Cabazitaxel EVER Pharma^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Ever Valinject, GmbH (Austria)

Manufactured By

Ever Pharma Jena, GmbH (Germany)

Contact Information

EVER Neuro Pharma LLC (Russia)

ATC Code

L01CD04 (Cabazitaxel)

Active Substance

Cabazitaxel (Rec.INN registered by WHO)

Dosage Form

Cabazitaxel EVER Pharma®

Concentrate for solution for infusion 10 mg/1 ml: vial 6 ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, slightly yellowish solution.

Excipients: polysorbate 80, anhydrous ethanol, macrogol 300, anhydrous citric acid.

6 ml – colorless glass vials with a capacity of 10 ml (1) – cardboard boxes^×.

^× protective stickers may additionally be applied.

Clinical-Pharmacological Group

Antitumor drug. Alkaloid

Pharmacotherapeutic Group

Antineoplastic agents; plant alkaloids and other natural substances; taxanes

Pharmacological Action

Mechanism of action

Cabazitaxel is an antitumor agent that acts by disrupting the cellular microtubule network. Cabazitaxel binds to tubulin and promotes the assembly of tubulin into microtubules while simultaneously inhibiting their disassembly. This leads to the stabilization of microtubules, which ultimately inhibits mitotic and interphase cellular activity.

Pharmacodynamic effects

Cabazitaxel has demonstrated a broad spectrum of antitumor activity against advanced stages of human tumors xenografted into mice. Cabazitaxel is active against docetaxel-sensitive tumors. Furthermore, Cabazitaxel has shown activity against tumor models resistant to chemotherapy, including docetaxel.

Clinical efficacy and safety

Adult patients

The efficacy and safety of cabazitaxel in combination with prednisone or prednisolone were evaluated in a randomized, open-label, international, multicenter phase III study (study EFC6193) in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-containing chemotherapy regimens.

The primary endpoint of the study was overall survival (OS).

Secondary endpoints included progression-free survival (PFS), defined as the time from randomization to tumor progression, biochemical progression (based on prostate-specific antigen (PSA) level), pain progression, or death from any cause, whichever occurred first; tumor response rate based on RECIST criteria (Response Evaluation Criteria in Solid Tumors); PSA progression (defined as a ≥25% increase or >50% increase in PSA level in non-responding and responding patients, respectively); PSA response (a reduction in serum PSA concentration by at least 50%); pain progression (assessed using the Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire and the Analgesic Score (AS)); and pain intensity response (defined as a 2-point reduction from the baseline median PPI value without an increase in AS scores, or a ≥50% reduction in analgesic use compared to the baseline mean AS score without a simultaneous increase in pain intensity).

A total of 755 patients were randomized to receive cabazitaxel at a dose of 25 mg/m² body surface area intravenously every 3 weeks for a maximum of 10 cycles in combination with prednisone or prednisolone at a dose of 10 mg/day daily (number of patients 378) or mitoxantrone at a dose of 12 mg/m² intravenously every 3 weeks with prednisone or prednisolone at a dose of 10 mg orally daily (number of patients 377).

This study included patients over 18 years of age with metastatic castration-resistant prostate cancer with measurable lesions according to RECIST criteria or with non-measurable lesions but with rising PSA levels or the appearance of new lesions, and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Only patients with neutrophil count >1500/mm³, platelet count >100,000/mm³, hemoglobin concentration >10 g/dL, creatinine < 1.5 × ULN, total bilirubin < 1 × ULN, AST/SGOT < 1.5 × ULN and ALT/SGPT < 1.5 × ULN were included. Patients with a history of congestive heart failure or myocardial infarction within the last 6 months or patients with uncontrolled cardiac arrhythmias, angina and/or arterial hypertension were not included in the study.

Demographic characteristics, including race, and ECOG performance status (0-2) were balanced between the treatment groups. In the cabazitaxel group, the median age of patients was 68 years (46-92 years), and the racial distribution was: 83.9% Caucasian, 6.9% Mongoloid, 5.3% Negroid and 4% other races.

The median number of cycles was 6 cycles in the cabazitaxel group and 4 cycles in the mitoxantrone group. The number of patients who received the planned 10 cycles of therapy was 29.4% in the cabazitaxel group and 13.5% in the mitoxantrone group.

Overall survival was longer in the cabazitaxel group, the risk of death was reduced by 30% in the cabazitaxel group compared to the mitoxantrone group (hazard ratio=0.70, 95% CI (0.59-0.83)) (see Table 1 and Figure 1).

Table 1. Efficacy of cabazitaxel in study EFC6193 in the treatment of patients with metastatic castration-resistant prostate cancer

¹HR was estimated using the Cox model; a hazard ratio of less than 1 favors cabazitaxel.

Figure 1. Kaplan-Meier overall survival curves (study EFC6193)

Progression-free survival in the cabazitaxel group compared to the mitoxantrone group was 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.

The tumor response rate in the cabazitaxel group was significantly higher and amounted to 14.4% (95% CI: 9.6-19.3) versus 4.4% (95% CI: 1.6-7.2) in the group of patients receiving mitoxantrone therapy, p=0.0005.

The benefit of cabazitaxel was demonstrated for secondary endpoints assessed by changes in PSA level. The median time to PSA progression was 6.4 months (95% CI: 5.1-7.3) for patients in the cabazitaxel group compared to 3.1 months (95% CI: 2.2-4.4) in the mitoxantrone group, HR 0.75 months (95% CI: 0.63-0.90), p=0.0010. PSA response was observed in 39.2% of patients in the cabazitaxel group (95% CI: 33.9-44.5) versus 17.8% of patients in the mitoxantrone group (95% CI: 13.7-22.0), p=0.0002.

Mitoxantrone is indicated for the treatment of patients with hormone-resistant prostate cancer with pain syndrome. No statistically significant differences were observed between the two groups regarding pain progression or pain response rate.

