Jevtana

Jevtana

Manufacturer:

sanofi-aventis

Distributor:

sanofi-aventis
Full Prescribing Info
Contents
Cabazitaxel.
Description
One ml of Jevtana concentrate contains: Cabazitaxel 40 mg.
Each single-use vial contains 60mg Cabazitaxel (solvent free and anhydrous) in a total volume of 1.5mL.
Cabazitaxel belongs to the taxanes class. It is prepared by semi synthesis with a precursor extracted from yew needles. Empirical formula: C45H57NO14,C3H6O.
Chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate - propan-2-one (1:1).
Physical properties: White to almost white powder.
Molecular weight: 894.01 (acetone solvate), 835.93 (solvent free).
Practically insoluble in water and soluble in alcohol.
Lipophilic.
Excipients/Inactive Ingredients: concentrate vial: polysorbate 80, citric acid.
Solvent vial: ethanol 96% (573.3 mg), water for injection.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Cabazitaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells. 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 results in the inhibition of mitotic and interphase cellular functions.
Pharmacodynamic Effects: Cabazitaxel demonstrated a broad spectrum of antitumour activity against advanced human tumors xenografted in mice, including intracranial human glioblastomas. Cabazitaxel is active in docetaxel-sensitive tumors. In addition cabazitaxel demonstrated activity in tumor models insensitive to chemotherapy, including docetaxel.
Clinical Efficacy/Clinical Studies: Adult patients: The efficacy and safety of Cabazitaxel (Jevtana) in combination with prednisone or prednisolone were evaluated in a randomized, open-label, international, multi-center, phase III study (EFC6193 study), in patients with metastatic castration resistant prostate cancer previously treated with a docetaxel-containing regimen.
Overall survival (OS) was the primary efficacy end-point of the study.
Secondary endpoints included Progression Free Survival [PFS (defined as time from randomization to tumor progression, Prostatic Specific Antigen (PSA) progression, pain progression, or death due to any cause, whichever occurred first] , PSA Progression (defined as a ≥25% increase, PSA response (declines in serum PSA levels of at least, Tumor Response Rate based on Response Evaluation Criteria in Solid Tumors (RECIST) or >50% in PSA non-responders or responders respectively) 50%), pain progression [assessed using the Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire and an Analgesic Score (AS)] and pain response (defined as 2 point greater reduction from baseline median PPI with no concomitant increase in AS, or reduction of ≥50% in analgesic use from baseline mean AS with no concomitant increase in pain).
A total of 755 patients were randomized to receive either cabazitaxel 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=377).
This study included patients over 18 years with metastatic castration resistant prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Patients had to have neutrophils >1,500/mm3, platelets >100,000/mm3, haemoglobin >10 g/dL, creatinine <1.5 x ULN, total bilirubin <1 x ULN, AST/SGOT <1.5 ULN, and ALT/SGPT <1.5 ULN.
Patients with a history of congestive heart failure, or myocardial infarction within last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.
Demographics, including age, race, and ECOG) performance status (0 to 2), were balanced between the treatment arms. In the Cabazitaxel (Jevtana) group, the mean age was 68 years range (46-92) and the racial distribution was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and (4%) Others.
The median number of cycles was 6 in the Cabazitaxel (Jevtana) group and 4 in the mitoxantrone group. The number of patients who completed the study treatment (10 cycles) was respectively 29.4% and 13.5% in the Cabazitaxel (Jevtana) group and in the comparator group.
Overall survival was longer in the cabazitaxel arm with cabazitaxel-treated patients having a 30% reduction in the risk of death compared to mitoxantrone [hazard ratio =0.70, 95% CI (0.59 – 0.83)] (see Table 1 and Figure 1). (See Table 1 and Figure 1.)

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There was an improvement in PFS in the Cabazitaxel (Jevtana) arm compared to mitoxantrone arm, 2.8 (2.4-3.0) months versus 1.4 (1.4-1.7) respectively, HR (95%CI) 0.74 (0.64-0.86), p<0.0001.
There was a significant higher rate of tumor response of 14.4% (95%CI: 9.6-19.3) in patients in the Cabazitaxel (Jevtana) arm compared to 4.4% (95%CI: 1.6-7.2) for patients in the mitoxantrone arm, p=0.0005.
PSA secondary endpoints were positive in the Cabazitaxel (Jevtana) arm. There was a median PSA progression of 6.4 months (95%CI: 5.1-7.3) for patients in Cabazitaxel (Jevtana) arm, compared to 3.1 months (95%CI: 2.2-4.4) in the mitoxantrone arm, HR 0.75 months (95%CI 0.63-0.90), p=0.0010. The PSA response was 39.2% in patients on Cabazitaxel (Jevtana) arm (95%CI: 33.9-44.5) versus 17.8% in patients on mitoxantrone (95% CI: 13.7-22.0), p=0.0002.
Mitoxantrone is indicated [according to local registration status] as initial chemotherapy for the treatment of patients with pain related to advanced metastatic castration resistant prostate cancer. There was no statistical difference between both treatment arms in pain progression and pain response.
