropathy prior to each drug administration. Treatment should be delayed until symptoms subside. In cases of persistent peripheral neuropathy ≥Grade II, the cabazitaxel dose should be reduced from 25 mg/m² to 20 mg/m² (see section "Dosage and administration").

Anemia. Anemia has been observed in patients receiving cabazitaxel (see section "Adverse reactions"). Hemoglobin and hematocrit levels should be checked before starting cabazitaxel therapy and whenever patients present signs or symptoms of anemia or blood loss. The use of this medicinal product is recommended with caution in patients with hemoglobin levels <10 g/dL, and appropriate measures should be taken when clinically indicated.

Risk of renal impairment. Renal disorders have been reported in association with sepsis, severe dehydration due to diarrhea or vomiting, and obstructive uropathy. Cases of renal failure, including fatal outcomes, have occurred. In case of renal dysfunction, appropriate diagnostic measures should be initiated and intensive treatment started.

Adequate hydration must be maintained throughout cabazitaxel therapy. Patients should promptly report any significant changes in daily urine output. Serum creatinine levels should be measured before treatment initiation, with each blood test, and whenever a change in urine volume is reported. Cabazitaxel treatment must be discontinued in case of any worsening of renal function to ≥Grade III renal impairment according to CTCAE (Common Terminology Criteria for Adverse Events) version 4.0.

Respiratory system disorders. Interstitial pneumonia/pneumonitis and interstitial lung disease, which may be fatal, can occur (see section "Adverse reactions").

In case of development or worsening of pulmonary symptoms, appropriate diagnostic measures should be taken and intensive treatment initiated. Interruption of cabazitaxel therapy is recommended until a diagnosis is established. Early supportive therapy may improve patient outcomes. The decision to resume cabazitaxel treatment should be carefully evaluated.

Risk of cardiac arrhythmias. Cases of cardiac arrhythmias, most commonly tachycardia and atrial fibrillation, have been reported (see section "Adverse reactions").

Elderly patients. The likelihood of certain adverse reactions, including neutropenia and febrile neutropenia, may be higher in elderly patients (aged ≥65 years) (see section "Adverse reactions").

Patients with hepatic impairment. Cabazitaxel Accord is contraindicated in patients with severe hepatic dysfunction (total bilirubin >3 × ULN) (see sections "Pharmacokinetics" and "Contraindications"). Dose reduction is required in patients with mild hepatic dysfunction (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) (see sections "Pharmacokinetics" and "Dosage and administration").

Interactions. Concomitant use of the drug with strong CYP3A4 inhibitors should be avoided, as they may increase plasma concentrations of cabazitaxel (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration"). If concomitant use with a strong CYP3A4 inhibitor cannot be avoided, close monitoring for signs of toxicity and dose reduction of cabazitaxel are recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Concomitant use with strong CYP3A4 inducers should be avoided, as they may reduce plasma concentrations of cabazitaxel (see sections "Interaction with other medicinal products and other forms of interaction" and "Dosage and administration").

Excipients. This medicinal product contains 1185 mg of alcohol (ethanol) per vial, equivalent to 395 mg/mL.

The amount of alcohol per dose is equivalent to 30 mL of beer or 12 mL of wine.

The small amount of alcohol in this medicinal product is unlikely to have a noticeable effect.

Harmful for individuals with alcohol dependence.

Should be taken into account when used in high-risk groups, particularly patients with liver disease or epilepsy, and patients with a history of alcoholism.

Cabazitaxel Accord may affect young children, for example by causing drowsiness. The alcohol content in the medicinal product may alter the effects of other medicinal products. Consultation with a physician is necessary before using this medicinal product if other medicinal products are being used concomitantly. Pregnant women and women during breastfeeding should consult a physician before using the medicinal product.

Patients with alcohol dependence should consult a physician before using Cabazitaxel Accord.

