`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`These highlights do not include all the information needed to use
`
`
`
`
`
`JEVTANA safely and effectively. See full prescribing information for
`
`JEVTANA.
`JEVTANA® (cabazitaxel) injection, for intravenous use
`
`
`
`
`
`
`Initial U.S. Approval: 2010
`
` WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
` See full prescribing information for complete boxed warning.
`
`
`• Neutropenic deaths have been reported. Obtain frequent blood
`
` counts to monitor for neutropenia. JEVTANA is contraindicated
`
`
` in patients with neutrophil counts of ≤1,500 cells/mm3. Primary
`
`
`
`
`
`
`prophylaxis with G-CSF is recommended in patients with high-
`
`
`risk clinical features. (4, 5.1, 5.2)
`
`
`
`• Severe hypersensitivity can occur and may include generalized
`
`
`
`
`rash/erythema, hypotension and bronchospasm. Discontinue
`
`JEVTANA immediately if severe reactions occur and administer
`
`
`
`appropriate therapy. (2.1, 5.2)
`
`
`• Contraindicated if history of severe hypersensitivity reactions to
`
`
`
`
`
`
` cabazitaxel or to drugs formulated with polysorbate 80. (4)
`----------------------------RECENT MAJOR CHANGES------------------------­
`
`
`
` Warnings and Precautions (5.9)
`
` 01/2020
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`
`
`
`
`
` JEVTANA is a microtubule inhibitor indicated in combination with
`
`
` prednisone for treatment of patients with metastatic castration-resistant
`
`
` prostate cancer previously treated with a docetaxel-containing treatment
`
`
`
`
` regimen. (1)
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
` Recommended Dose: JEVTANA 20 mg/m2 administered every three weeks
`
`
`
`
`
`
`
`
`
`
`
`
`
`as a one-hour intravenous infusion in combination with oral prednisone 10 mg
`
`
`
`administered daily throughout JEVTANA treatment. (2.1)
`A dose of 25 mg/m2 can be used in select patients at the discretion of the
`
`
`
`
`
`
`
`
`
`treating healthcare provider. (2.1, 5.1, 5.2, 6.1, 14)
`• JEVTANA requires two dilutions prior to administration. (2.5)
`
`
`
`
`
`• Use the entire contents of the accompanying diluent to achieve a
`
`
`
`
`concentration of 10 mg/mL JEVTANA. (2.5)
`
`
`
`• PVC equipment should not be used. (2.5)
`
`
`
`
`
`• Premedication Regimen: Administer intravenously 30 minutes before
`
`
`
`
`
`
`each dose of JEVTANA:
`
`
`o Antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg
`
`
`
`
`or equivalent antihistamine)
`
`
`o Corticosteroid (dexamethasone 8 mg or equivalent steroid)
`
`
`
`
`o H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist) (2.1)
`
`
`
`
`Antiemetic prophylaxis (oral or intravenous) is recommended as needed.
`
`
`
`
`(2.1)
`
`• Dosage Modifications: See full prescribing information (2.2, 2.3, 2.4)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`• Single dose vial 60 mg/1.5 mL, supplied with diluent (5.7 mL) for
`
`
`
`
`JEVTANA (3)
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`• Neutrophil counts of ≤1,500/mm3 (2.2, 4)
`
`
`
`
`• History of severe hypersensitivity to JEVTANA or polysorbate 80 (4)
`
`
`
`
`• Severe hepatic impairment (Total Bilirubin >3 × ULN) (4)
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Information
`
`
`2.2 Dose Modifications for Adverse Reactions
`
`
`2.3 Dose Modifications for Hepatic Impairment
`
`
`2.4 Dose Modifications for Use with Strong CYP3A Inhibitors
`
`
`
`2.5 Preparation and Administration
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Bone Marrow Suppression
`
`
`5.2
`Increased Toxicities in Elderly Patients
`
`
`
`5.3 Hypersensitivity Reactions
`
`
`5.4 Gastrointestinal Adverse Reactions
`
`
`5.5 Renal Failure
`
`
`5.6 Urinary Disorders Including Cystitis
`
`
`
`
`