In a non-inferiority, multicenter, multinational, randomized, open label phase III study (EFC11785 study), 1200 patients with metastatic castration resistant prostate cancer, previously treated with a docetaxel-containing regimen, were randomized to receive either cabazitaxel 25 mg/m2 (n=602) or 20 mg/m2 (n=598) dose. Overall survival (OS) was the primary efficacy end-point.
The study met its primary objective of demonstrating the non-inferiority of cabazitaxel 20 mg/m2 in comparison with 25 mg/m2 (see Table 2). A statistically significantly higher percentage (p<0.001) of patients showed a PSA response in the 25 mg/m2 group (42.9%) compared to the 20 mg/m2 group (29.5%).
A statistically significantly higher risk of PSA progression in patients with the 20 mg/m2 dose with respect to the 25 mg/m2 dose was observed (HR 1.195 ; 95%CI: 1.025 to 1.393). There was no statistically difference with regards to the other secondary endpoints (PFS, tumor and pain response, tumor and pain progression, and four subcategories of FACT-P). (See Table 2.)

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EFC11785 study demonstrated a better safety profile for the cabazitaxel 20 mg/m2 dose. The safety profile of cabazitaxel 25 mg/m2 observed in this study was qualitatively and quantitatively similar to that observed in the study EFC6193. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (21.5%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3.2%) had a dose reduced from 20 to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 58 patients (10.0%) had a dose reduced from 20 to 15 mg/m2 and 9 patients (1.6%) had a dose reduced from 15 to 12 mg/m2. All grade adverse reactions with an incidence higher than 10% were higher in patients treated at 25 mg/m2 than in patients treated at 20 mg/m2 : diarrhea (39.8% versus 30.7%), nausea (32.1% versus 24.5%), fatigue (27.1% versus 24.7%), haematuria (20.8% versus 14.1%), asthenia (19.7% versus 15.3%), decreased appetite (18.5% versus 13.1%), vomiting (18.2% versus 14.5%), constipation (18.0% versus 17.6%), back pain (13.9% versus 11.0%), clinical neutropenia (10.9% versus 3.1%), urinary tract infection (10.8% versus 6.9%), peripheral sensory neuropathy (10.6% versus 6.6%) and dysgeusia (10.6% versus 7.1%). Grade ≥ 3 adverse reactions with an incidence higher than 5% were observed in patients treated at 25 mg/m2 only: clinical neutropenia (9.6% at 25 mg/m2 versus 2.4% at 20 mg/m2) and febrile neutropenia (9.2% at 25 mg/m2 versus 2.1% at 20 mg/m2). EFC11785 study demonstrated a better safety profile for the cabazitaxel 20 mg/m2 dose. The safety profile of cabazitaxel 25 mg/m2 observed in this study was qualitatively and quantitatively similar to that observed in the study EFC6193. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (21.5%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3.2%) had a dose reduced from 20 to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 58 patients (10.0%) had a dose reduced from 20 to 15 mg/m2 and 9 patients (1.6%) had a dose reduced from 15 to 12 mg/m2. All grade adverse reactions with an incidence higher than 10% were higher in patients treated at 25 mg/m2 than in patients treated at 20 mg/m2 : diarrhea (39.8% versus 30.7%), nausea (32.1% versus 24.5%), fatigue (27.1% versus 24.7%), haematuria (20.8% versus 14.1%), asthenia (19.7% versus 15.3%), decreased appetite (18.5% versus 13.1%), vomiting (18.2% versus 14.5%), constipation (18.0% versus 17.6%), back pain (13.9% versus 11.0%), clinical neutropenia (10.9% versus 3.1%), urinary tract infection (10.8% versus 6.9%), peripheral sensory neuropathy (10.6% versus 6.6%) and dysgeusia (10.6% versus 7.1%). Grade ≥ 3 adverse reactions with an incidence higher than 5% were observed in patients treated at 25 mg/m2 only: clinical neutropenia (9.6% at 25 mg/m2 versus 2.4% at 20 mg/m2) and febrile neutropenia (9.2% at 25 mg/m2 versus 2.1% at 20 mg/m2). There were fewer reported hematology abnormalities for patients treated at 20 mg/m2 compared with patients treated at 25 mg/m2 based on laboratory values: 73.3% at 25 mg/m2 versus 41.8% at 20 mg/m2 for grade ≥ 3 neutropenia, 13.7% versus 9.9% respectively for grade ≥ 3 anemia, 4.2% versus 2.6% respectively for grade ≥ 3 thrombocytopenia.
Pediatric patients: Cabazitaxel (Jevtana) was evaluated in an open label, multi-center study conducted in two parts in a total of 39 pediatric patients. The Phase 1 part dose escalation established the maximum tolerated dose (MTD) of cabazitaxel in pediatric patients (aged from 4-18 years) with recurrent or refractory solid tumors based on related dose-limiting toxicities (DLTs). The Phase 2 part evaluated the activity and safety of cabazitaxel at the MTD in pediatric patients (aged from 3-16 years) with recurrent or refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). The primary endpoints in the phase 2 part were objective response rate and duration of response. All patients received prophylactic G-CSF. In the Phase 1 part, 23 patients were enrolled and treated at doses between 20 mg/m2 and 35 mg/m2. The maximum tolerated dose (MTD) was established at the 30 mg/m2 dose level.