In a multicenter, multinational, randomized, open-label, non-inferiority design phase III study (study EFC11785), 1200 patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-containing chemotherapy were randomized into 2 groups: therapy with cabazitaxel at a dose of 25 mg/m² (n=602) or at a dose of 20 mg/m² (n=598). The primary endpoint of the study was OS.

The study met its primary endpoint, demonstrating non-inferior efficacy of cabazitaxel at a dose of 20 mg/m² compared to the 25 mg/m² dose (see Table 2). The PSA response rate was statistically significantly higher in the cabazitaxel 25 mg/m² group (42.9%) compared to the 20 mg/m² group (29.5%), p< 0.001.

In the cabazitaxel 20 mg/m² group, the risk of PSA progression was statistically significantly higher than in the patient group with the 25 mg/m² dose (HR 1.195; 95% CI: 1.025-1.393). No statistically significant difference was observed between the comparison groups regarding other secondary endpoints (progression-free survival, tumor response and pain response, tumor and pain progression, 4 subcategories of the Functional Assessment of Cancer Therapy-Prostate (FACT-P)).

Table 2. Overall survival in study EFC11785 in the cabazitaxel 25 mg/m² group compared to the cabazitaxel 20 mg/m² group

Caba20 = Cabazitaxel 20 mg/m², Caba25 = Cabazitaxel 25 mg/m², P = prednisone/prednisolone, CI = confidence interval, LCI = lower confidence interval, UCI = upper confidence interval, OS – overall survival.

^α– Hazard ratio was estimated using the Cox Proportional Hazard model.

A ratio of < 1 indicates a lower risk in the cabazitaxel 20 mg/m² group compared to the 25 mg/m² dose.

Study EFC11785 showed a better safety profile for cabazitaxel at a dose of 20 mg/m². The safety profile of cabazitaxel 25 mg/m² observed in this study was quantitatively and qualitatively similar to the safety profile observed in study EFC6193. The median number of treatment courses for patients in the 20 mg/m² group was 6 courses (median treatment duration – 18 weeks), while the median treatment in the 25 mg/m² group was 7 cycles (median treatment duration – 21 weeks). In the cabazitaxel 25 mg/m² group, the drug dose was reduced from 25 to 20 mg/m² in 128 patients (21.5%), the cabazitaxel dose was reduced from 20 to 15 mg/m² in 19 patients (3.2%) and the drug dose was reduced from 15 to 12 mg/m² in 1 patient (0.2%). In the cabazitaxel 20 mg/m² group, the dose was reduced from 20 to 15 mg/m² in 58 patients (10.0%) and from 15 to 12 mg/m² in 9 patients (1.6%). All adverse events of any severity with a frequency of more than 10% were more common in patients receiving 25 mg/m² than in patients receiving 20 mg/m²: diarrhea (39.8% vs. 30.7%), nausea (32.1% vs. 24.5%), weakness (27.1% vs. 24.7%), hematuria (20.8% vs. 14.1%), asthenia (19.7% vs. 15.3%), decreased appetite (18.5% vs. 13.1%), vomiting (18.2% vs. 14.5%), constipation (18.0% vs. 17.6%), back pain (13.9% vs. 11.0%), clinical neutropenia (10.9% vs. 3.1%), urinary tract infection (10.8% vs. 6.9%), peripheral sensory neuropathy (10.6% vs. 6.6%) and dysgeusia (10.6% vs. 7.1%). Adverse events of severity ≥3 with a frequency greater than 5% were observed only in patients receiving the 25 mg/m² dose: clinical neutropenia (9.6% at 25 mg/m² vs. 2.4% at 20 mg/m²) and febrile neutropenia (9.2% at 25 mg/m² vs. 2.1% at 20 mg/m²). According to laboratory data, fewer hematological abnormalities were noted in patients receiving Cabazitaxel 20 mg/m² compared to patients receiving 25 mg/m²: 73.3% at 25 mg/m² vs. 41.8% at 20 mg/m² for neutropenia ≥ grade 3, 13.7% vs. 9.9%, respectively, for anemia ≥ grade 3, 4.2% vs. 2.6%, respectively, for thrombocytopenia ≥ grade 3.

Children

Cabazitaxel was evaluated in a multicenter, open-label study conducted in two phases (n=39). In phase 1, the maximum tolerated dose (MTD) of cabazitaxel was determined in children (aged 4-18 years) with recurrent or refractory solid tumors based on dose-limiting toxicities (DLTs). In phase 2 of the study, the activity and safety of cabazitaxel at the maximum tolerated dose were evaluated in children (aged 3-16 years) with recurrent or refractory high-grade glioma or diffuse intrinsic pontine glioma. The primary endpoints of phase 2 of the study were the determination of the objective response rate and the duration of response.

All patients received G-CSF prophylaxis. In phase 1 of the study, 23 patients received Cabazitaxel at doses ranging from 20 mg/m² to 35 mg/m². The maximum tolerated dose was 30 mg/m².

In phase 2 of the study, 16 patients received Cabazitaxel at a dose of 30 mg/m². Treatment efficacy was evaluated in 11 patients. No objective responses to therapy were observed in patients with diffuse intrinsic pontine glioma and high-grade glioma.

The most frequent adverse events of any severity occurring during treatment (≥25%) were weakness (39.1%), headache, diarrhea, nausea (all 34.8%), vomiting (30.4%) and constipation (26.1%) in phase 1 of the study; diarrhea (43.8%), dysphagia (37.5%), nausea (31.3%), vomiting and headache (both 25.0%) in patients in phase 2 of the study.

Serious adverse events, noted in more than 2 patients in any phase of the study, included: in phase 1 – febrile neutropenia in 5 patients (21.7%) and in phase 2 – febrile neutropenia, anaphylactic reaction and disease progression in 3 patients (18.8%).