`5.7 Respiratory Disorders
`
`
`
`
`
`Reference ID: 4570032
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Bone marrow suppression (particularly neutropenia) and its clinical
`
`
`
`consequences (febrile neutropenia, neutropenic infections, and death):
`
`
`
`Monitor blood counts frequently to determine if dosage modification or
`
`
`
`
`
`initiation of G-CSF is needed. Primary prophylaxis with G-CSF is
`
`
`
`
`recommended in patients with high-risk clinical features. Closely monitor
`
`
`
`patients with hemoglobin <10 g/dL. (2.2, 4, 5.1)
`
`
`• Increased toxicities in elderly patients: Patients ≥65 years of age were
`
`
`
`
`
`more likely to experience fatal outcomes and certain adverse reactions,
`including neutropenia and febrile neutropenia. Monitor closely. (5.2, 8.5)
`
`
`
`
`• Hypersensitivity: Severe hypersensitivity reactions can occur.
`
`
`
`Premedicate with corticosteroids and H2 antagonists. Discontinue infusion
`
`
`
`
`immediately if hypersensitivity is observed and treat as indicated. (4, 5.3)
`
`
`
`
`• Gastrointestinal disorders: Nausea, vomiting, and diarrhea may occur.
`
`
`
`Mortality related to diarrhea has been reported. Rehydrate and treat with
`
`
`
`
`antiemetics and antidiarrheals as needed. If experiencing Grade ≥3
`
`
`diarrhea, dosage should be modified. (2.2) Deaths have occurred due to
`
`
`
`
`
`gastrointestinal hemorrhage, perforation and neutropenic enterocolitis.
`
`
`
`Delay or discontinue JEVTANA and treat as indicated. (5.4)
`
`
`
`
`
`
`
`• Renal failure, including cases with fatal outcomes, has been reported.
`
`
`Identify cause and manage aggressively. (5.5)
`
`
`
`
`
`• Urinary disorders including cystitis: Cystitis, radiation cystitis, and
`
`
`hematuria may occur. Monitor patients who previously received pelvic
`
`
`
`
`radiation for signs and symptoms of cystitis. Interrupt or discontinue
`
`
`
`
`JEVTANA and provide medical or surgical supportive care, as needed, in
`
`
`patients experiencing severe hemorrhagic cystitis.
`
`
`
`• Respiratory disorders: Interstitial pneumonia/pneumonitis, interstitial lung
`
`disease and acute respiratory distress syndrome, including fatal outcomes,
`
`
`
`have been reported. Delay or discontinue JEVTANA and treat as indicated.
`
`(5.7)
` • Hepatic impairment: Administer JEVTANA at a dose of 20 mg/m2 in
`
`
`
`
`
`
`
` patients with mild hepatic impairment. Administer JEVTANA at a dose of
` 15 mg/m2 in patients with moderate hepatic impairment. (2.3, 5.8)
`
`
`
`
`
`
`
`
`• Embryo-fetal toxicity: JEVTANA can cause fetal harm and loss of
`
`
`pregnancy. Advise males with female partners of reproductive potential to
`
`
`
`use effective contraception. (5.9, 8.1, 8.3)
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
`
`Most common all grades adverse reactions and laboratory abnormalities
`
`(≥10%) with JEVTANA 20 mg/m² or 25 mg/m² are neutropenia, anemia,
`
`
`
`leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting,
`
`constipation, asthenia, abdominal pain, hematuria, back pain, anorexia,
`
`peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and
`
`alopecia. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
`
`
`U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS------------------------------­
`
`Avoid coadministration of JEVTANA with strong CYP3A inhibitors. If
`
`
`
`patients require coadministration of a strong CYP3A inhibitor, consider a 25%
`
`JEVTANA dose reduction. (2.4, 7.1, 12.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`Revised: 03/2020
`
`
`
`5.8 Use in Patients with Hepatic Impairment
`
`
`5.9 Embryo-Fetal Toxicity
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 CYP3A Inhibitors
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`
`
`
` 1
`
`