In the Phase 2 part, 16 patients were enrolled and treated at 30 mg/m2. 11 patients were evaluable for efficacy. There was no objective response in patients with DIPG or HGG.
The most frequent TEAEs (≥25%) of any grade were fatigue (39.1%), headache, diarrhea, nausea (all at 34.8%), vomiting (30.4%) and constipation (26.1%) in Phase 1 patients; and diarrhea (43.8%), dysphagia (37.5%), nausea (31.3%), vomiting and headache (both at 25.0%) in Phase 2 patients.
SAEs reported in more than 2 patients in either part of the study included febrile neutropenia in 5 patients (21.7%) in Phase 1; and febrile neutropenia, anaphylactic reaction and disease progression, all reported in 3 patients (18.8%) in Phase 2.
Pharmacokinetics: A population pharmacokinetic analysis was carried out 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 doses of cabazitaxel ranging from 10 to 30 mg/m2 weekly or every 3 weeks.
Absorption: After a 1-hour IV administration dose of cabazitaxel at 25 mg/m2, in patients with metastatic prostate cancer (n=67), the mean Cmax was 226 ng/mL (coefficient of variation, CV 107%) and was reached at the end of the 1-hour infusion (Tmax). The mean AUC was 991 ng.h/mL (CV: 34%).
No major deviation to the dose proportionality was observed from 10 to 30 mg/m2 in patients with advanced solid tumors (n=126).
Distribution: The volume of distribution (Vss) was 4870 L (2640 L/m2 for a patient with a median BSA of 1.84 m2) at steady state.
In vitro, the binding of cabazitaxel to human serum proteins was 89 to 92% and was not saturable up to 50,000 ng/mL, which covers the maximum concentration observed in clinical studies. Cabazitaxel is mainly bound to human serum albumin (82.1%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). The in vitro blood-to-plasma concentration ratios in human blood ranged from 0.90 to 0.99 indicating that cabazitaxel was equally distributed between blood and plasma.
Metabolism: Cabazitaxel is extensively metabolized in the liver (≥95%), mainly by the CYP3A isoenzyme (80 to 90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites were detected in plasma (including 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of parent exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and feces.
Based on in vitro studies, the potential risk of inhibition by cabazitaxel at clinically relevant concentrations is possible towards drugs that are mainly substrate of CYP3A. Cabazitaxel does not inhibit other CYP enzymes. In addition, cabazitaxel did not induce CYP isozymes (CYP1A, CYP2C, and CYP3A) in vitro. Interaction studies in humans have shown that cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did not modify the plasma levels of midazolam, a probe substrate of CYP3A. Therefore, cabazitaxel is not an inhibitor of CYP3A in vivo.
Elimination: After a 1-hour IV infusion [14C]-cabazitaxel at 25 mg/m2 in patients, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for less than 3.7% of the dose (2.3% as unchanged drug in urine). Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively. Cabazitaxel had a high plasma clearance of 48.5 L/h (26.4 L/h/m2 for a patient with a median BSA of 1.84 m2).
Drug Interactions: Cabazitaxel is mainly metabolized by CYP3A.
Repeated administration of ketoconazole (400 mg once daily), a strong CYP3A inhibitor, resulted in a 20% decrease in cabazitaxel clearance corresponding to a 25% increase in AUC. Concomitant administration of aprepitant, a moderate CYP3A inhibitor, had no effect on cabazitaxel clearance or exposure.
Repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, resulted in an increase in cabazitaxel clearance of 21% corresponding to a decrease in AUC of 17%.
Prednisone/prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
In vitro cabazitaxel did not inhibit Multi-drug Resistance Protein (MRP): MRP1 and MRP2, Breast Cancer Resistant Proteins ( 151 or Organic Cation Transporter (OCT1). Cabazitaxel inhibited the transport of P-glycoprotein (P-gp) (digoxin, vinblastine)BCRP) (methotrexate) and Organic Anion Transporting Polypeptides (OATP1B3) (CCK8) at concentrations at least 15 fold what was observed in clinical settings while it inhibited the transport of OATP1B1 (Estradiol-17β-glucuronide) at concentrations only 5 fold what was observed in clinical settings. Therefore the risk of interaction with substrates of MRP, OCT1, P-gp, and OATP1B3 is unlikely in vivo at the dose of 25mg/m2. The risk of interaction with the OATP1B1 transporter is possible notably during the infusion duration (1 hour) and up to 20 minutes after the end of the infusion.
Special Populations: Elderly: In the population pharmacokinetic analysis no significant difference was observed in the pharmacokinetics of cabazitaxel between patients < 65 years (n=100) and older (n=70).
Paediatric patients: Pharmacokinetic parameters for cabazitaxel were determined in one phase 1/2 study in pediatric patients with solid tumor using a population PK model developed in pediatric population.
Following cabazitaxel administration at 20-35 mg/m2 as a 1-h infusion every 3 weeks in n=31 patients aged from 3 to 18 years old, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 3.5 minutes, 1.1 hour, and 59.0 hours, respectively.