Pharmacokinetics

Population analysis of pharmacokinetic parameters was performed in patients with locally advanced solid tumors, metastatic breast cancer and metastatic prostate cancer. These patients received Cabazitaxel in a dose range of 10-30 mg/m² body surface area weekly or every 3 weeks.

Absorption

After a one-hour intravenous infusion of cabazitaxel at a dose of 25 mg/m² body surface area in patients with metastatic prostate cancer, the C_max of cabazitaxel in plasma was reached at the end of the one-hour infusion T_max, the mean C_max was 226 ng/ml. The mean AUC was 991 ng×h/ml.

In patients with locally advanced solid tumors, no major deviations from dose proportionality of cabazitaxel plasma concentrations were observed in the dose range of 10-30 mg/m² body surface area.

Distribution

The volume of distribution at steady state (V_ss) 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 serum proteins was 89-92% and was non-saturable up to a concentration of 50000 ng/ml, which exceeds the C_max observed during clinical use of the drug. Cabazitaxel mainly binds to serum albumin (82.0%) and lipoproteins (87.9% for HDL, 69.8% for LDL and 55.8% for VLDL). In vitro in human blood, the blood-to-plasma concentration ratio ranges from 0.90 to 0.99, indicating similar distribution of cabazitaxel in blood and plasma. Studies in animals have shown that Cabazitaxel and its metabolites are excreted in breast milk, and Cabazitaxel also crosses the placental barrier.

Metabolism

Cabazitaxel is extensively metabolized in the liver (≥95%), mainly by CYP3A subfamily isoenzymes (80-90%). Cabazitaxel is the main compound circulating in plasma. In addition, 7 metabolites (including 3 active metabolites formed by O-demethylation) were identified in plasma. The plasma concentration of the main one of these metabolites is 5% of the plasma concentration of unchanged cabazitaxel. About 20 metabolites of cabazitaxel are excreted in urine and feces.

According to in vitro studies, a potential risk of inhibition of hepatic metabolism by cabazitaxel at clinically significant concentrations is possible for drugs that are mainly substrates of CYP3A subfamily isoenzymes. However, there is no potential risk of inhibition of metabolism of drugs that are substrates of other CYP isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP2D6). Also in vitro, Cabazitaxel does not induce CYP2C9 isoenzyme and CYP1A and CYP3A subfamily isoenzymes. Interaction studies conducted in humans have shown that Cabazitaxel (administered as a one-hour intravenous infusion at a dose of 25 mg/m² body surface area) did not alter the plasma concentrations of midazolam, a reference substrate for CYP3A subfamily isoenzymes. Thus, in vivo, Cabazitaxel does not inhibit CYP3A subfamily isoenzymes.

Strong inducers or inhibitors of CYP3A subfamily isoenzymes may alter plasma concentrations of cabazitaxel, since Cabazitaxel is mainly metabolized by CYP3A subfamily isoenzymes.

Prednisone, taken at a dose of 10 mg/day, does not alter the pharmacokinetics of cabazitaxel. In vitro, Cabazitaxel does not inhibit multidrug resistance-associated proteins (MRP1 and MRP2) or the organic cation transporter (OCT1). Cabazitaxel inhibits the transport of P-glycoprotein (Pgp) (digoxin, vinblastine), breast cancer resistance protein (BCRP) (methotrexate) and organic anion transporting polypeptides (OATP1B3) (cholecystokinin – CCK8) at concentrations at least 15 times higher than those observed clinically, and also inhibits OATP1B1 transport (estradiol-17β-glucuronide) at concentrations only 5 times higher than those observed clinically. Therefore, at a dose of 25 mg/m² body surface area, the risk of in vivo interaction of cabazitaxel with substrates of MRP, OCT1, Pgp, BCRP and OATP1B3 is unlikely. The risk of interaction of cabazitaxel with the OATP1B1 transporter is possible, especially during intravenous infusion (1 h) and up to 20 minutes after the end of the infusion (see section “Drug Interactions”).

Elimination

After a one-hour intravenous infusion of [¹⁴C]-cabazitaxel (radioisotope-labeled cabazitaxel) at a dose of 25 mg/m² of body surface area in cancer patients, approximately 80% of the administered dose is eliminated within 2 weeks. Cabazitaxel is primarily eliminated from the body via the intestine (in feces) as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and its metabolites accounts for less than 4% of the administered dose (2.3% of the administered dose is excreted unchanged in urine).

Cabazitaxel has a high plasma clearance of 48.5 L/h (26.44 L/h/m² of body surface area in patients with a median body surface area of 1.84 m²), and a long T_1/2 of 95 hours.

Pharmacokinetics in special patient groups

Elderly patients. In a population analysis of pharmacokinetic data from patients aged 65 years and older, no influence of age on the pharmacokinetics of cabazitaxel was observed.

Hepatic impairment.Cabazitaxel is eliminated from the body mainly through hepatic metabolism. Mild (serum total bilirubin >1 and ≤ 1.5×ULN or serum AST >1.5×ULN) and moderate (total bilirubin >1.5 and ≤ 3.0×ULN) hepatic impairment did not affect the pharmacokinetics of cabazitaxel in patients in a dedicated study. In patients with severe hepatic impairment (total bilirubin >3.0×ULN), a 39% decrease in cabazitaxel clearance was observed, indicating an effect of severe hepatic impairment on the pharmacokinetics of the drug.