Administration of 60 mg of Cabazitaxel Accord to an adult weighing 70 kg may result in an ethanol dose of 17 mg/kg, potentially increasing blood alcohol concentration (BAC) to 2.8 mg/100 mL. For comparison, BAC in an adult who consumed 500 mL of beer is approximately 50 mg/100 mL.

Use during pregnancy or breastfeeding.

Contraception. Due to the genotoxic risk of cabazitaxel, men should use effective contraception during treatment and for 6 months after discontinuation of cabazitaxel therapy.

Pregnancy. Data on the use of cabazitaxel in pregnant women are lacking. Animal studies have shown toxic effects on the reproductive system at maternally toxic doses, and cabazitaxel has been shown to cross the placental barrier. Like other cytotoxic medicinal products, cabazitaxel may have harmful effects on the fetus when administered to pregnant women.

Cabazitaxel is not indicated for use in women.

Breastfeeding. Pharmacokinetic data from animal studies indicate excretion of cabazitaxel and its metabolites into milk. Risk to breastfed infants cannot be excluded. Cabazitaxel should not be used during breastfeeding.

Fertility. Animal studies have shown effects of cabazitaxel on the male reproductive system of rats and dogs without any functional impact on fertility. However, considering the pharmacological activity of taxanes, their genotoxic potential via an aneugenic mechanism, and the effects of several compounds in this class on fertility in animal studies, an effect on male fertility in humans cannot be ruled out. Given the potential exposure via seminal fluid, men receiving cabazitaxel should avoid exposing others to semen throughout the treatment period. Men undergoing cabazitaxel therapy are advised to seek counseling regarding sperm cryopreservation prior to starting treatment.

Ability to affect reaction speed when driving or operating machinery.

Cabazitaxel Accord has a moderate influence on the ability to drive and operate machinery due to possible side effects such as increased fatigue and dizziness. Patients should refrain from driving and operating machinery if they experience these adverse reactions during treatment.

Administration and Dosage.

The use of the medicinal product Cabazitaxel Accord is possible only in specialized institutions where cytotoxic therapy is administered, and its administration must be performed exclusively under the supervision of a physician experienced in anticancer chemotherapy. It is necessary to ensure the availability of medicinal products and equipment for the treatment of severe hypersensitivity reactions, such as arterial hypotension and bronchospasm (see section "Special Warnings and Precautions for Use").

Premedication. To reduce the risk and severity of hypersensitivity reactions, premedication should be administered intravenously at least 30 minutes before each administration of Cabazitaxel Accord:

• antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg, or equivalent);
• corticosteroids (dexamethasone 8 mg or equivalent);
• H2-receptor antagonists (ranitidine or equivalent) (see section "Special Warnings and Precautions for Use").

Prophylactic oral or intravenous antiemetic agents are recommended as needed.

Adequate hydration should be maintained throughout the treatment period to prevent complications, including renal impairment.

Dosage. The recommended dose of Cabazitaxel Accord for adults is 25 mg/m², administered as a one-hour intravenous infusion once every 3 weeks in combination with daily oral prednisone or prednisolone 10 mg throughout the treatment period.

Dose adjustment. Dosage adjustments should be made if adverse reactions develop in the patient (see Table 5).

Table 5

Recommended dose adjustments in the event of adverse reactions in patients

receiving the medicinal product

Adverse reactions	Dose adjustment
Prolonged neutropenia ≥ grade III (longer than 1 week), despite appropriate medical treatment including use of G-CSF.	Withhold treatment until neutrophil count is > 1500 cells/mm3, then reduce the dose of Cabazitaxel Accord from 25 mg/m2 to 20 mg/m2.
Febrile neutropenia or neutropenic infection.	Withhold treatment until improvement or recovery and until neutrophil count is > 1500 cells/mm3, then reduce the dose of Cabazitaxel Accord from 25 mg/m2 to 20 mg/m2.
Diarrhea ≥ grade III or persistent diarrhea, despite appropriate medical treatment and correction of fluid and electrolyte imbalances.	Withhold treatment until improvement or recovery, then reduce the dose of Cabazitaxel Accord from 25 mg/m2 to 20 mg/m2.
Peripheral neuropathy ≥ grade II.	Withhold treatment until reduction or resolution of adverse reaction symptoms, then reduce the dose of Cabazitaxel Accord from 25 mg/m2 to 20 mg/m2.

