Jevtana: Package Insert and Label Information (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

14 CLINICAL STUDIES

14.1 TROPIC Trial (JEVTANA + prednisone compared to mitoxantrone)

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.

Table 5: Efficacy of JEVTANA in TROPIC in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (intent-to-treat analysis)
JEVTANA + Prednisonen=378Mitoxantrone + Prednisonen=377
*
Hazard ratio estimated using Cox model; a hazard ratio of less than 1 favors JEVTANA.
Overall Survival
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)
p-value<0.0001

Figure 1: Kaplan-Meier Overall Survival Curves (TROPIC)

Figure 1
(click image for full-size original)

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.

14.2 PROSELICA Trial (comparison of two doses of JEVTANA)

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.

Table 6: Overall Survival in PROSELICA for JEVTANA 20 mg/m2 versus JEVTANA 25 mg/m2 (intent-to-treat analysis)
CBZ20+PREDn=598CBZ25+PREDn=602
CBZ20=Cabazitaxel 20 mg/m2 , CBZ25=Cabazitaxel 25 mg/m2 , PRED=Prednisone/Prednisolone.
CI=confidence interval.
*
Hazard ratio is estimated using a Cox Proportional Hazards regression model. A hazard ratio <1 indicates a lower risk of death for Cabazitaxel 20 mg/m2 with respect to 25 mg/m2.
Adjusted for interim OS analyses. The noninferiority margin is 1.214.
Overall Survival
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)

Figure 2: Kaplan-Meier Overall Survival Curves (intent-to-treat population) (PROSELICA)

Figure 2
(click image for full-size original)

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.

Table 7: Efficacy of JEVTANA in CARD Trial in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (intent-to-treat analysis)
JEVTANA + prednisone/prednisolone + G-CSF n=129Abiraterone + prednisone/prednisolone or Enzalutamide n=126
*
Investigator assessed.
Stratified log-rank test, significance threshold = 0.05.
Overall survival was statistically significant.
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)
p-value <0.0001
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]
p-value0.0078

Figure 3: Kaplan-Meier of Radiographic PFS (ITT Population)

Figure 3
(click image for full-size original)

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.

15 REFERENCES

  1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

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).

16.2 Storage

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.

16.3 Handling and Disposal

JEVTANA is a cytotoxic anticancer drug. Follow applicable special handling and disposable procedures [see References (15)].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions

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

Inform elderly patients that certain side effects may be more frequent or severe [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5)].

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)].

Respiratory Disorders

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)].

Drug Interactions

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)].

Embryo-Fetal Toxicity

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)].

Infertility

Advise male patients that JEVTANA may impair fertility [see Use in Specific Populations (8.3)].

Manufactured by:
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 the most important information I should know about JEVTANA? JEVTANA may cause serious side effects including:

  • Low white blood cells. Low white blood cells can cause you to get serious infections, and may lead to death. Men who are 65 years or older may be more likely to have these problems. Your healthcare provider:
    • will do blood tests regularly to check your white blood cell counts during your treatment with JEVTANA.
    • may lower your dose of JEVTANA, change how often you receive it, or stop JEVTANA until your healthcare provider decides that you have enough white blood cells.
    • may prescribe a medicine for you called G-CSF to help prevent complications if your white blood cell count is too low.
    Tell your healthcare provider right away if you have any of these symptoms of infection during treatment with JEVTANA:
    • fever. Take your temperature often during treatment with JEVTANA.
    • cough
    • burning on urination
    • muscle aches
    Also, tell your healthcare provider if you have any diarrhea during the time that your white blood cell count is low. Your healthcare provider may prescribe treatment for you as needed.
  • Severe allergic reactions. Severe allergic reactions can happen within a few minutes after your infusion of JEVTANA starts, especially during the first and second infusions. Your healthcare provider should prescribe medicines before each infusion to help prevent severe allergic reactions. Tell your healthcare provider or nurse right away if you have any of these symptoms of a severe allergic reaction during or soon after an infusion of JEVTANA:
  • rash or itching
  • feeling dizzy or faint
  • chest or throat tightness
  • skin redness
  • breathing problems
  • swelling of your face
  • Severe stomach and intestine (gastrointestinal) problems.
    • JEVTANA can cause severe vomiting and diarrhea, which may lead to death. Severe vomiting and diarrhea with JEVTANA can lead to loss of too much body fluid (dehydration), or too much of your body salts (electrolytes). Death has happened from having severe diarrhea and losing too much body fluid or body salts with JEVTANA. You may need to go to a hospital for treatment. Your healthcare provider will prescribe medicines to prevent or treat vomiting and diarrhea, as needed, with JEVTANA.Tell your healthcare provider right away if you develop vomiting or diarrhea or if your symptoms get worse or do not get better.
    • JEVTANA can cause a leak in the stomach or intestine, intestinal blockage, infection, and bleeding in the stomach or intestine, which may lead to death. Tell your healthcare provider if you develop any of these symptoms:
      • severe stomach-area (abdomen) pain
      • constipation
      • fever
      • blood in your stool, or changes in the color of your stool
  • Kidney failure. Kidney failure may happen with JEVTANA, because of severe infection, loss of too much body fluid (dehydration), and other reasons, which may lead to death. Your healthcare provider will check you for this problem and treat you if needed.Tell your healthcare provider if you develop these signs or symptoms:
    • swelling of your face or body
    • decrease in the amount of urine that your body makes each day
    • blood in your urine
  • Lung or breathing problems. Lung or breathing problems may happen with JEVTANA and may lead to death. Men who have lung disease before receiving JEVTANA may have a higher risk for developing lung or breathing problems with JEVTANA treatment. Your healthcare provider will check you for this problem and treat you if needed.Tell your healthcare provider right away if you develop any new or worsening symptoms, including trouble breathing, shortness of breath, chest pain, cough or fever.
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:
  • your white blood cell (neutrophil count) is too low
  • you have had a severe allergic reaction to cabazitaxel or other medicines that contain polysorbate 80. Ask your healthcare provider if you are not sure.
  • you have severe liver problems
Before receiving JEVTANA, tell your healthcare provider about all your medical conditions, including if you:
  • are over the age of 65
  • had allergic reactions in the past
  • have kidney or liver problems
  • have lung problems
  • are pregnant or plan to become pregnant. JEVTANA can cause harm to your unborn baby and loss of pregnancy (miscarriage).
  • are a male with a female partner who is able to become pregnant. Males should use effective birth control (contraception) during treatment with JEVTANA and for 3 months after the last dose of JEVTANA.
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?
  • JEVTANA will be given to you by an intravenous (IV) infusion into your vein.
  • Your treatment will take about 1 hour.
  • JEVTANA is usually given every 3 weeks. Your healthcare provider will decide how often you will receive JEVTANA.
  • Your healthcare provider will also prescribe another medicine called prednisone for you to take by mouth every day during treatment with JEVTANA.
  • Your healthcare provider will tell you how and when to take your prednisone.
  • It is important that you take prednisone exactly as prescribed by your healthcare provider. If you forget to take your prednisone, or do not take it on schedule, make sure to tell your healthcare provider or nurse.
  • Before each infusion of JEVTANA, you may receive other medicines to prevent or treat side effects.
What are the possible side effects of JEVTANA?JEVTANA may cause serious side effects including:
  • See “What is the most important information I should know about JEVTANA?
  • Inflammation of the bladder and blood in the urine. Blood in the urine is common with JEVTANA, but it can also sometimes be severe. Some people who have had pelvic radiation in the past may develop inflammation of the bladder and blood in the urine that is severe enough that they need to be hospitalized for medical treatment or surgery. Your healthcare provider will check you for these problems during treatment with JEVTANA. Your healthcare provider may stop your treatment with JEVTANA for a short time, or permanently, if you develop inflammation of the bladder and bleeding that is severe.
The most common side effects of JEVTANA include:
  • Low red blood cell count (anemia). Low red blood cell count is common with JEVTANA, but can sometimes also be serious. Your healthcare provider will regularly check your red blood cell count. Symptoms of anemia include shortness of breath and tiredness.
  • Low blood platelet count. Low platelet count is common with JEVTANA, but can sometimes also be serious. Tell your healthcare provider if you have any unusual bruising or bleeding.
  • diarrhea
  • nausea
  • tiredness
  • weakness
  • vomiting
  • blood in urine
  • constipation
  • decreased appetite
  • back pain
  • stomach (abdominal) pain
  • JEVTANA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.
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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