`

`
`
`
`
`
` 10 OVERDOSAGE
`
`
` 11 DESCRIPTION
` 12 CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
` 14 CLINICAL STUDIES
`
`
`
`
` 14.1 TROPIC Trial (JEVTANA + prednisone compared to mitoxantrone)
`
`
`
`
`
`
`
`
`
`
`
`
`
` 14.2 PROSELICA Trial (comparison of two doses of JEVTANA)
`
` 15 REFERENCES
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 16.1 How Supplied
`
`
` 16.2 Storage
`
`
`
`
` 16.3 Handling and Disposal
`
` 17 PATIENT COUNSELING INFORMATION
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
`
`
`
`
`
`
`Reference ID: 4570032
`
`
`
` 2
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
`
`
`Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with
`
`
`
`
`
`frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil
`
`
`
` counts of ≤1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients
`
`with high-risk clinical features [see Contraindications (4) and Warnings and Precautions
`
`
`(5.1, 5.2)].
`
`
`
`
`Severe hypersensitivity: Severe hypersensitivity reactions can occur and may include
`
`
`
`
`generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity
`
`
`
`reactions require immediate discontinuation of the JEVTANA infusion and administration
`of appropriate therapy. Patients should receive premedication. JEVTANA is
`
`
`contraindicated in patients who have a history of severe hypersensitivity reactions to
`cabazitaxel or to other drugs formulated with polysorbate 80 [see Dosage and
`
`
`
`
`Administration (2.1), Contraindications (4), and Warnings and Precautions (5.3)].
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`JEVTANA® is indicated in combination with prednisone for the treatment of patients with
`
`
`
`
`
`
`
`
`
`metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing
`
`treatment regimen.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Dosing Information
`
`
`The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA),
`and is 20 mg/m2 administered as a one-hour intravenous infusion every three weeks in
`
`
`
`
`
`
`
`
`combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment.
`A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare
`
`
`
`
`provider [see Warnings and Precautions (5.1, 5.2), Adverse Reactions (6.1), and Clinical Studies
`
`
`
`
`
`(14)].
`
`
`
`
`Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous
`
`
`medications to reduce the risk and/or severity of hypersensitivity [see Warnings and Precautions
`
`
`(5.3)]:
`
`
`
`
`• antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent
`
`antihistamine),
`
`
`• corticosteroid (dexamethasone 8 mg or equivalent steroid),
`
`
`
`
`
`• H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist).
`Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see
`
`
`
`Warnings and Precautions (5.3)].
`JEVTANA injection single-use vial requires two dilutions prior to administration [see Dosage
`
`
`and Administration (2.5)].
`
`
`Reference ID: 4570032
`
`
`
`
` 3
`
`

`

`
`
` 2.2 Dose Modifications for Adverse Reactions
`
`
`
`
`
`
`
` Reduce or discontinue JEVTANA dosing for adverse reactions as described in Table 1.
`
`
`
`
`
`
`
` Table 1: Recommended Dosage Modifications for Adverse Reactions in Patients Treated
`
`
` with JEVTANA
`
` Toxicity
` Prolonged grade ≥3 neutropenia (greater than 1 week)
`
`
`
`
`
`
` despite appropriate medication including granulocyte­
`
`colony stimulating factor (G-CSF)
`
`
`
` Dosage Modification
`
` Delay treatment until neutrophil count is
`
` >1,500 cells/mm3, then reduce dosage of JEVTANA
`
`
` by one dose level. Use G-CSF for secondary
`
`prophylaxis.
` Delay treatment until improvement or resolution, and
`
`
` until neutrophil count is >1,500 cells/mm3, then
` reduce dosage of JEVTANA by one dose level. Use
`
`
` G-CSF for secondary prophylaxis.
`
`
` Delay treatment until improvement or resolution, then
`
`
` reduce dosage of JEVTANA by one dose level.
`
`
`
`
`
`
` Delay treatment until improvement or resolution, then
`
`
`
` reduce dosage of JEVTANA by one dose level.
`
` Discontinue JEVTANA.
`
`
`
`
` Febrile neutropenia or neutropenic infection
`
` Grade ≥3 diarrhea or persisting diarrhea despite
`
`
`
`
` appropriate medication, fluid and electrolytes
`
`replacement
` Grade 2 peripheral neuropathy
`
`
`
`
`
` Grade ≥3 peripheral neuropathy
`
`
`
`
`
`
`
` Patients at a 20 mg/m2 dose who require dose reduction should decrease dosage of JEVTANA to
`
`
` 15 mg/m2 [see Adverse Reactions (6.1)].
`
`
` Patients at a 25 mg/m2 dose who require dose reduction should decrease dosage of JEVTANA to
`
`
` 20 mg/m2. One additional dose reduction to 15 mg/m2 may be considered [see Adverse
`
`Reactions (6.1)].
`
`2.3 Dose Modifications for Hepatic Impairment
`
`
`
`
` • Mild hepatic impairment (total bilirubin >1 to ≤1.5 × Upper Limit of Normal (ULN) or AST
`
`
` >1.5 × ULN): Administer JEVTANA at a dose of 20 mg/m2.
`
`
`
`
`
`
` • Moderate hepatic impairment (total bilirubin >1.5 to ≤3 × ULN and AST = any): Administer
`
`
` JEVTANA at a dose of 15 mg/m2 based on tolerability data in these patients; however, the
`
`
`
`
`
`efficacy of this dose is unknown.
`
`
`
`
` • Severe hepatic impairment (total bilirubin >3 × ULN): JEVTANA is contraindicated in
`
` patients with severe hepatic impairment [see Warning and Precautions (5.8) and Clinical
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`2.4 Dose Modifications for Use with Strong CYP3A Inhibitors
`
`
`Concomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole,
`
`clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
`
`
`voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of
`
`JEVTANA with these drugs. If patients require coadministration of a strong CYP3A inhibitor,
`consider a 25% JEVTANA dose reduction [see Drug Interactions (7.1) and Clinical
`
`
`
`
`Pharmacology (12.3)].
`
`
`2.5 Preparation and Administration
`
`
`JEVTANA is a cytotoxic anticancer drug. Follow applicable special handling and disposal
`
`
`
`procedures [see References (15)]. If JEVTANA first diluted solution, or second (final) dilution
`
`
`
`
`
`Reference ID: 4570032
`
`
`
`
` 4
`
`