Renal impairment.Cabazitaxel is minimally eliminated by the kidneys (2.3% of the dose). A population pharmacokinetic analysis of data from 170 patients, including 59 patients with mild renal impairment (CrCl 50-80 mL/min) and 14 patients with moderate renal impairment (CrCl 30-50 mL/min), showed that mild and moderate renal impairment did not have a significant effect on the pharmacokinetics of cabazitaxel. This was confirmed by a comparative pharmacokinetic study in patients with solid tumors with normal renal function (8 patients), patients with moderate renal impairment (8 patients), and patients with severe renal impairment (9 patients) who were treated with cabazitaxel as an intravenous infusion at a dose of up to 25 mg/m² of body surface area. The study included two patients with CrCl < 15 mL/min/1.73 m² (8 mL/min/1.73 m² and 14 mL/min/1.73 m²). Consequently, there are limited data on the use of cabazitaxel in patients with end-stage renal disease. Results from a pharmacokinetic and safety study of cabazitaxel in 8 patients showed that severe renal impairment did not significantly affect the pharmacokinetics and safety of cabazitaxel.

Pharmacokinetic interaction with other medicinal products

Cabazitaxel is primarily metabolized by CYP3A isoenzymes.

Concomitant administration of ketoconazole (400 mg twice daily), a strong inhibitor of CYP3A isoenzymes, resulted in a 20% decrease in cabazitaxel clearance with a corresponding 25% increase in its AUC. Concomitant administration of aprepitant, a moderate inhibitor of CYP3A isoenzymes, had no effect on the clearance and systemic exposure of cabazitaxel.

Concomitant administration of rifampin (600 mg once daily), a strong inducer of CYP3A isoenzymes, resulted in a 21% increase in clearance and a corresponding 17% decrease in AUC.

Children

The safety and efficacy of cabazitaxel in children and adolescents under 18 years of age have not been established.

Preclinical safety data

General toxicity

Effect on the liver. Bile duct hyperplasia, arterial/periarterial necrosis and/or hepatocellular necrosis were observed in dogs after single-dose administration (0.25 mg/kg (5 mg/m²)), 5-day administration (0.2 mg/kg (4 mg/m²)) and weekly administration (0.325 mg/kg (6.5 mg/m²)). In rats, Kupffer cell pigmentation and bile duct degeneration/regeneration in the liver were observed upon exposure to cabazitaxel at the highest lethal dose of 10 mg/kg (60 mg/m²) in a 10-cycle rat study.

Neurotoxicity

In mice, irreversible peripheral neurotoxicity, histologically characterized by degeneration of the sciatic nerves and lumbosacral nerve roots, was observed 10 or 20 weeks after a single administration. The no-observed-effect level (NOEL) was 15 mg/kg (45 mg/m²) after a single 1-hour intravenous administration.

Central neurotoxicity, histopathologically characterized by necrosis and/or vacuolation of neurons in the brain, axonal edema and degeneration of the cervical spinal cord, was noted in mice after a single one-hour intravenous infusion at a dose of 15 mg/kg (45 mg/m²), considered sufficient to exceed the maximum drug exposure in humans. The no-observed-effect level (NOEL) was 10 mg/kg (30 mg/m²) (approximately 7-fold the AUC in cancer patients at the recommended human dose) after a single 1-hour intravenous administration.

Eye disorders

Subcapsular edema/degeneration of lens fibers was observed in rats during a 10-cycle toxicity study at doses of 10-20 mg/kg (60-120 mg/m²) (approximately 2-fold the AUC in cancer patients at the recommended human doses). The no-observed-effect level (NOEL) for the lens was 5 mg/kg (30 mg/m²) (approximately the AUC in cancer patients at the recommended human doses). These effects were irreversible after 8 weeks.

Environmental risk assessment

Results of the environmental risk assessment showed that Cabazitaxel does not have any significant impact on the environment.

Carcinogenicity

Long-term animal studies to assess the carcinogenic potential of cabazitaxel have not been conducted.

Mutagenicity

The bacterial reverse mutation assay (Ames test) for cabazitaxel was negative.

Genotoxicity

Cabazitaxel showed no clastogenicity in an in vitro human lymphocyte test (Cabazitaxel did not induce structural chromosomal aberrations but increased the number of polyploid cells) and induced an increase in micronuclei in vivo in rats at doses ≥0.5 mg/kg. However, these genotoxicity data are inherent to the compound’s pharmacological activity (inhibition of tubulin depolymerization).

Teratogenicity

Preclinical studies in rats and rabbits have shown that Cabazitaxel has embryotoxic, fetotoxic and abortifacient effects. When female rats were administered Cabazitaxel intravenously once daily from day 6 to day 17 of gestation, embryofetal toxicity was observed at systemic exposures lower than those observed in humans receiving clinically relevant doses of cabazitaxel, and manifested as fetal death and reduced mean embryo weight associated with delayed skeletal ossification. Cabazitaxel did not cause fetal developmental abnormalities in rats and rabbits. Cabazitaxel crossed the placental barrier in rats.

After a single intravenous administration of [¹⁴C]-cabazitaxel at a dose of 0.08 mg/kg to lactating female rats, less than 1.5% of the administered dose was detected in breast milk within 24 hours.

Fertility Impairments

Cabazitaxel did not affect mating ability or fertility of male rats administered doses of 0.05, 0.1 and 0.2 mg/kg/day. However, in multi-cycle studies in rats administered Cabazitaxel intravenously at a dose of 5 mg/kg, degeneration of the seminal vesicles and atrophy of the seminiferous tubules were observed, and in dogs administered Cabazitaxel at a dose of 0.5 mg/kg, minimal testicular degeneration (minimal necrosis of single epithelial cells in the epididymis) was observed. Systemic exposure in animals was similar to or lower than that observed in humans at clinically relevant doses of cabazitaxel.

Indications

Cabazitaxel EVER Pharma^® is indicated for use in adults

• Treatment of metastatic castration-resistant prostate cancer in patients previously treated with a docetaxel-containing chemotherapy regimen (in combination with prednisone).