Cabazitaxel had a high plasma clearance of 37.7 L/h (35.6 L/h/m2 for a patient with a median BSA of 1.06 m2) and a large volume of distribution at steady state of 1889 L (1782 L/m2 for a patient with a median BSA of 1.06 m2).
At the maximum tolerated dose of 30 mg/m2, the mean Cmax was 331 ng/mL (CV 54%, n=14) and the mean AUC was 863 ng.h/mL (CV:36%, n=20) in pediatric patients.
Hepatic impairment: Cabazitaxel is eliminated primarily via hepatic metabolism.
A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (total bilirubin >1 to ≤ 1.5 x ULN or AST >1.5 x ULN) or moderate (total bilirubin >1.5 to ≤3.0 x ULN) hepatic impairment on cabazitaxel pharmacokinetics. The maximum tolerated cabazitaxel dose (MTD) was 20 and 15 mg/m2, respectively.
In 3 patients with severe hepatic impairment (total bilirubin > 3 x ULN), a 39% decrease in clearance was observed when compared to patients with mild hepatic impairment, indicating some effect of severe hepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severe hepatic impairment was not established.
Based on safety and tolerability data, cabazitaxel dose should be reduced in patients with mild hepatic impairment (see section Dosage and administration). Cabazitaxel is contraindicated in patients with severe hepatic impairment (see Contraindications).
Renal impairment: Cabazitaxel is minimally excreted via the kidney (2.3% of the dose). No formal pharmacokinetic studies were conducted with cabazitaxel in patients with renal impairment. However, the population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel.
Effect on Electrocardiograms: In a multi-center, open-label, single-arm trial, 94 evaluable patients with solid tumors received cabazitaxel at a dose of 25 mg/m2 every 3 weeks. Assessments during Cycle 1 on Day 1 up to 24 hours showed no changes >10 ms in the mean QTc interval from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to cabazitaxel cannot be excluded due to study design limitations.
Toxicology: Non-Clinical Safety Data: General Toxicology: Effects on the liver: Bile ductule hyperplasia, arteriolar/periarteriolar necrosis, and/or hepatocellular necrosis were observed in dogs after single dose (0.25 mg/kg [5 mg/m2]), 5-day (0.2 mg/kg [4 mg/m2]) and weekly (0.325 mg/kg [6.5 mg/m2]) administration. In rats showed Kupffer cells pigmentation and bile ducts degeneration/regeneration were observed in the liver at the highest lethal dose of 10 mg/kg (60 mg/m2) in a 10-cycle study in rats.
Neurotoxicity: Non-reversible peripheral neurotoxicity characterized histopathologically by degeneration in the sciatic nerves and lumbosacral nerve roots was observed in mice after 10 or 20 weeks following a single administration. The No-Observable Effect Level was 15 mg/kg (45 mg/m2) after single intravenous administration over 1 hour.
Central neurotoxicity characterized histopathologically by neuron necrosis and/or vacuolation in the brain, axonal swelling and degeneration in the cervical spinal cord was noted in mice after a single 1-hour intravenous administration at 15 mg/kg (45 mg/m2) considered sufficiently in excess of the maximum human exposure. The No-Observable Effect Level was 10 mg/kg (30 mg/m2) (approximately 7-fold the AUC in cancer patients at the recommended human dose) after single intravenous administration over 1 hour.
Eye disorders: Subcapsular lens fiber swelling/degeneration was observed in rats during a 10-cycle toxicity study at 10-20 mg/kg (60-120 mg/m2 [approximately 2-fold the AUC in cancer patients at the recommended human dose]). The No-Observable Effect Level for microscopic lens findings was 5 mg/kg (30 mg/m2 [approximately the AUC in cancer patients at the recommended human dose]). These effects were not reversible after 8 weeks.
Environmental Risk: assessment Results of environmental risk assessment studies indicate that Cabazitaxel (Jevtana) does not show significant environmental effects (see Preparation and Handling under Cautions for Usage).
Carcinogenicity: Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel.
Mutagenicity: Cabazitaxel was found negative in the bacterial reverse mutagenic (Ames) test.
Genotoxicity: Cabazitaxel was not clastogenic in an in vitro test in human lymphocytes (no induction of structural chromosomal aberration but it increased number of polyploid cells) and induced an increase of micronuclei in the in vivo test in rats at doses >0.5 mg/kg .However, these genotoxicity findings are inherent to the pharmacological activity of the compound (inhibition of tubulin depolymerization).
Teratogenicity: Non-clinical studies in rats and rabbits have shown that cabazitaxel is embryotoxic, fetotoxic, and abortifacient. When female rats were given cabazitaxel intravenously once daily from gestational days 6 through 17, embryofetal toxicity was observed at exposures lower than those seen in humans receiving clinically relevant doses of cabazitaxel consisting of fetal deaths and decreased mean fetal weight associated with a delay in skeletal ossification.
Cabazitaxel did not produce fetal abnormalities in rats and rabbits. Cabazitaxel crossed the placenta 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 dose was found in the maternal milk over 24 hours.