If any of these reactions continue to occur at a dose of 20 mg/m², further dose reduction to 15 mg/m² or discontinuation of the medicinal product Cabazitaxel Accord should be considered. Data in patients receiving doses below 20 mg/m² are limited.

Special patient groups

Patients with hepatic impairment. Cabazitaxel is predominantly metabolized in the liver. In patients with mild hepatic dysfunction (total bilirubin > ULN to ≤ 1.5 × ULN or AST > 1.5 × ULN), the cabazitaxel dose should be reduced to 20 mg/m². Administration of cabazitaxel to patients with mild hepatic dysfunction requires caution and close monitoring of safety parameters.

In patients with moderate hepatic dysfunction (total bilirubin > 1.5 to ≤ 3.0 × ULN), the MTD of the drug was 15 mg/m². If treatment with the drug is planned in patients with moderate hepatic dysfunction, the cabazitaxel dose should not exceed 15 mg/m². However, data on efficacy with this dose are currently limited.

Cabazitaxel is contraindicated in patients with severe hepatic dysfunction (total bilirubin > 3 × ULN) (see sections «Pharmacokinetics», «Special instructions» and «Contraindications»).

Patients with renal impairment. Cabazitaxel is minimally excreted by the kidneys. Dose adjustment is not recommended for patients with renal impairment who do not require hemodialysis. For patients with end-stage renal disease (creatinine clearance (CLCR) < 15 ml/min/1.73 m²), the drug should be administered with caution and careful monitoring during treatment due to their condition and limited available data (see sections «Pharmacokinetics» and «Special instructions»).

Elderly patients. There are no recommendations for special dose adjustment of the medicinal product Cabazitaxel Accord in elderly patients (see also sections «Pharmacokinetics», «Special instructions» and «Side effects»).

Concomitant use of medicinal products. Concomitant use of medicinal products that are strong inducers or strong inhibitors of CYP3A should be avoided (see sections «Interaction with other medicinal products and other forms of interaction» and «Special instructions»).

Children. The medicinal product Cabazitaxel Accord is not indicated for use in children. Safety and efficacy of this medicinal product in children and adolescents have not been established.

Method of administration. The medicinal product Cabazitaxel Accord is intended for intravenous use.

Precautions to be taken prior to handling or administration of the medicinal product. Only personnel specially trained in handling cytotoxic agents should handle Cabazitaxel Accord. Pregnant staff should not be involved in handling the product. Specific precautions for handling Cabazitaxel Accord are described in the subsection «Special precautions for disposal and other handling of the medicinal product».

Instructions for preparation and administration of the drug are provided in the subsection «Special precautions for disposal and other handling of the medicinal product».

Special precautions for disposal and other handling of the medicinal product. As with any other antineoplastic agent, care should be taken during handling and preparation of solutions of Cabazitaxel Accord, using closed-system devices, personal protective equipment (e.g., gloves), and performing preparatory procedures. In case of skin contact at any stage of handling, wash immediately and thoroughly with soap and water. In case of contact with mucous membranes, rinse immediately and thoroughly with water.

Preparation of solution for intravenous administration

IT IS PROHIBITED to use the medicinal product in combination with other medicinal products containing cabazitaxel at different concentrations. The medicinal product Cabazitaxel Accord contains 20 mg/ml of cabazitaxel (nominal volume of at least 3 ml).

Each vial is for single use only and should be used immediately. Any unused solution should be discarded. More than one vial of Cabazitaxel Accord may be required to administer the prescribed dose.

The dilution process for preparing the infusion solution must be performed under aseptic conditions.