ICD codes

Dosage Regimen

Administration of the drug Cabazitaxel EVER Pharma^® should be carried out only in specialized oncology departments under the supervision of a physician trained in anticancer chemotherapy. The department must have the necessary conditions and medications to provide assistance in case of hypersensitivity reactions, including decreased blood pressure and bronchospasm (see section “Special Instructions”).

Premedication

To reduce the risk and severity of hypersensitivity reactions, the following intravenous medications are administered as premedication prior to the administration of Cabazitaxel EVER Pharma^®:

• Antihistamines (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or an equivalent drug in equivalent doses);
• Glucocorticosteroids (dexamethasone 8 mg or equivalent doses of another glucocorticosteroid);
• Histamine H₂-receptor blockers (ranitidine or an equivalent drug in equivalent doses) (see section “Special Instructions”).

Prophylactic use of antiemetics orally or, if necessary, intravenously is recommended.

Dosage regimen

The recommended dose of Cabazitaxel EVER Pharma^® is 25 mg/m² of body surface area, administered as a one-hour intravenous infusion every 3 weeks in combination with oral prednisone 10 mg daily throughout the treatment period with Cabazitaxel EVER Pharma^®.

Dose adjustment Recommended dose modifications due to the development of adverse reactions in patients receiving Cabazitaxel.

If any of the above reactions continue to occur in a patient receiving the drug at a dose of 20 mg/m² of body surface area, it is recommended to reduce the dose of Cabazitaxel EVER Pharma^® to 15 mg/m² of body surface area or consider discontinuing treatment with Cabazitaxel EVER Pharma^®. Data on the use of the drug at doses less than 20 mg/m² of body surface area are limited.

Special patient groups

Elderly patients

No special dose adjustment is required when using Cabazitaxel EVER Pharma^® in elderly patients (see sections “Special Instructions”, “Pharmacokinetics”).

Patients with hepatic impairment

Cabazitaxel is primarily metabolized by the liver.

In patients with mild hepatic impairment (serum total bilirubin >1 to ≤ 1.5×ULN or serum AST >1.5×ULN), the dose of cabazitaxel should be reduced to 20 mg/m² of body surface area, and caution is required, patients should be closely monitored and adverse reactions should be monitored.

In patients with moderate hepatic impairment (serum total bilirubin >1.5 to ≤3×ULN), the maximum tolerated dose of cabazitaxel is 15 mg/m² of body surface area. If treatment of patients with moderate hepatic impairment is planned, the dose of cabazitaxel should not exceed 15 mg/m² of body surface area. However, there are limited data on the efficacy of this dose.

Cabazitaxel EVER Pharma^® is contraindicated in patients with severe hepatic impairment (serum total bilirubin >3×ULN) (see sections “Contraindications”, “Special Instructions”, “Pharmacokinetics”).

Patients with renal impairment

Cabazitaxel is minimally eliminated by the kidneys.

No dose adjustment is required in patients with renal impairment not requiring hemodialysis. However, in patients with end-stage renal disease (CrCl < 15 mL/min/1.73 m²), due to their condition and limited data, treatment should be conducted with caution and under close medical supervision during treatment.

Concomitant use of cabazitaxel with inducers and inhibitors of CYP3A isoenzymes

Concomitant use of medicinal products that are strong inducers of CYP3A isoenzymes or strong inhibitors of CYP3A isoenzymes should be avoided. However, if a patient requires concomitant use of cabazitaxel and strong inhibitors of CYP3A isoenzymes, a 25% reduction in the cabazitaxel dose should be considered (see sections “Drug Interactions” and “Pharmacokinetics”).

Children

The safety and efficacy of Cabazitaxel EVER Pharma^® in children aged 0 to 18 years have not been established to date. Available data to date are provided in the “Pharmacological Properties” section, however, it is not possible to make dosing recommendations.

Method of administration

Intravenous infusion.

Precautions to be taken before handling or administering the drug

As with other anticancer drugs, caution should be exercised and gloves should be worn when handling Cabazitaxel EVER Pharma^® and preparing its infusion solution. If the solution of Cabazitaxel EVER Pharma^® comes into contact with the skin at any stage of handling, the contact area should be washed immediately and thoroughly with soap and water. If the drug gets on the mucous membranes, they should be rinsed immediately and thoroughly with water. Handling of Cabazitaxel EVER Pharma^® should only be performed by personnel trained in handling cytotoxic drugs.

Pregnant women should not handle this drug.

Please read all of the following information for preparing the drug for intravenous administration before mixing and diluting it.

Before administration, Cabazitaxel EVER Pharma^® must be diluted once. The preparation instructions provided below must be followed.

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

Steps for preparing the infusion solution

Step 1 aseptically withdraw the required amount of concentrate (10 mg/mL cabazitaxel) using a graduated syringe with a needle. For example, to prepare a 45 mg dose of Cabazitaxel EVER Pharma^®, 4.5 mL of concentrate will be required.

Cabazitaxel EVER Pharma^®, concentrate for solution for infusion, 10 mg/mL, contains an overfill. This overfill ensures a withdrawable volume of 4.5 mL, 5 mL or 6 mL containing 10 mg/mL cabazitaxel.

Step 2 inject the contents of the syringe into a non-PVC sterile container containing either 5% glucose solution or 0.9% sodium chloride solution for infusion. The concentration of the infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.

Step 3: remove the syringe and mix the contents of the infusion bag or vial manually using a swirling motion.

Step 4 as with all parenteral drugs, the resulting infusion solution should be visually inspected before administration. Since the infusion solution is supersaturated, it may crystallize over time. In such a case, the solution must not be used and must be discarded.

The infusion solution should be used immediately.

During the intravenous administration of the cabazitaxel infusion solution, an in-line filter with a nominal pore size of 0.22 µm must be used.

