Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel.
Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses ≥0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization).
In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. In repeat-dose toxicology studies in rats with intravenous cabazitaxel administration once every three weeks for up to 6 months, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses ≥1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose).
In a fertility study in male rats, cabazitaxel did not affect mating performances or fertility at doses of 0.05, 0.1, or 0.2 mg/kg/day. In repeat-dose toxicology studies with intravenous cabazitaxel administration once every three weeks for up to 9 months, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats at a dose of 1 mg/kg (approximately 0.2 times the AUC in patients at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated at a dose of 0.5 mg/kg (approximately 0.1 times the AUC in patients at the recommended human dose).
The efficacy and safety of JEVTANA in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen (TROPIC, NCT00417079).
A total of 755 patients were randomized to receive either JEVTANA 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.
This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3 , platelets >100,000 cells/mm3 , hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the 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 (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the JEVTANA group.
Efficacy results for the JEVTANA arm versus the control arm are summarized in Table 5 and Figure 1.
|JEVTANA + Prednisonen=378||Mitoxantrone + Prednisonen=377|
|Number of deaths (%)||234 (61.9%)||279 (74.0%)|
|Median survival (month) (95% CI)||15.1 (14.1–16.3)||12.7 (11.6–13.7)|
|Hazard Ratio * (95% CI)||0.70 (0.59–0.83)|
Figure 1: Kaplan-Meier Overall Survival Curves (TROPIC)
Investigator-assessed tumor response of 14.4% (95% CI: 9.6–19.3) was higher for patients in the JEVTANA arm compared to 4.4% (95% CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005.
The efficacy and safety of JEVTANA were evaluated in a noninferiority, multicenter, randomized, open-label study (PROSELICA, NCT01308580). A total of 1200 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen were randomized to receive either JEVTANA 25 mg/m2 (n=602) or 20 mg/m2 (n=598) dose. Overall survival (OS) was the major efficacy outcome.
Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 45–89) and the racial distribution for all groups was 87% Caucasian, 6.9% Asian, 2.3% Black, and 3.8% Others in the JEVTANA 20 mg/m2 group. The median age was 69 years (range 45–88) and the racial distribution for all groups was 88.7% Caucasian, 6.6% Asian, 1.8% Black, and 2.8% Others in the JEVTANA 25 mg/m2 group.
The study demonstrated noninferiority in overall survival (OS) of JEVTANA 20 mg/m2 in comparison with JEVTANA 25 mg/m2 in an intent-to-treat population (see Table 6 and Figure 2). Based on the per-protocol population, the estimated median OS was 15.1 months on JEVTANA 20 mg/m2 and 15.9 months on JEVTANA 25 mg/m2 , the observed hazard ratio (HR) of OS was 1.042 (97.78% CI: 0.886, 1.224). Among the subgroup analyses intended for assessing the heterogeneity, no notable difference in OS was observed on the JEVTANA 25 mg/m2 arm compared to the JEVTANA 20 mg/m2 arm in subgroups based on the stratification factors of ECOG performance status score, measurability of disease, or region.
|CBZ20=Cabazitaxel 20 mg/m2 , CBZ25=Cabazitaxel 25 mg/m2 , PRED=Prednisone/Prednisolone.|
|Number of deaths, n (%)||497 (83.1%)||501 (83.2%)|
|Median survival (95% CI) (months)||13.4 (12.2 to 14.9)||14.5 (13.5 to 15.3)|
|Hazard Ratio * (97.78% CI †)||1.024 (0.886, 1.184)|
14.3 CARD Trial (JEVTANA 25 mg/m2 + prednisone/prednisolone + primary prophylaxis with G-CSF compared to abiraterone acetate + prednisone/prednisolone or enzalutamide)
The efficacy and safety of JEVTANA were evaluated in a multinational, randomized, active-controlled, open-label study (CARD: NCT02485691) in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel containing regimen and had progressed within 12 months of initiating either abiraterone or enzalutamide. A total of 255 patients were randomized to receive either JEVTANA 25 mg/m2 every 3 week plus prednisone/prednisolone 10 mg daily (n=129), abiraterone 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily depending on prior therapy received (n=126). Primary prophylactic G-CSF was administered at each cycle for patients in the JEVTANA arm. This study included patients over 18 years of age with ECOG performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3 , platelets >100,000 cells/mm3 , hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study. Randomization was stratified by ECOG performance status (0 or 1 vs 2), time from abiraterone acetate or enzalutamide to disease progression, and receipt of abiraterone acetate or enzalutamide before or after docetaxel containing regimen.
The major efficacy outcome measure was radiographic progression free-survival (rPFS) as defined by Prostate Cancer Working Group-2 (PCWG2) assessed by study investigators. Other efficacy outcome measures included overall survival and objective response rate.
Demographics and baseline disease characteristics were balanced between treatment arms. The overall median age was 70 years (range 45 to 88), 95% of patients had an ECOG PS of 0 to 1 and median Gleason score was 8. A majority of the patients (61%) had their prior treatment with abiraterone acetate or enzalutamide after docetaxel. There were 36% of patients on the cabazitaxel arm with visceral disease (liver 8%, lung 8%, other 20%) and 57% with bone-only disease. Race and ethnicity data were not collected. Approximately 92% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy during the first 3 cycles and, overall, 90% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy at each cycle.