Impairment of Fertility: Cabazitaxel did not affect mating performances or fertility of treated male rats at doses of 0.05, 0.1 and 0.2 mg/kg/day. However, in multiple-cycle studies, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats treated intravenously with cabazitaxel at a dose of 5 mg/kg; and minimal testicular degeneration in dogs (minimal epithelial single cell necrosis in epididymis) treated at a dose of 0.5 mg/kg. Exposures in animals were similar or lower than those seen in humans receiving clinically relevant doses of cabazitaxel.
Indications/Uses
In combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration resistant prostate cancer previously treated with a docetaxel containing regimen.
Dosage/Direction for Use
General: The use of Cabazitaxel (Jevtana) should be confined to units specialized in the administration of cytotoxics and it should be administered under the supervision of a physician experienced in the use of anticancer chemotherapy (see Preparation and Handling under Cautions for Usage).
Premedication: Premedicate prior to each administration of Cabazitaxel (Jevtana) with the following intravenous medications to reduce the incidence and severity of a hypersensitivity reaction: antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent), corticosteroid (dexamethasone 8 mg or equivalent) and with H2 antagonist (ranitidine or equivalent) (see Precautions).
Antiemetics prophylaxis is recommended and can be given orally or intravenously as needed.
Posology: The recommended dose of Cabazitaxel (Jevtana) is 25 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone (or prednisolone) 10 mg administered daily throughout Cabazitaxel (Jevtana) treatment.
Dose adjustments: Dosage modifications should be made if patients experience the following adverse reactions. (See Table 3.)

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If patients continue to experience any of these reactions at 20 mg/m2, a further dose reduction to 15 mg/m2 or discontinuation of Cabazitaxel (Jevtana) may be considered.
Data in patients below 20 mg/m2 dose are limited.
Special Populations: Children: The safety and the efficacy of Cabazitaxel (Jevtana) in children have not been established (see Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Elderly Patients: No specific dose adjustment for the use of Cabazitaxel (Jevtana) in elderly patients is recommended (see Precautions, Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic impairment: Cabazitaxel (Jevtana) is extensively metabolized by the liver.
Patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 x Upper Limit of Normal (ULN) or AST >1.5 x ULN), should have cabazitaxel dose reduced to 20 mg/m2. Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety.
Limited efficacy data for cabazitaxel at 15 mg/m2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3.0 x ULN), are available to recommend this dose in this population. (see Pharmacology: Pharmacokinetics under Actions).
Cabazitaxel (Jevtana) should not be given to patients with severe hepatic impairment (total bilirubin >3 x ULN) (see Contraindications, Precautions and Pharmacology: Pharmacokinetics under Actions).
Patients with Renal impairment: Cabazitaxel (Jevtana) is minimally excreted through the kidney. No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis. Patients presenting end-stage renal disease (CLCR <15 mL/min/1.73 m2), by their condition and the limited amount of available data, therefore these patients should be treated with caution and monitored carefully during treatment (see Pharmacology: Pharmacokinetics under Actions).
Concomitant drug use: Concomitant drugs that are strong CYP3A inducers or strong CYP3A inhibitors should be avoided (see Interactions and Pharmacology: Pharmacokinetics: Special Populations under Actions). However, if patients require co-administration of a strong CYP3A inhibitor, a 25% Cabazitaxel dose reduction should be considered (see Interactions and Pharmacology: Pharmacokinetics: Drug Interactions under Actions).
Overdosage
Signs and Symptoms: The anticipated complications of overdose would be exacerbation of adverse reactions as bone marrow suppression and gastrointestinal disorders.
Management: There is no known antidote to Cabazitaxel (Jevtana). In case of overdose, the patient should be kept in a specialized unit and closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken.
Contraindications
In patients with: a history of severe hypersensitivity reactions to Cabazitaxel or other drugs formulated with polysorbate 80; neutrophil counts less than 1,500/mm3; severe hepatic impairment (total bilirubin > 3 × ULN).
Special Precautions
Bone marrow suppression: Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia, or pancytopenia may occur (see additional information in the Neutropenia and Anemia precautions as follows).
Neutropenia: Patients treated with Cabazitaxel (Jevtana) may receive prophylactic G-CSF as per American Society of Clinical Oncology (ASCO) and/or current institutional guidelines, to reduce the risk or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection). Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia.
The use of G-CSF has been shown to limit the incidence and severity of neutropenia.
Neutropenia is the most common adverse reaction of Cabazitaxel (Jevtana) (see Adverse Reactions). Monitoring of complete blood count is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed (see Dosage & Administration).
Reduce dose in case of febrile neutropenia, or prolonged neutropenia despite appropriate treatment (see Dosage & Administration).
Retreat only when neutrophils recover to a level ≥1,500/mm3 (see Contraindications).
Hypersensitivity reactions: All patients should be premedicated prior to the initiation of the infusion of Cabazitaxel (Jevtana) (see Dosage & Administration).
Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of Cabazitaxel, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of Cabazitaxel and appropriate therapy. Patients who have a history of severe hypersensitivity reactions should not be rechallenged with Cabazitaxel (Jevtana) (see Contraindications).