Cabazitaxel EVER Pharma^® contains polysorbate 80, which is known to increase the rate of extraction of di-(2-ethylhexyl) phthalate from PVC. Therefore, PVC infusion containers and polyurethane intravenous infusion sets must not be used for the preparation and administration of the cabazitaxel infusion solution.

Cabazitaxel EVER Pharma^® must not be mixed with any other medicinal products except those indicated.

All unused medicinal product and waste should be disposed of in accordance with established procedures.

More than one vial of concentrate may be required to administer the prescribed dose.

Adverse Reactions

Summary of the safety profile

The safety of cabazitaxel in combination with prednisone/prednisolone was evaluated in 371 patients with metastatic castration-resistant prostate cancer. The median number of cabazitaxel cycles received by patients was 6 cycles. Very common (≥10%) adverse reactions of all grades were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, arthralgia, anorexia, peripheral neuropathy (including peripheral sensory and motor neuropathies), pyrexia, dyspnea, dysgeusia, cough, alopecia.

The common (≥5%) adverse reactions (ARs) of ≥Grade 3 severity with cabazitaxel use were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, increased fatigue, and asthenia.

Treatment discontinuation due to ARs occurred in 68 (18.3%) patients receiving cabazitaxel therapy. The most frequent ARs leading to discontinuation of cabazitaxel were neutropenia and renal failure. The most common ARs leading to death in patients treated with cabazitaxel were infections. Most fatal infection ARs occurred after a single administration of cabazitaxel.

Tabulated summary of adverse reactions

The following are ARs grouped by system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA). The severity of ARs was classified according to the Common Terminology Criteria for Adverse Events (CTCAE 4.0) (severity grade ≥3 = G≥3).

The WHO classification for AR frequency was used: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Within each frequency grouping, ARs are presented in order of decreasing seriousness.

* See description of selected adverse reactions.

Post-marketing data

Renal and urinary disorders

Uncommon: radiation recall cystitis.

Description of selected adverse reactions

Neutropenia

Neutropenic complications included neutropenic infection, neutropenic sepsis, and septic shock, which were fatal in some cases.

The use of G-CSF has been shown to reduce the incidence and severity of neutropenia (see sections “Dosage and Administration” and “Special Instructions”).

Cardiac disorders

Cases of cardiac failure (in two patients) were observed with cabazitaxel use. One patient in the cabazitaxel group died from cardiac failure. Fatal ventricular fibrillations were observed in 1 patient and cardiac arrest in 2 patients. However, none of these cases were considered by the investigators to be related to cabazitaxel use.

Respiratory disorders

Cases of interstitial pneumonia/pneumonitis, interstitial lung disease, acute respiratory distress syndrome, including fatal cases, have been reported.

Hematuria

In 2/3 of cases, aggravating factors were identified, such as disease progression, instrumental interventions, concomitant infections, concurrent use of anticoagulants, NSAIDs, acetylsalicylic acid.

Other special populations

Elderly patients

Of the 371 patients treated with cabazitaxel in the prostate cancer study, 240 patients were 65 years of age and older, of whom 70 patients were over 75 years of age. The following ARs occurred at a ≥5% higher frequency in patients aged 65 years and older compared to younger patients: increased fatigue, clinically significant neutropenia, asthenia, pyrexia, dizziness, urinary tract infections, and dehydration.

The frequency of the following ARs of ≥Grade 3 severity was higher in patients ≥65 years of age compared to younger patients: laboratory neutropenia, clinically significant neutropenia, and febrile neutropenia (see sections “Dosage and Administration” and “Special Instructions”).

Of the 595 patients treated with cabazitaxel in the EFC11785 prostate cancer study, 420 patients were 65 years of age and older.

The following ARs occurred at a ≥5% higher frequency compared to younger patients: diarrhea, increased fatigue, asthenia, constipation, clinically significant neutropenia, febrile neutropenia, dyspnea.

Contraindications

• Hypersensitivity to cabazitaxel, other taxanes, polysorbate-80, or to any of the excipients of the drug;
• Neutrophil count in peripheral blood less than 1500/mm³;
• Severe hepatic impairment (total serum bilirubin >3×ULN);
• Concomitant use with yellow fever vaccine, as well as with other live attenuated vaccines (see section “Drug Interactions”).

Use in Pregnancy and Lactation

Contraception in men and women

Due to the potential adverse effects on male gametes and potential excretion of the drug in semen, men receiving cabazitaxel treatment and their female partners of childbearing potential should use reliable methods of contraception during treatment and for 6 months after the last dose of cabazitaxel.

Pregnancy and lactation

Due to the potential excretion of cabazitaxel in semen, men receiving cabazitaxel treatment should prevent contact of ejaculate with another person’s tissues, including pregnant and breastfeeding women, during treatment.

Fertility

Patients scheduled for cabazitaxel treatment are advised to perform sperm cryopreservation before starting treatment.

Use in Hepatic Impairment

Cabazitaxel EVER Pharma^® is contraindicated in patients with severe hepatic impairment (total serum bilirubin >3×ULN). In patients with mild hepatic impairment (total serum bilirubin >1 to ≤ 1.5×ULN or serum AST >1.5×ULN), the cabazitaxel dose should be reduced to 20 mg/m² body surface area, while caution is required, patients should be closely monitored, and adverse reactions should be monitored.

Use in Renal Impairment

No dose adjustment is required in patients with renal impairment not requiring hemodialysis. However, in patients with end-stage renal disease (CrCl < 15 ml/min/1.73 m²), due to their condition and limited data, treatment should be administered with caution and under close medical supervision during treatment.

Pediatric Use

The safety and efficacy of cabazitaxel in children and adolescents under 18 years of age have not been established.

Geriatric Use

No special dose adjustment is required when using Cabazitaxel EVER Pharma^® in elderly patients.

Special Precautions

Bone marrow suppression

With cabazitaxel use, bone marrow suppression manifests as neutropenia, anemia, thrombocytopenia, or possibly pancytopenia (see additional information below in the subsections “Neutropenia” and “Anemia”).