Preparation of infusion solution

Step 1 Under aseptic conditions, using a graduated syringe with a needle, draw up the required amount of Cabazitaxel Accord medicinal product. For example, for a 45 mg cabazitaxel dose, 2.25 mL of Cabazitaxel Accord will be required.

Step 2 Transfer into a sterile, non-PVC container containing an infusion solution: 5% glucose solution or 9 mg/mL (0.9%) sodium chloride. The concentration of the infusion solution should be between 0.10 mg/mL and 0.26 mg/mL. Step 3 Remove the syringe and gently mix the contents of the infusion bag or vial by swirling it in your hands. The infusion solution should be uniform and clear. Step 4 Prior to administration of this infusion solution, as with all parenteral medicinal products, it should be inspected visually. If the solution becomes supersaturated, crystals may form over time. In such a case, the solution should not be used and must be discarded.

The infusion solution should be used immediately. However, if storage conditions described in the section "Shelf life" are observed, the solution remains suitable for use for an additional period.

During infusion, it is recommended to use an in-line filter with a nominal pore diameter of 0.22 µm (which may also be indicated as 0.2 µm).

Infusion containers containing PVC or infusion systems containing polyurethane must not be used for the preparation and administration of Cabazitaxel Accord.

Cabazitaxel Accord must not be mixed with any other medicinal products except those specified above.

Any unused volume of the medicinal product or waste should be disposed of in accordance with local requirements.

Children.

The safety and efficacy of Cabazitaxel Accord in children (under 18 years of age) have not been established.

Overdose.

There are no known antidotes for cabazitaxel. Expected complications of overdose may include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. In case of overdose, the patient should be hospitalized in a specialized facility and kept under close observation. Therapy with G-CSF should be initiated as soon as possible after detection of overdose. Other appropriate symptomatic measures should also be taken.

Adverse reactions

Short description of the safety profile

The safety of cabazitaxel in combination with prednisone or prednisolone was evaluated in 3 randomized, open-label, controlled studies (TROPIC, PROSELICA, and CARD), involving 1092 patients with hormone-refractory metastatic prostate cancer who received 25 mg/m² of cabazitaxel once every 3 weeks. Patients received a median of 6 to 7 cycles of cabazitaxel treatment.

The frequency derived from the pooled analysis of these 3 studies is presented below and in the list (see Table 6).

The most common adverse reactions of all grades were: anemia (99.0%), leukopenia (93.0%), neutropenia (87.9%), thrombocytopenia (41.1%), diarrhea (42.1%), fatigue (25.0%), and asthenia (15.4%). The most common adverse reactions of ≥ Grade III occurring in at least 5% of patients receiving cabazitaxel were neutropenia (73.1%), leukopenia (59.5%), anemia (12.0%), febrile neutropenia (8.0%), and diarrhea (4.7%).

Treatment discontinuation due to adverse reactions occurred at a similar frequency across the 3 studies (18.3% in TROPIC, 19.5% in PROSELICA, and 19.8% in CARD) among patients receiving cabazitaxel. The most common adverse reactions (>1.0%) leading to discontinuation of cabazitaxel were hematuria, increased fatigue, and neutropenia.

Adverse reactions are listed in Table 6 by MedDRA system organ classes and frequency of occurrence. Within each frequency group, adverse reactions are listed in order of decreasing severity. Severity of adverse reactions was determined according to CTCAE 4.0 (Grade ≥ III = G ≥ 3). Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

Table 6

Adverse reactions and blood disorders reported with cabazitaxel in combination with prednisone or prednisolone in the pooled analysis study (n = 1092)