Efficacy results from the CARD trial are summarized in Table 7 and Figure 3.
|JEVTANA + prednisone/prednisolone + G-CSF n=129||Abiraterone + prednisone/prednisolone or Enzalutamide n=126|
|Radiographic Progression Free Survival (rPFS)|
|Number of events (%)*||95 (73.6%)||101 (80.2%)|
|Median rPFS (months) (95% CI)||8.0 (5.7 to 9.2)||3.7 (2.8 to 5.1)|
|Hazard Ratio (95% CI)||0.54 (0.40 to 0.73)|
|Overall Survival (OS) ‡|
|Median OS [95% CI] (months)||13.6 [11.5; 17.5]||11.0 [9.2; 12.9]|
|Hazard Ratio (95% CI)||0.64 [0.46; 0.89]|
Figure 3: Kaplan-Meier of Radiographic PFS (ITT Population)
In terms of therapy sequence prior to randomization, rPFS was consistent across the subgroups of patients who received abiraterone acetate/enzalutamide prior to docetaxel (HR=0.61, 95% CI: 0.39, 0.96) and those who received abiraterone acetate/enzalutamide after docetaxel (HR=0.48, 95% CI: 0.32, 0.70).
Objective tumor response rate assessed by study investigators was 36.5% (95% CI: 26.6 to 48.4) for JEVTANA arm versus 11.5% (95% CI: 2.9 to 20.2) for abiraterone acetate plus prednisone/prednisolone or enzalutamide arm, p=0.004.
- OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
JEVTANA is supplied as a kit, NDC 0024-5824-11, that contains the following:
- One single-dose vial of JEVTANA (cabazitaxel) injection: a clear yellow to brownish-yellow viscous solution of 60 mg/1.5 mL in a clear glass vial with a grey rubber closure, aluminum cap, and light green plastic flip-off cap (JEVTANA vial NDC 0024-5823-15).
- One single-dose vial of Diluent for JEVTANA: a clear colorless solution of 13% (w/w) ethanol in water for injection in a clear glass vial with a grey rubber closure, gold-color aluminum cap, and colorless plastic flip-off cap (diluent vial NDC 0024-5822-01).
JEVTANA injection and Diluent for JEVTANA:
Store at 25°C (77°F); excursions permitted between 15°C–30°C (59°F–86°F).
Do not refrigerate.
JEVTANA is a cytotoxic anticancer drug. Follow applicable special handling and disposable procedures [see References (15)].
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Educate patients about the risk of potential hypersensitivity associated with JEVTANA. Confirm patients do not have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80. Instruct patients to immediately report signs of a hypersensitivity reaction [see Contraindications (4) and Warnings and Precautions (5.3)].
Bone Marrow Suppression
Inform patients that JEVTANA decreases blood count such as white blood cells, platelets and red blood cells. Thus, it is important that periodic assessment of their blood count be performed to detect the development of neutropenia, thrombocytopenia, anemia, and/or pancytopenia [see Contraindications (4) and Warnings and Precautions (5.1)]. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever to their healthcare provider.
Increased Toxicities in Elderly Patients
Importance of Prednisone
Explain that it is important to take the oral prednisone as prescribed. Instruct patients to report if they were not compliant with oral corticosteroid regimen [see Dosage and Administration (2.1)].
Infections, Dehydration, Renal Failure
Explain to patients that severe and fatal infections, dehydration, and renal failure have been associated with cabazitaxel exposure. Patients should immediately report fever, significant vomiting or diarrhea, decreased urinary output, and hematuria to their healthcare provider [see Warnings and Precautions (5.1, 5.4, 5.5)].
Urinary Disorders Including Cystitis
Inform patients that hematuria may occur during treatment with JEVTANA. Inform patients that previously received pelvic radiation that cystitis and radiation cystitis may occur during treatment with JEVTANA. Advise patients to report any occurrence of hematuria, or any signs and symptoms of cystitis or radiation cystitis, to their healthcare provider [see Warnings and Precautions (5.6)].
Explain to patients that severe and fatal interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have occurred with JEVTANA. Instruct patients to immediately report new or worsening pulmonary symptoms to their healthcare provider [see Warnings and Precautions (5.7)].
Inform patients about the risk of drug interactions and the importance of providing a list of prescription and non-prescription drugs to their healthcare provider [see Drug Interactions (7.1)].
Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of JEVTANA [see Use in Specific Populations (8.3)].
Advise male patients that JEVTANA may impair fertility [see Use in Specific Populations (8.3)].
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY
JEVTANA is a registered trademark of sanofi-aventis©2021 sanofi-aventis U.S. LLC
|Patient InformationJEVTANA® (JEV-ta-na)(cabazitaxel)Injection|
|This Patient Information has been approved by the U.S. Food and Drug Administration.||Revised: February 2021|
| || |
|What is JEVTANA? JEVTANA is a prescription medicine used with the steroid medicine prednisone. JEVTANA is used to treat men with castration-resistant prostate cancer (prostate cancer that is resistant to medical or surgical treatments that lower testosterone) that has spread to other parts of the body, and that has worsened (progressed) after treatment with other medicines that included docetaxel.It is not known if JEVTANA is safe and effective in children.|
| Who should not receive JEVTANA?Do not receive JEVTANA if: |
|Before receiving JEVTANA, tell your healthcare provider about all your medical conditions, including if you:|
|Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.JEVTANA can interact with many other medicines. Do not take any new medicines without asking your healthcare provider first. Your healthcare provider will tell you if it is safe to take the new medicine with JEVTANA.|
| How will I receive JEVTANA? |
| What are the possible side effects of JEVTANA?JEVTANA may cause serious side effects including: |
| || |
|Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of JEVTANA. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.|
|General information about the safe and effective use of JEVTANA Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about JEVTANA that is written for health professionals.|
|What are the ingredients in JEVTANA? Active ingredient: cabazitaxelInactive ingredients: polysorbate 80, citric acid monohydrateManufactured by: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807 A SANOFI COMPANYJEVTANA is a registered trademark of sanofi-aventis. ©2021 sanofi-aventis U.S. LLCFor more information, go to www.sanofi-aventis.us or call 1-800-633-1610.|
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