Neutropenia

In accordance with the recommendations of the American Society of Clinical Oncology and/or current approved guidelines, to reduce the risk or treat neutropenic complications (febrile neutropenia, prolonged neutropenia, or neutropenic infection), patients receiving cabazitaxel therapy may prophylactically receive G-CSF.

Primary prophylaxis of neutropenia with G-CSF should be considered in patients with high-risk factors for neutropenia that increase the likelihood of complications from prolonged neutropenia (age over 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation therapy, poor nutritional status, or other serious comorbidities).

The use of G-CSF has been shown to reduce the incidence and severity of neutropenia.

Neutropenia is the most common AR with cabazitaxel use (see section “Adverse Reactions”). Weekly monitoring of blood cell counts (complete blood count) is required during the first cycle (cycle 1) of treatment and then before each subsequent treatment cycle in order to reduce the drug dose in the next cycle if necessary (see section “Dosage and Administration”).

If febrile neutropenia or prolonged neutropenia develops despite appropriate treatment, cabazitaxel therapy may be continued only after the neutrophil count in peripheral blood increases to ≥1500/mm³ (see section “Contraindications”).

Hypersensitivity reactions

All patients must receive premedication before administration of Cabazitaxel EVER Pharma^® (see section “Dosage and Administration”).

Patients should be closely monitored for the development of hypersensitivity reactions, especially during the first and second intravenous infusions of cabazitaxel. Hypersensitivity reactions may develop within the first few minutes after the start of the intravenous infusion of cabazitaxel, so all necessary equipment and medications for emergency treatment of decreased blood pressure or bronchospasm must be available. Severe reactions, such as generalized skin rash/erythema, decreased blood pressure, and bronchospasm, may develop. If severe hypersensitivity reactions occur, immediate discontinuation of the intravenous infusion of cabazitaxel and necessary treatment are required. Patients with a history of severe hypersensitivity reaction should not be re-administered Cabazitaxel EVER Pharma^® (see section “Contraindications”).

Risk of nausea, vomiting, diarrhea, and dehydration

If patients develop diarrhea after administration of Cabazitaxel EVER Pharma^®, they should be treated with commonly used antidiarrheal medications. Appropriate measures should be taken to restore fluid losses, determine and correct serum electrolyte composition, especially potassium concentration. Diarrhea may occur more frequently in patients who have previously received radiotherapy to the abdominopelvic area. Dehydration occurs more frequently in patients 65 years of age and older. If diarrhea of ≥Grade 3 severity develops, delay of the next treatment cycle or dose reduction may be required (see section “Dosage and Administration”). If the patient experiences nausea and vomiting, antiemetics may be used.

Risk of serious gastrointestinal reactions

Gastrointestinal hemorrhage and perforation, intestinal obstruction, colitis, including fatal cases, have been reported in patients receiving cabazitaxel therapy (see section “Adverse Reactions”). Caution should be exercised in patients at high risk of developing gastrointestinal complications, namely patients with neutropenia, elderly patients, those concurrently taking NSAIDs, receiving antiplatelet therapy or anticoagulants, as well as patients with prior pelvic radiotherapy, gastrointestinal diseases such as a history of gastrointestinal ulcerative lesions and gastrointestinal bleeding.

Early manifestations of serious gastrointestinal toxicity may include symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhea with or without neutropenia. The patient’s condition should be regularly monitored for these symptoms, and if detected, they should be treated immediately. Delay or discontinuation of cabazitaxel treatment may be required.

Peripheral neuropathy

Cases of peripheral neuropathy, including peripheral sensory neuropathy (paresthesia, dysesthesia) and peripheral motor neuropathy, have been observed in patients treated with cabazitaxel. Patients receiving cabazitaxel therapy should be advised to inform their treating physician about any developed neuropathy symptoms, such as pain, burning sensation, tingling, numbness, or increased fatigue, before continuing treatment. The physician should assess the presence or worsening of neuropathy symptoms before each treatment cycle. Administration of cabazitaxel should be delayed until symptoms decrease. For persistent peripheral neuropathy of ≥Grade 2 severity, the cabazitaxel dose should be reduced from 25 mg/m² to 20 mg/m² body surface area (see section “Dosage and Administration”).

Risk of renal failure

Renal function impairment has been reported in association with sepsis, severe dehydration (due to diarrhea, vomiting), and obstructive uropathy. Renal failure has developed, including fatal cases. Appropriate measures should be taken to identify the cause of renal failure and provide intensive therapy to patients with developing renal failure. Renal function should be monitored.

Adequate patient hydration should be maintained during cabazitaxel therapy. The patient should be advised to immediately report any changes in daily urine output. Serum creatinine should be determined before treatment, at each complete blood count test, and if the patient reports changes in urine output. If renal failure of ≥Grade 3 severity develops, cabazitaxel treatment should be discontinued.

The drug should be used with caution in patients with end-stage renal failure (CrCl< 15 ml/min) (due to their condition and limited data, treatment should be carried out with caution and under careful medical supervision during therapy) (see sections “Pharmacokinetics”, “Dosage Regimen”).

Risk of cystitis due to radiation recall phenomenon

In patients who previously received radiation therapy to the pelvic area and a treatment regimen containing docetaxel, the development of cystitis due to radiation recall phenomenon in the previously irradiated area has been reported. Therefore, appropriate measures should be taken if this adverse reaction occurs. It may be necessary to interrupt or discontinue cabazitaxel therapy.

Risk of cardiac arrhythmias

The development of cardiac arrhythmias, most often tachycardia and atrial fibrillation, has been reported (see section 4.8).

Risk of respiratory system disorders

Cases of interstitial pneumonia/pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, including fatal outcomes, have been reported (see section “Adverse Reactions”).