System organ class	Adverse reactions	All grades n (%)			Grade > 3 n(%)
		Very common	Common	Uncommon
Infections and infestations	Neutropenic infection/sepsis*		48 (4.4)		42 (3.8)
	Septic shock			10 (0.9)	10 (0.9)
	Sepsis		13 (1.2)		13 (1.2)
	Cellulitis			8 (0.7)	3 (0.3)
	Urinary tract infection		103 (9.4)		19 (1.7)
	Influenza		22 (2.0)		0
	Cystitis		22 (2.0)		2 (0.2)
	Upper respiratory tract infection		23 (2.1)		0
	Herpes zoster		14 (1.3)		0
	Candidiasis		11 (1.0)		1 (< 0.1)
Blood and lymphatic system disorders	Neutropeniaa*	950 (87.9)			790 (73.1)
	Anemiaa	1073 (99.0)			130 (12.0)
	Leukopeniaa	1008 (93.0)			645 (59.5)
	Thrombocytopeniaa	478 (44.1)			44 (4.1)
	Febrile neutropenia		87 (8.0)		87 (8.0)
Immune system disorders	Hypersensitivity		7 (0.6)		0
Metabolism and nutrition disorders	Decreased appetite	192 (17.6)			11 (1.0)
	Dehydration		27 (2.5)		11 (1.0)
	Hyperglycemia		11 (1.0)		7 (0.6)
	Hypokalemia			8 (0.7)	2 (0.2)
Psychiatric disorders	Insomnia		45 (4.1)		0
	Anxiety		13 (1.2)		0
	Confusional state		12 (1.1)		2 (0.2)
Nervous system disorders	Dysgeusia		64 (5.9)		0
	Taste disturbance		56 (5.1)		0
	Peripheral neuropathy		40 (3.7)		2 (0.2)
	Peripheral sensory neuropathy		89 (8.2)		6 (0.5)
	Polyneuropathy			9 (0.8)	2 (0.2)
	Paraesthesia		46 (4.2)		0
	Hypoesthesia		18 (1.6)		1 (< 0.1)
	Dizziness		63 (5.8)		0
	Headache		56 (5.1)		1 (< 0.1)
	Lethargy		15 (1.4)		1 (< 0.1)
	Sciatica			9 (0.8)	1 (< 0.1)
Eye disorders	Conjunctivitis		11 (1.0)		0
	Increased lacrimation		22 (2.0)		0
Ear and labyrinth disorders	Tinnitus			7 (0.6)	0
	Vertigo		15 (1.4)		1 (< 0.1)
Cardiac disorders*	Atrial fibrillation		14 (1.3)		5 (0.5)
	Tachycardia		11 (1.0)		1 (< 0.1)
Vascular disorders	Arterial hypotension		38 (3.5)		5 (0.5)
	Deep vein thrombosis		12 (1.1)		9 (0.8)
	Arterial hypertension		29 (2.7)		12 (1.1)
	Orthostatic hypotension			6 (0.5)	1 (< 0.1)
	Flushing		23 (2.1)		1 (< 0.1)
	Hot flush			9 (0.8)	0
Respiratory, thoracic and mediastinal disorders	Dyspnea		97 (8.9)		9 (0.8)
	Cough		79 (7.2)		0
	Oropharyngeal pain		26 (2.4)		1 (< 0.1)
	Pneumonia		26 (2.4)		16 (1.5)