`

`
`
`
`
`
`
` for intravenous infusion should come into contact with the skin or mucous, immediately and
`
` thoroughly wash with soap and water.
`Do not use PVC infusion containers or polyurethane infusions sets for preparation and
`administration of JEVTANA infusion solution.
`
`JEVTANA should not be mixed with any other drugs.
`
`Preparation
`
`Read this entire section carefully before mixing and diluting. JEVTANA requires two dilutions
`
`
`
`
`
`
`prior to administration. Follow the preparation instructions provided below, as improper
`
`preparation may lead to overdose [see Overdosage (10)].
`
`
`
`
`Note: Both the JEVTANA injection and the diluent vials contain an overfill to compensate for
`
`liquid loss during preparation. This overfill ensures that after dilution with the entire contents
`
`
`
`of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL
`
`JEVTANA.
`
`Inspect the JEVTANA injection and supplied diluent vials. The JEVTANA injection is a clear
`
`
`
`yellow to brownish-yellow viscous solution.
`
`Step 1 – first dilution
`
`
`
`Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents
`
`
`
`of supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.
`
`When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject
`
`slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted
`
`
`
`solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and
`
`
`diluent. Do not shake.
`
`
`Let the solution stand for a few minutes to allow any foam to dissipate, and check that the
`
`
`
`solution is homogeneous and contains no visible particulate matter. It is not required that all
`
`foam dissipate prior to continuing the preparation process.
`
`
`
`
`
`The resulting initial diluted JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution
`
`
`
`
`
`
`before administration. The second dilution should be done immediately (within 30 minutes) to
`
`
`obtain the final infusion as detailed in Step 2.
`
`
`
`Step 2 – second (final) dilution
`
`
`
`Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as
`
`
`
`
`prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free
`
`
`
`container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose
`
`
`greater than 65 mg of JEVTANA is required, use a larger volume of the infusion vehicle so that
`
`
`
`a concentration of 0.26 mg/mL JEVTANA is not exceeded. The concentration of the JEVTANA
`
`final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
`
`
`
`
`Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or
`
`bottle.
`
`
`
`As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this
`
`
`occurs and discard.
`
`Reference ID: 4570032
`
`
`
`
` 5
`
`