Gastrointestinal symptoms: If patients experience diarrhea following administration of Cabazitaxel (Jevtana) they should be treated with commonly used anti-diarrheal medications. Appropriate measures should be taken to rehydrate the patients. Treatment delay or dosage reduction may be necessary for grade ≥3 diarrhea (see Dosage & Administration). If patients experience nausea or vomiting, they may be treated with commonly used anti-emetics.
Gastrointestinal (GI) hemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with Cabazitaxel. Caution is advised with treatment of patients most at risk of developing gastrointestinal complications: those with neutropenia, the elderly, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, gastrointestinal disease, such as ulceration and GI bleeding.
Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary.
Anemia: Anemia has been observed in patients receiving cabazitaxel (see Adverse Reactions). Hemoglobin and hematocrit should be checked before treatment with cabazitaxel and if patients exhibit signs or symptoms of anemia or blood loss. Caution is recommended in patients with hemoglobin <10 g/dl and appropriate measures should be taken as clinically indicated.
Renal disorders: Renal disorders, have been reported in association with sepsis, severe dehydration due to diarrhea, vomiting and obstructive uropathy. Renal failure including cases with fatal outcome has been observed. Appropriate measures should be taken to identify the cause and intensively treat the patients if this occurs. Renal function should be monitored.
Urinary disorders: Cystitis due to radiation recall phenomenon has been reported with cabazitaxel therapy in patients who have previously received pelvic radiation therapy and docetaxel containing regimen (see Adverse Reactions). Appropriate measures should be initiated. Interruption or discontinuation of cabazitaxel therapy may be necessary.
Respiratory disorders: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome (see Adverse Reactions).
If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated, and appropriately treated. Interruption of cabazitaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may help improve the condition. The benefit of resuming cabazitaxel treatment must be carefully evaluated.
Cardiac arrhythmias: Cardiac arrhythmias have been reported, most commonly tachycardia and atrial fibrillation (see Adverse Reactions).
Patients with hepatic impairment: Cabazitaxel is extensively metabolized in the liver (see Pharmacology: Pharmacokinetics under Actions).
Cabazitaxel (Jevtana) is contraindicated in patients with severe hepatic impairment (total bilirubin > 3 x ULN) (see Contraindications). Dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 x ULN or AST >1.5 x ULN) hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Driving a Vehicle or Performing other Hazardous Tasks: No studies on the effects on the ability to drive and use machines have been performed. However, based on the safety profile, Cabazitaxel (Jevtana) may have moderate influence on the ability to drive and use machines as it may cause fatigue and dizziness. Patients should be advised to not drive or use machines if they experience these adverse reactions during treatment.
Use in the Elderly: Elderly patients (≥65 years of age) may be more likely to experience certain adverse reactions including neutropenia or febrile neutropenia (see Adverse Reactions).
Use In Pregnancy & Lactation
Pregnancy: Due to potential exposure via seminal liquid, men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of Cabazitaxel (Jevtana).
There are no data from the use of Cabazitaxel in pregnant women. In non-clinical studies in rats and rabbits, Cabazitaxel was embryotoxic,fetotoxic, and abortifacient at exposures significantly lower than t hose expected at the recommended human dose level. Cabazitaxel crosses the placenta barrier (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions). Cabazitaxel (Jevtana) is not recommended during pregnancy.
Lactation: Available pharmacokinetics data in animals have shown excretion of cabazitaxel and its metabolites in milk (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions). Cabazitaxel (Jevtana) should not be used during breast-feeding.
Fertility: The effect of Cabazitaxel (Jevtana) on human fertility is unknown. Animal studies showed that Cabazitaxel affected reproductive system in male rats and dogs (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).
Adverse Reactions
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%; not known (cannot be estimated from the available data).
Clinical Studies: The safety of Cabazitaxel (Jevtana) in combination with prednisone or prednisolone was evaluated in 371 patients with metastatic castration resistant prostate cancer, in a randomized open label, controlled phase III study. Patients received a median duration of 6 cycles of Cabazitaxel (Jevtana) or 4 of mitoxantrone.
Very common (≥ 10%) grade 1-4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy (including peripheral sensory and motor neuropathy), pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia.
Common (>5%) Grade ≥3 adverse reactions in patients who received cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. Discontinuation of treatment due to adverse drug reactions occurred in 68 patients (18.3%) in the Cabazitaxel group and 31 patients (8.4%) in the mitoxantrone group. The most common adverse reaction leading to treatment discontinuation in the Cabazitaxel (Jevtana) group was neutropenia and renal failure.
Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (4.9%) Cabazitaxel (Jevtana)-treated patients and 3 (< 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in Cabazitaxel (Jevtana)-treated patients were due to infections (n=5). The majority (4 of 5 patients) of fatal infection-related adverse reactions in TROPIC occurred after a single dose of Cabazitaxel (Jevtana). (See Table 4.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: General disorders and administration site conditions: Peripheral oedema was observed at an incidence of 9.2% in all grades, and an incidence of 0.5% and 0.3% in grade ≥3 in the Cabazitaxel (Jevtana) arm and mitoxantrone arm, respectively.