	Pulmonary embolism		30 (2.7)		23 (2.1)
Gastrointestinal disorders	Diarrhea	460 (42.1)			51 (4.7)
	Nausea	347 (31.8)			14 (1.3)
	Vomiting	207 (19.0)			14 (1.3)
	Constipation	202 (18.5)			8 (0.7)
	Abdominal pain		105 (9.6)		15 (1.4)
	Dyspepsia		53 (4.9)		0
	Upper abdominal pain		46 (4.2)		1 (< 0.1)
	Hemorrhoids		22 (2.0)		0
	Gastroesophageal reflux disease		26 (2.4)		1 (< 0.1)
	Rectal hemorrhage		14 (1.3)		4 (0.4)
	Dry mouth		19 (1.7)		2 (0.2)
	Abdominal distension		14 (1.3)		1 (< 0.1)
	Stomatitis		46 (4.2)		2 (0.2)
	Intestinal obstruction*			7 (0.6)	5 (0.5)
	Gastritis			10 (0.9)	0
	Colitis*			10 (0.9)	5 (0.5)
	Gastrointestinal perforation			3 (0.3)	1 (< 0.1)
	Gastrointestinal hemorrhage			2 (0.2)	1 (< 0.1)
Skin and subcutaneous tissue disorders	Alopecia		80 (7.3)		0
	Dry skin		23 (2.1)		0
	Erythema			8 (0.7)	0
	Nail disorders		18 (1.6)
Musculoskeletal and connective tissue disorders	Back pain	166 (15.2)			24 (2.2)
	Arthralgia		88 (8.1)		9 (0.9)
	Limb pain		76 (7.0)		9 (0.8)
	Muscle spasms		51 (4.7)		0
	Myalgia		40 (3.7)		2 (< 0.2)
	Musculoskeletal chest pain		34 (3.1)		3 (0.3)
	Muscle weakness		31 (2.8)		1 (0.2)
	Flank pain		17 (1.6)		5 (0.5)
Renal and urinary disorders	Acute kidney injury		21 (1.9)		14 (1.3)
	Kidney injury			8 (0.7)	6 (0.5)
	Dysuria		52 (4.8)		0
	Renal colic		14 (1.3)		2 (0.2)
	Hematuria	205 (18.8)			33 (3.0)
	Frequency of urination		26 (2.4)		2 (0.2)
	Hydronephrosis		25 (2.3)		13 (1.2)
	Urinary retention		36 (3.3)		4 (0.4)
	Urinary incontinence		22 (2.0)		0
	Ureteric obstruction			8 (0.7)	6 (0.5)
Reproductive system and breast disorders	Pelvic pain		20 (1.8)		5 (0.5)
General disorders and administration site conditions	Increased fatigue	333 (30.5)			42 (3.8)
	Asthenia	227 (20.8)			32 (2.9)
	Pyrexia		90 (8.2)		5 (0.5)
	Peripheral edema		96 (8.8)		2 (0.2)
	Mucosal inflammation		23 (2.1)		1 (< 0.1)
	Pain		36 (3.3)		7 (0.6)
	Chest pain		11 (1.0)		2 (0.2)
	Edema			8 (0.7)	1 (< 0.1)
	Chills		12 (1.1)		0
	Malaise		21 (1.9)		0
Investigations	Weight decreased		81 (7.4)		0
	Increased AST level		13 (1.2)		1 (< 0.1)
	Increased transaminases			7 (0.6)	1 (< 0.1)