`

`
`
`
`
`
`
` Fully prepared JEVTANA infusion solution (in either 0.9% sodium chloride solution or 5%
`
`
` dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour
` infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated
`
`
` conditions.
` Discard any unused portion.
`
` Administration
`Inspect visually for particulate matter, any crystals and discoloration prior to administration. If
`
`
`
`
`
`the JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to
`
`have precipitation, it should be discarded.
`
`Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer)
`
`
`during administration.
`
`The final JEVTANA infusion solution should be administered intravenously as a one-hour
`
`
`
`
`
`infusion at room temperature.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`JEVTANA (cabazitaxel) injection is supplied as a kit consisting of the following:
`
`
`
`
`• Cabazitaxel injection: 60 mg/1.5 mL; a clear yellow to brownish-yellow viscous solution
`
`
`
`
`
`
`• Diluent: 5.7 mL of 13% (w/w) ethanol in water; a clear colorless solution
`
`
`
`
`
`
`
`
`CONTRAINDICATIONS
`4
`
`
`JEVTANA is contraindicated in patients with:
`
`
`
` • neutrophil counts of ≤1,500/mm3 [see Warnings and Precautions (5.1)]
`
`
`
`
`
` • history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated
`
`
`
`
` with polysorbate 80 [see Warnings and Precautions (5.3)]
` severe hepatic impairment (total bilirubin >3 × ULN) [see Warnings and Precautions
`
`
`
`
` (5.8)]
`
`
`•
`
`
`
`
`
`
`
`
`
` 5
` WARNINGS AND PRECAUTIONS
`
`
`
`
` 5.1 Bone Marrow Suppression
` JEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3 [see Contraindications
`(4)]. Closely monitor patients with hemoglobin <10 g/dL.
`
`Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or
`
`
`
`pancytopenia may occur. Neutropenic deaths have been reported.
`
`
`
`
`
`In a randomized trial (TROPIC) in previously treated patients with metastatic castration-resistant
`
`
`
`
`
`
`prostate cancer, five patients (1.3%) died from infection (sepsis or septic shock). All had grade 4
`
`
`neutropenia and one had febrile neutropenia. One additional patient’s death was attributed to
`
`
`neutropenia without a documented infection. Twenty-two (6%) patients discontinued JEVTANA
`
`
`treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common
`adverse reaction leading to treatment discontinuation in the JEVTANA group was neutropenia
`
`
`
`(2%). Grade 3-4 neutropenia has been observed in 82% of patients treated with JEVTANA in the
`
`
`randomized trial.
`
`
`Reference ID: 4570032
`
`
`
`
` 6
`
`

`

`
`
`
`
`
`
` In a randomized trial (PROSELICA) comparing two doses of JEVTANA in previously treated
`metastatic castration-resistant prostate cancer, 8 patients (1%) on the 20 mg/m2 arm and 15
`
`
`
`
`patients (3%) on the 25 mg/m2 arm died from infection; of these, 4 deaths on the 20 mg/m2 arm
`
`
`
`
`
`
`
`and 8 deaths on the 25 mg/m2 arm occurred within the first 30 days of treatment.
`
`
`
`
`Fewer patients receiving JEVTANA 20 mg/m2 were reported to have infectious adverse
`
`
`reactions. Grade 1-4 infections were experienced by 160 patients (28%) on the 20 mg/m2 arm
`
`
`
`
`
`and 227 patients (38%) on the 25 mg/m2 arm. Grade 3-4 infections were experienced by 57
`
`
`
`patients (10%) on the 20 mg/m2 arm and 120 patients (20%) on the 25 mg/m2 arm.
`
`
`
`
`
`Noninferiority for overall survival was demonstrated between these two arms [see Clinical
`
`Studies (14)].
`
`
`
`
`Based on guidelines for the use of G-CSF and the adverse reactions profile of JEVTANA,
`
`
`
`
`primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features
`
`(older patients, 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 effectiveness of primary prophylaxis
`
`
`with G-CSF in patients receiving JEVTANA has not been studied. Therapeutic use of G-CSF
`
`
`
`
`and secondary prophylaxis should be considered in all patients at increased risk for neutropenia
`
`complications.
`
`
`
`
`Monitoring of complete blood counts 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 and
`
`Administration (2.2)].
`
`
`Increased Toxicities in Elderly Patients
`5.2
`
`
`
`
`
`In a randomized trial (TROPIC), 2% of patients (3/131) <65 years of age and 6% (15/240) ≥65
`
`
`
`years of age died of causes other than disease progression within 30 days of the last JEVTANA
`
`
`dose. Patients ≥65 years of age are more likely to experience certain adverse reactions, including
`
`
`
`neutropenia and febrile neutropenia. The incidence of the following grade 3-4 adverse reactions
`
`
`
`were higher in patients ≥65 years of age compared to younger patients; neutropenia (87% vs
`
`74%), and febrile neutropenia (8% vs 6%).
`
`In a randomized clinical trial (PROSELICA) comparing two doses of JEVTANA, deaths due to
`
`infection within 30 days of starting JEVTANA occurred in 0.7% (4/580) patients on the 20
`
`
`mg/m2 arm and 1.3% (8/595) patients on the 25 mg/m2 arm; all of these patients were >60 years
`
`
`
`
`
`
`of age.
`
`In PROSELICA, on the 20 mg/m2 arm, 3% (5/178) of patients <65 years of age and 2% (9/402)
`
`
`
`
`
`
`
`
`≥65 years of age died of causes other than disease progression within 30 days of the last
`
`
`
` JEVTANA dose. On the 25 mg/m2 arm, 2% (3/175) patients <65 years of age and 5% (20/420)
`
`
`
`
`
` ≥65 years of age died of causes other than disease progression within 30 days of the last
`
`
`
`
` JEVTANA dose [see Adverse Reactions (6) and Use in Specific Populations (8.5)].
`
`
`
`
`
`
` 5.3 Hypersensitivity Reactions
`
`
`
`
` Hypersensitivity reactions may occur within a few minutes following the initiation of the
` infusion of JEVTANA, thus facilities and equipment for the treatment of hypotension and
`
`
` bronchospasm should be available. Severe hypersensitivity reactions can occur and may include
`
`
`
`
`
` generalized rash/erythema, hypotension and bronchospasm.
`
`
`
`
`
`
`
`
`
`Reference ID: 4570032
`
`
`
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` 7
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`