Patients should be closely monitored, promptly examined, and receive appropriate treatment if new respiratory symptoms develop or existing symptoms worsen. It is recommended to interrupt cabazitaxel therapy until the diagnosis is confirmed. Early supportive care may improve the patient’s condition. The benefit of resuming cabazitaxel therapy should be carefully evaluated.

Elderly patients

Elderly patients (≥65 years) may be more susceptible to certain adverse reactions, including neutropenia or febrile neutropenia (see section “Adverse Reactions”).

Patients with hepatic impairment

Cabazitaxel is extensively metabolized in the liver (see section “Pharmacokinetics”). Cabazitaxel EVER Pharma^® is contraindicated in patients with severe hepatic impairment (total bilirubin >3×ULN) (see sections “Contraindications” and “Pharmacokinetics”). In patients with mild hepatic impairment (serum total bilirubin >1 and ≤ 1.5×ULN or AST >1.5×ULN) and moderate hepatic impairment (total bilirubin >1 to ≤ 3×ULN), the dose of cabazitaxel should be reduced (see sections “Dosage Regimen” and “Pharmacokinetics”). In such cases, caution is required, patients should be closely monitored, and adverse reactions should be monitored.

Anemia

The development of anemia has been reported in patients receiving cabazitaxel treatment (see section “Adverse Reactions”). Hemoglobin and hematocrit levels should be checked before starting cabazitaxel therapy and if patients have symptoms or signs of anemia or blood loss. Cabazitaxel should be used with caution in patients with a peripheral blood hemoglobin level < 10 g/dL. Appropriate therapeutic measures aimed at increasing the peripheral blood hemoglobin level should be carried out.

Drug interactions

Concomitant use of strong inhibitors and inducers of CYP3A isoenzymes with cabazitaxel should be avoided, as they may, respectively, increase or decrease the plasma concentration of cabazitaxel (see sections “Dosage Regimen” and “Drug Interactions”).

Excipients

Each ml of concentrate for solution for infusion contains 197.5 mg of ethanol.

1 vial of 6 ml contains 1.185 g of ethanol (19.75% w/w). The amount of 6 ml in this medicinal product is equivalent to 30.0 ml of beer or 12.5 ml of wine.

Caution should be exercised when used in persons with alcoholism.

High-risk groups such as patients with liver disease and epilepsy should be taken into account.

Effect on ability to drive and use machines

Based on the safety profile of cabazitaxel, the drug may have a moderate effect on the ability to drive vehicles or use other machinery, as it may cause increased fatigue and dizziness. If such adverse reactions occur during treatment, patients should be advised to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Expected symptoms of overdose: increased dose-dependent adverse reactions, such as symptoms of bone marrow suppression and gastrointestinal disorders.

Treatment

There is no known antidote for cabazitaxel. In case of overdose, the patient should be placed in a specialized unit under close medical supervision. After an overdose is known, patients should start receiving G-CSF as soon as possible. Other symptomatic treatment should also be administered.

Drug Interactions

Inhibitors of CYP3A isoenzymes

The metabolism of cabazitaxel is altered with the concomitant use of substances known as strong inhibitors of CYP3A isoenzymes (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

Concomitant use of strong inhibitors of CYP3A isoenzymes should be avoided. If concomitant use of cabazitaxel and a strong inhibitor of CYP3A isoenzymes cannot be avoided, careful monitoring of the patient and a reduction in the dose of cabazitaxel should be considered (see sections “Dosage Regimen” and “Special Instructions”).

Caution should be exercised when cabazitaxel is used concomitantly with moderate inhibitors of CYP3A isoenzymes.

Inducers of CYP3A isoenzymes

The metabolism of cabazitaxel is altered with the concomitant use of substances known as strong inducers of CYP3A isoenzymes (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital).

Concomitant use of strong inducers of CYP3A isoenzymes should be avoided, as they may reduce the systemic exposure to cabazitaxel (see sections “Dosage Regimen” and “Special Instructions”).

St. John’s wort

Patients receiving cabazitaxel treatment should refrain from taking preparations of St. John’s wort (as it is also an inducer of the CYP3A4 isoenzyme).

Substrates of the organic anion transporting polypeptide (OATP1B1)

Cabazitaxel in vitro has also demonstrated the ability to inhibit OATP1B1. The risk of interaction with OATP1B1 substrates (e.g., HMG-CoA reductase inhibitors (statins), valsartan, repaglinide) is possible during intravenous infusion (1 hour) and up to 20 minutes after its completion, and during this time an increase in the systemic exposure of OATP1B1 substrates is possible. The following time intervals are recommended for the concomitant use of OATP1B1 substrates: take them 12 hours before cabazitaxel administration and at least 3 hours after cabazitaxel administration.

Prednisolone

Prednisolone/prednisone, taken at 10 mg daily, does not affect the pharmacokinetics of cabazitaxel.

Warfarin

Cabazitaxel does not inhibit in vitro the main pathway of warfarin biotransformation to 7-hydroxywarfarin, which is carried out by the CYP2C9 isoenzyme. Therefore, no pharmacokinetic interaction between cabazitaxel and warfarin is expected in vivo.

Vaccination

The use of live vaccines or attenuated live vaccines in patients with immunosuppression resulting from treatment with chemotherapeutic agents may lead to the development of serious or fatal infections. Vaccination with live attenuated vaccines should be avoided in patients receiving cabazitaxel treatment. Killed or inactivated vaccines can be used; however, the body’s response to such vaccines may be less pronounced.

Storage Conditions

The drug should be stored in the original packaging (cardboard box) at a temperature not exceeding 30°C (86°F). Do not freeze.

Shelf Life

The shelf life of the unopened vial is 2 years.

After first opening, the prepared solution – from a microbiological point of view, the concentrate and the infusion solution should be used immediately.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.