Pain was observed at an incidence of 5.4% and 4.9% in all grades and 1.1% and 1.9% in grades ≥3 in the Cabazitaxel (Jevtana) arm and mitoxantrone arm, respectively.
Neutropenia and associated clinical events: Incidence of grade ≥3 neutropenia based on laboratory data was 81.7%. The incidence of grade >3 clinical neutropenia and febrile neutropenia adverse reactions were respectively 21.3% and 7.5%. Neutropenia was the most common adverse reaction leading to drug discontinuation (2.4%). Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases resulted in a fatal outcome.
The use of G-CSF has been shown to limit the incidence and severity of neutropenia (see Dosage & Administration and Precautions).
Cardiac disorders and arrhythmias: All Grade events among cardiac disorders were more common in Cabazitaxel (Jevtana) group of which 6 patients (1.6%) had Grade ≥3 cardiac arrhythmias. The incidence of tachycardia in Cabazitaxel (Jevtana) group was 1.6%, none of which were Grade ≥3. The incidence of atrial fibrillation was 1.1% in the Cabazitaxel (Jevtana) group.
Renal and urinary tract disorders: Renal failure was observed at 2.2% in all grades and 1.6% in grades ≥3 in the Cabazitaxel (Jevtana) arm.
Gastrointestinal Disorders: Colitis, enterocolitis, gastritis, neutropenic enterocolitis have been observed. Gastrointestinal hemorrhage and perforation, ileus and intestinal obstruction have also been reported.
Respiratory disorders: Cases of interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome, including cases with fatal outcome have been reported (see Precautions).
Investigations: The incidence of grade ≥3 anemia, increased AST/SGOT, increased ALT/SGPT, and increased bilirubin based on laboratory abnormalities were 10.6%, 0.9%, 1.1%, and 0.6%, respectively.
Decreased weight was observed at 8.6% and 7.5% in all grades and 0% and 0.3% in grades grade ≥ 3 in the Cabazitaxel (Jevtana) arm and mitoxantrone arm, respectively.
Elderly population: Of the 371 patients treated with Cabazitaxel (Jevtana) in the prostate cancer study, 240 patients were 65 years or over including 70 patients older than 75 years. The following adverse reactions reported at rates ≥5% higher in patients 65 years of age or greater compared to younger patients were: fatigue (40.4% vs. 29.8%), neutropenia (24.2% vs. 17.6%), asthenia (23.8% vs. 14.5%), pyrexia (14.6% vs. 7.6%), dizziness (10.0% vs. 4.6%), urinary tract infection (9.6% vs 3.1%) and dehydration (6.7% vs. 1.5%), respectively.
The incidence of the following grade ≥3 adverse reactions were higher in patients ≥65 years of age compared to younger patients: neutropenia based on laboratory abnormalities (86.3% vs. 73.3%), clinical neutropenia (23.8% vs. 16.8%) and febrile neutropenia (8.3% vs. 6.1%) (see Dosage & Administration and Precautions).
Of the 595 patients treated with cabazitaxel 25 mg/m2 in the prostate cancer EFC 11785 study, 420 patients were 65 years or over. The adverse reactions reported at rates of at least 5% higher in patients 65 years of age or greater compared to younger patients were diarrhoea (42.9% vs. 32.6%), fatigue (30.2% vs. 19.4%), asthenia (22.4% vs. 13.1%), constipation (20.2% vs. 12.6%), clinical neutropenia (12.9% vs. 6.3%), febrile neutropenia (11.2% vs. 4.6%) and dyspnoea (9.5% vs. 3.4%).
Post Marketing Experiences: Renal and urinary disorders: Cystitis due to radiation recall phenomenon was reported uncommonly. (see Precautions).
Drug Interactions
The metabolism of Cabazitaxel is modified by the concomitant administration of compounds which are known to be strong inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or strong inducers (e.g., rifampin, carbamazepine or phenytoin) of CYP3A. Co-administration with strong CYP3A inhibitors should be avoided. If co-administration with a strong CYP3A inhibitor cannot be avoided, close monitoring for toxicity and a Cabazitaxel dose reduction should be considered (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Co-administration with strong CYP3A inducers should be avoided as they may decrease Cabazitaxel exposure (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
In vitro, Cabazitaxel has also been shown to inhibit the transport proteins of the Organic Anion Transport Polypeptides OATP1B1. The risk of interaction with OATP1B1 substrates (e.g. statins, valsartan, repaglinide) is possible notably during the infusion duration (1 hour) and up to 20 minutes after the end of the infusion, and may lead to an increase of exposure of OATP1B1 substrates.
Prednisone/prednisolone administered at 10 mg daily did not affect the pharmacokinetics of Cabazitaxel. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents may result in serious or fatal infections. Vaccination with a live attenuated vaccine should be avoided in patients receiving Cabazitaxel. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Caution For Usage
Incompatibilities/Compatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Preparation and Handling as follows.
Always dilute Cabazitaxel (Jevtana) 60 mg/1.5 mL concentrate for solution for infusion with the supplied solvent before adding to infusion solutions.