`

`
`
`
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`
`
`
`
`
`
` Premedicate all patients prior to the initiation of the infusion of JEVTANA [see Dosage and
` Administration (2.1)]. Observe patients closely for hypersensitivity reactions, especially during
`
`
`
` the first and second infusions. Severe hypersensitivity reactions require immediate
` discontinuation of the JEVTANA infusion and appropriate therapy. JEVTANA is
`
`
`
` contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to
`
`
` other drugs formulated with polysorbate 80 [see Contraindications (4)].
`
` 5.4 Gastrointestinal Adverse Reactions
`
`
`
`
` Nausea, vomiting and severe diarrhea, at times, may occur. Deaths related to diarrhea and
` electrolyte imbalance occurred in the randomized clinical trials. Intensive measures may be
`
` required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis is recommended.
`
`
`
` Treat patients with rehydration, antidiarrheal or antiemetic medications as needed. Treatment
`
`
`
`
`
`
`
` delay or dosage reduction may be necessary if patients experience Grade ≥3 diarrhea [see
`
`
`
` Dosage and Administration (2.2)].
` Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis,
`
` including fatal outcome, have been reported in patients treated with JEVTANA [see Adverse
`
`
` Reactions (6.2)]. Risk may be increased with neutropenia, age, steroid use, concomitant use of
`
` NSAIDs, antiplatelet therapy or anticoagulants, and patients with a prior history of pelvic
`
` radiotherapy, adhesions, ulceration and GI bleeding.
` Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without
`
`
`
` neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be
` evaluated and treated promptly. JEVTANA treatment delay or discontinuation may be
`
`
` necessary.
`
` The incidence of gastrointestinal adverse reactions is greater in the patients who have received
` prior radiation. In PROSELICA, diarrhea was reported in 41% (297/732) of patients who had
`
`
`
`
`
` received prior radiation and in 27% (118/443) of patients without prior radiation. Of the patients
`
`
`
`
`
`
`who had previously received radiation, more patients on the 25 mg/m2 arm reported diarrhea,
`
`
`
`
`compared to patients on the 20 mg/m2 arm.
`
`
`
`
`
`5.5 Renal Failure
`
`
`
`
`
`
`In the randomized clinical trial (TROPIC), renal failure of any grade occurred in 4% of the
`
`
`
`
`patients being treated with JEVTANA, including four cases with fatal outcome. Most cases
`
`
`
`
`occurred in association with sepsis, dehydration, or obstructive uropathy [see Adverse Reactions
`
`
`
`
`(6.1)]. Some deaths due to renal failure did not have a clear etiology. Appropriate measures
`
`
`
`
`
`should be taken to identify causes of renal failure and treat aggressively.
`
`
`
`5.6 Urinary Disorders Including Cystitis
`
`
`
`Cystitis, radiation cystitis, and hematuria, including that requiring hospitalization, has been
`
`reported with JEVTANA in patients who previously received pelvic radiation [see Adverse
`
`
`
`Reactions (6.2)]. In PROSELICA, cystitis and radiation cystitis were reported in 1.2% and 1.5%
`
`
`of patients who received prior radiation, respectively. Hematuria was reported in 19.4% of
`
`patients who received prior radiation and in 14.4% of patients who did not receive prior
`
`
`
`radiation. Cystitis from radiation recall may occur late in treatment with JEVTANA. Monitor
`
`patients who previously received pelvic radiation for signs and symptoms of cystitis while on
`
`
`
`JEVTANA. Interrupt or discontinue JEVTANA in patients experiencing severe hemorrhagic
`
`
`
`cystitis. Medical and/or surgical supportive treatment may be required to treat severe
`
`
`
`
`
`Reference ID: 4570032
`
`
`
`
` 8
`
`