a Based on laboratory parameter assessments.

* See detailed description below.

Description of selected adverse reactions

Neutropenia and associated clinical manifestations

The incidence of laboratory-confirmed grade ≥ III neutropenia was 81.7%. The incidence of adverse reactions of neutropenia with clinical manifestations and febrile neutropenia was 21.3% and 7.5%, respectively. Neutropenia was the most common adverse reaction leading to discontinuation of the medicinal product (2.4%). Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases led to fatal outcomes. It has been demonstrated that the use of G-CSF reduces the frequency and severity of neutropenia (see sections "Special precautions" and "Dosage and administration").

The incidence of laboratory-confirmed grade ≥ III neutropenia varied depending on G-CSF use from 44.7% to 76.7%. The lowest incidence was observed with prophylactic use of G-CSF: the incidence of grade ≥ III febrile neutropenia ranged from 3.2% to 8.6%.

Neutropenic complications (including febrile neutropenia, neutropenic infection/sepsis, and neutropenic colitis), which in some cases led to fatal outcomes, were recorded in 4.0% of patients receiving primary prophylaxis with G-CSF, and in 12.8% of patients in other cases.

Cardiac disorders and arrhythmias

According to the results of the pooled analysis, cardiac disorders were reported in 5.5% of patients, of which 1.1% experienced grade ≥ III cardiac arrhythmia. The incidence of tachycardia in the cabazitaxel treatment group was 1.0%, with less than 0.1% being grade ≥ III events. The incidence of atrial fibrillation in the cabazitaxel treatment group was 1.3%. Cases of heart failure were observed in 2 patients (0.2%), one of which had a fatal outcome. One case of fatal ventricular fibrillation (0.3%) and cardiac arrest in 3 patients (0.5%) were reported. None of these events were considered by the investigator to be related to cabazitaxel administration.

Hematuria

In the pooled analysis, the incidence of hematuria of all grades was 18.8% at a dose of 25 mg/m² (see section "Pharmacodynamics"). Causes of confounding factors during reporting, including disease progression, instrumentation, infection, or therapy with anticoagulants/NSAIDs/acetylsalicylic acid, were identified in nearly half of the cases.

Other laboratory parameter abnormalities

The incidence of grade ≥ III anemia, increased AST, ALT, and bilirubin levels, based on laboratory parameter deviation analysis, was 12.0%, 1.3%, 1.0%, and 0.5%, respectively.

Gastrointestinal disorders

Cases of colitis (including enterocolitis and neutropenic enterocolitis) and gastritis were reported. Cases of gastrointestinal hemorrhage, gastrointestinal perforation, and ileus (intestinal obstruction) were also observed (see section "Special precautions").

Respiratory system disorders

Cases of interstitial pneumonia/pneumonitis and interstitial lung disease, which may be fatal, have been reported; frequency is unknown (see section "Special precautions").

Renal and urinary system disorders

Uncommon cases of cystitis due to a flare-up inflammatory reaction in previously irradiated areas were reported, including cases of hemorrhagic cystitis.

Children

See section "Dosage and administration".

Other special patient groups

Elderly patients

Among 1092 patients who received cabazitaxel in prostate cancer studies, 755 patients were aged 65 years or older, including 238 patients aged 75 years or older.

The following adverse reactions were reported at least 5% more frequently in patients aged 65 years or older compared to younger patients: increased fatigue (33.5% vs. 23.7%), asthenia (23.7% vs. 14.2%), constipation (20.4% vs. 14.2%), and dyspnea (10.3% vs. 5.6%).

Neutropenia (90.9% vs. 81.2%) and thrombocytopenia (48.8% vs. 36.1%) were also observed at least 5% more frequently in patients aged ≥ 65 years compared to younger patients. Grade ≥ III neutropenia and febrile neutropenia were reported with the highest frequency difference between both age groups (14% and 4% higher, respectively, in patients aged ≥ 65 years compared to younger patients) (see sections "Dosage and administration" and "Special precautions").

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life.

Unopened vials

3 years.

After opening

Each vial is intended for single use and should be used immediately after opening. If the medicinal product is not used immediately after opening, the responsibility for the duration and conditions of storage of opened vials lies with the user.

After final dilution in an infusion bag/bottle

The infusion solution has been shown to remain chemically and physically stable for 8 hours (including 1 hour of infusion) when stored at room temperature (15–30 °C), and for 48 hours when stored refrigerated (including 1 hour of infusion).

From a microbiological standpoint, the infusion solution should be used immediately. If not used immediately after preparation, the responsibility for the duration and conditions of storage lies with the user. Generally, it can be stored for no more than 24 hours at 2–8 °C, except when dilution was performed under controlled and validated aseptic conditions.

Storage conditions.

The medicinal product does not require special storage temperature conditions. Protect from light by storing in the original packaging. Keep out of reach of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except as specified in the section "Special precautions".

Do not use polyvinyl chloride infusion containers and polyurethane infusion sets for the preparation and administration of the infusion solution.

Packaging. 3 ml (60 mg/3 ml) in a vial, 1 vial per pack.

Prescription status.

Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Sklad Importera/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and location of its operations.

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

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

Inquiries regarding substandard quality of the medicinal product; issues related to safety of use, improper use of the medicinal product, or complaints are accepted 24/7 via phone: +380993100335 or by email at: [email protected].

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