Cabazitaxel (Jevtana) contains polysorbate 80 which is known to increase the rate of di-(2-ethylhexyl) phthalate extraction (DEHP) from polyvinyl chloride (PVC).
Preparation and Handling: As for any other antineoplastic agent, caution should be exercised when handling and preparing Cabazitaxel (Jevtana) solutions. The use of gloves is recommended.
If Cabazitaxel (Jevtana), at any step of its handling, should come into contact with the skin, wash immediately and thoroughly with soap and water. If it should come into contact with mucous membranes, wash immediately and thoroughly with water.
Cabazitaxel (Jevtana) should only be prepared and administered by personnel trained in handling cytotoxic agents. Pregnant staff should not handle it.
Preparation steps: Read this ENTIRE section carefully before mixing and diluting. Cabazitaxel (Jevtana) requires TWO dilutions prior to administration. Follow the preparation instructions provided as follows.
Note: Both the Cabazitaxel (Jevtana) 60 mg/1.5 ml concentrate vial (fill volume: 73.2 mg of cabazitaxel/1.83 ml) and the solvent vials (fill volume: 5.67 ml) contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the ENTIRE contents of the accompanying solvent, there is an initial diluted solution containing 10 mg/ml Cabazitaxel (Jevtana).
The following two-step dilution process must be carried out in an aseptic manner for preparing the solution for infusion.
Step 1: First dilution.
Step 1.1: Inspect the Cabazitaxel (Jevtana) 60 mg/1.5 ml concentrate vial and the supplied solvent. The concentrate solution should be clear.
Step 1.2: Using a syringe fitted with a needle, aseptically withdraw the entire contents of the supplied solvent by partially inverting the vial.
Step 1.3: Inject the entire contents into the corresponding vial of Cabazitaxel (Jevtana).
To limit foaming as much as possible when injecting the solvent, direct the needle onto the inside wall of the vial of concentrate solution and inject slowly.
Once reconstituted, the resultant solution contains 10 mg/ml of Cabazitaxel (Jevtana).
Step 1.4: Remove the syringe and needle and mix manually and gently by repeated inversions until obtaining a clear and homogeneous solution. It could take approximately 45 seconds.
Step 1.5: Let this solution stand for approximately 5 minutes and check then that the solution is homogeneous and clear. It is normal for foam to persist after this time period.
This resulting concentrate-solvent mixture contains 10 mg/ml of Cabazitaxel (Jevtana) (at least 6 ml deliverable volume. The second dilution should be done immediately (within 1 hour) as detailed in Step 2.
More than one vial of the initial diluted solution may be necessary to administer the prescribed dose. As an example, a dose of 45 mg Cabazitaxel (Jevtana) would require 4.5 ml of the concentrate-solvent mixture prepared following Step 1.
Step 2: Second (final) dilution for infusion.
Step 2.1: Aseptically withdraw the required amount of initial diluted Cabazitaxel (Jevtana) solution (10 mg/ml of Cabazitaxel (Jevtana)), with a graduated syringe fitted with a needle.
Step 2.2: Inject in a sterile PVC-free container of 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.
Since foam may persist on the wall of the vial of this solution, following its preparation described in Step 1, it is preferable to place the needle of the syringe in the middle when extracting.
Step 2.3: Remove the syringe and mix the content of the infusion bag or bottle manually using a rocking motion.
Step 2.4: As with all parenteral products, the resulting infusion solution should be visually inspected prior to use. Solution containing a precipitate should be discarded.
Preparation and administration: Cabazitaxel (Jevtana) is administered as a 1 hour infusion.
Do not use PVC infusion containers.
Do not use polyurethane infusion sets.
Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.
The Cabazitaxel (Jevtana) infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions (see Storage).
As the infusion solution is supersaturated, it may crystallize over time. In this case, the solution must not be used and should be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Cabazitaxel (Jevtana) must not be mixed with any other medicines.
Storage
Before dilution: Store between +15°C and +30°C.
Do not refrigerate.
After dilutions: For storage conditions of the diluted medicinal product (see Preparation and Handling under Cautions for Usage).
Shelf-life: Concentrate vial: 3 years.
Solvent vial: 3 years.
Stability of the initial diluted solution in the vial: After initial dilution of Cabazitaxel (Jevtana) 60 mg/1.5 mL concentrate with the solvent, the resulting concentrate-solvent mixture is stable for 1 hour if stored at ambient temperature.
Stability of the final dilution solution in the infusion bag: After final dilution in the infusion bag/bottle, the infusion solution may be stored up to 8 hours at ambient temperature (including the 1 hour infusion).
Chemical and physical stability of the infusion solution has been demonstrated for 48 hours under refrigerated conditions (including the 1 hour infusion).
As the infusion solution is supersaturated, it may crystallize over time. In this case, the solution must not be used and should be discarded.
ATC Classification
L01CD04 - cabazitaxel ; Belongs to the class of taxanes from plant alkaloids and other natural products. Used in the treatment of cancer.
Presentation/Packing
Soln for infusion 60 mg/1.5 mL {15 mL vial [1.5 mL concentrate (clear yellow to brownish-yellow oily)] + 15 mL vial [4.5 mL solvent (clear and colorless)]} x 1's.
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