`

`
`
`
`
`
`
` hemorrhagic cystitis.
`
`
`
` 5.7 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
` (6.2)]. Patients with underlying lung disease may be at higher risk for these events. Acute
`
`
`
`
`respiratory distress syndrome may occur in the setting of infection.
`Interrupt JEVTANA if new or worsening pulmonary symptoms develop. Closely monitor,
`promptly investigate, and appropriately treat patients receiving JEVTANA. Consider
`
`discontinuation. The benefit of resuming JEVTANA treatment must be carefully evaluated.
`5.8 Use in Patients with Hepatic Impairment
`
`
`
`Cabazitaxel is extensively metabolized in the liver.
`
`
`JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin >3 ×
`
`
`
`
`
`ULN) [see Contraindications (4)]. Dose should be reduced for patients with mild (total bilirubin
`
`
`
`
`
`>1 to ≤1.5 × ULN or AST >1.5 × ULN) and moderate (total bilirubin >1.5 to ≤3.0 × ULN and
`
`
`
`
`
`
`any AST) hepatic impairment, based on tolerability data in these patients [see Dosage and
`
`
`
`Administration (2.3) and Use in Specific Populations (8.7)]. Administration of JEVTANA to
`
`
`
`
`patients with mild and moderate hepatic impairment should be undertaken with caution and close
`
`monitoring of safety.
`
`5.9 Embryo-Fetal Toxicity
`
`
`Based on findings in animal reproduction studies and its mechanism of action, JEVTANA can
`
`cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
`
`
`
`There are no available data in pregnant women to inform the drug-associated risk. In animal
`
`
`
`reproduction studies, intravenous administration of cabazitaxel in pregnant rats during
`
`
`organogenesis caused embryonic and fetal death at doses lower than the maximum recommended
`
`
`human dose (approximately 0.06 times the Cmax in patients at the recommended human dose).
`
`
`Advise males 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
`
`
`(8.1, 8.3)].
`
`
`ADVERSE REACTIONS
`6
`
`
`The following serious adverse reactions are discussed in greater detail in another section of the
`label:
`
`• Bone Marrow Suppression [see Warnings and Precautions (5.1)]
`
`
`
`Increased Toxicities in Elderly Patients [see Warnings and Precautions (5.2)]
`
`
`
`
`•
`• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.4)]
`
`
`
`
`
`• Renal Failure [see Warnings and Precautions (5.5)]
`
`
`
`
`
`
`• Urinary Disorders Including Cystitis [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`• Respiratory Disorders [see Warnings and Precautions (5.7)]
`
`
`
`
`• Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.8)]
`
`
`
`
`
`Reference ID: 4570032
`
`
`
`
` 9
`
`

`

`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
` Because clinical trials are conducted under widely varying conditions, the adverse reaction rates
`
`
`
`
` observed cannot be directly compared to rates in other trials and may not reflect the rates
` observed in clinical practice.
`
`
`
` TROPIC Trial (JEVTANA + prednisone compared to mitoxantrone)
`The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with
`
`
`metastatic castration-resistant prostate cancer treated in the randomized TROPIC trial, compared
`
`
`
`
`to mitoxantrone plus prednisone.
`
`Deaths due to causes other than disease progression within 30 days of last study drug dose were
`
`
`
`reported in 18 (5%) JEVTANA-treated patients and 3 (<1%) mitoxantrone-treated patients. The
`
`
`
`
`
`
`most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and
`
`
`
`renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions
`
`
`
`
`
`
`occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated
`
`
`
`
`
`
`patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.
`
`
`The most 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, pyrexia, dyspnea, dysgeusia, cough,
`arthralgia, and alopecia.
`
`
`The most