`
`-------------------------------CONTRAINDICATIONS------------------------------
`
` Neutrophil counts of ≤1,500/mm3 (2.2)(4)
`
`
`
`
`History of severe hypersensitivity to JEVTANA or polysorbate 80 (4)
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`Neutropenia, febrile neutropenia: Neutropenic deaths have been
`
`reported. Monitor blood counts frequently to determine if initiation of
`G-CSF and/or dosage modification is needed. Primary prophylaxis with
`G-CSF should be considered in patients with high-risk clinical features.
`
`(2.2)(4)(5.1)
`
`Hypersensitivity: Severe hypersensitivity reactions can occur.
`
`Premedicate with corticosteroids and H2 antagonists. Discontinue
`infusion immediately if hypersensitivity is observed and treat as
`indicated. (4)(5.2)
`Gastrointestinal symptoms (nausea, vomiting, diarrhea): Mortality
`
`related to diarrhea has been reported. Rehydrate and treat with anti-
`emetics and anti-diarrheals as needed. If experiencing Grade ≥ 3
`
`diarrhea, dosage should be modified. (2.2)(5.3)
`
`Renal failure, including cases with fatal outcomes, has been reported.
`
`Identify cause and manage aggressively. (5.4)
`
`
`Elderly patients: Patients ≥ 65 years of age were more likely to
`
`experience fatal outcomes not related to disease progression and certain
`adverse reactions, including neutropenia and febrile neutropenia.
`
`
`
`Monitor closely (5.5)(6)(8.5).
`
`Hepatic impairment: Patients with impaired hepatic function were
`excluded from the randomized clinical trial. Hepatic impairment is likely
`to increase the cabazitaxel concentrations. JEVTANA should not be
`
`given to patients with hepatic impairment. (5.6)(8.7)
`JEVTANA can cause fetal harm when administered to a pregnant
`
`woman. (5.7)(8.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common all grades adverse reactions (≥10%) 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-------------------------------
`
`Use with caution in patients taking concomitant medicines that induce or
`
`
`
`inhibit CYP3A. (7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`
`
`
`
`Revised: 0X/201X
`
`
`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, 60 mg/1.5 mL,
`for intravenous infusion only
`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. Do not give JEVTANA if neutrophil counts
`are ≤1,500 cells/mm3. (2.2)(4)
`
` Severe hypersensitivity can occur and may include generalized
`rash/erythema, hypotension and bronchospasm. Discontinue
`
`JEVTANA immediately if severe reactions occur and administer
`appropriate therapy. (2.3)(5.2)
`
` Contraindicated if history of severe hypersensitivity reactions to
`JEVTANA or to drugs formulated with polysorbate 80. (4)
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`JEVTANA is a microtubule inhibitor indicated in combination with
`
`prednisone for treatment of patients with hormone-refractory metastatic
`
`prostate cancer previously treated with a docetaxel-containing treatment
`regimen. (1)
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`Recommended dose: JEVTANA 25 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)
`
`
`
`
`
`
`
`
`
`
`
`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 (dexchloropheniramine 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)
`
`
`(2.3)
`Antiemetic prophylaxis (oral or intravenous) is recommended as needed.
`
`(2.3)
`Dosage Modifications: See full prescribing information (2.2)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Single use vial 60 mg/1.5 mL, supplied with diluent (5.7 mL) for
`
`
`
`JEVTANA (3)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`
`2.2 Dose Modifications
`
`2.3 Premedication
`
`2.4 Administration Precautions
`
`
`2.5
`Instructions for Preparation
`
`2.6 Administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Neutropenia
`
`5.2 Hypersensitivity Reactions
`
`
`5.3 Gastrointestinal Symptoms
`
`5.4 Renal Failure
`
`5.5 Elderly Patients
`
`5.6 Hepatic Impairment
`
`
`5.7 Pregnancy
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
`7 DRUG INTERACTIONS
`
`7.1 Drugs That May Increase Cabazitaxel Plasma Concentrations
`
`7.2 Drugs That May Decrease Cabazitaxel Plasma Concentrations
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`8.7 Hepatic Impairment
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`12.6 Cardiac Electrophysiology
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`Reference ID: 3188106
`
`1
`
`
`
`14 CLINICAL STUDIES
`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: 3188106
`
`2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
`
`Neutropenic deaths have been reported. In order to monitor the occurrence of
`neutropenia, frequent blood cell counts should be performed on all patients receiving
`JEVTANA. JEVTANA should not be given to patients with neutrophil counts of ≤1,500
`cells/mm3.
`
`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 [see
`Warnings and Precautions (5.2)]. Patients should receive premedication [see Dosage and
`Administrations (2.3)]. JEVTANA must not be given to patients who have a history of
`severe hypersensitivity reactions to JEVTANA or to other drugs formulated with
`polysorbate 80 [see Contraindications (4)].
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`JEVTANA® is a microtubule inhibitor indicated in combination with prednisone for the
`treatment of patients with hormone-refractory metastatic prostate cancer previously treated with
`a docetaxel-containing treatment regimen.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`
`
` The individual dosage of JEVTANA is based on calculation of the Body Surface Area (BSA)
`and is 25 mg/m2 administered as a one-hour intravenous infusion every three weeks in
`combination with oral prednisone 10 mg administered daily throughout JEVTANA
`treatment.
`
` Premedication is recommended prior to treatment [see Dosage and Administration (2.3)].
`
`
`JEVTANA should be administered under the supervision of a qualified physician
`
`experienced in the use of antineoplastic medicinal products. Appropriate management of
`complications is possible only when the adequate diagnostic and treatment facilities are
`readily available.
`
`JEVTANA Injection single-use vial requires two dilutions prior to administration [see
`Dosage and Administration (2.5)].
`
` Do not use PVC infusion containers and polyurethane infusions sets for preparation and
`
`administration of JEVTANA infusion solution [see Dosage and Administration (2.5)].
`
` Both the JEVTANA Injection and the diluent vials contain an overfill to compensate for
`liquid loss during preparation.
`
`
`
`Reference ID: 3188106
`
`3
`
`
`
`
`
`
`
` 2.2 Dose Modifications
`
`The JEVTANA dose should be reduced to 20 mg/m2 if patients experience the following adverse
`reactions.
`
`
`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 G-CSF
`
`
`Febrile neutropenia
`
`Dosage Modification
`Delay treatment until neutrophil count is
`> 1,500 cells/mm3, then reduce dosage of
`JEVTANA to 20 mg/m2 . 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 to 20 mg/m2 . Use G-CSF for
`
`secondary prophylaxis.
`Delay treatment until improvement or
`resolution, then reduce dosage of JEVTANA to
`
` 20 mg/m2 .
`
`Grade ≥ 3 diarrhea or persisting diarrhea
`despite appropriate medication, fluid and
`
` electrolytes replacement
`
`Discontinue JEVTANA treatment if a patient continues to experience any of these reactions at
`20 mg/m2.
`
`
`2.3 Premedication
`
`
`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:
`
` 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.
`
`2.4 Administration Precautions
`
`JEVTANA is a cytotoxic anticancer drug and caution should be exercised when handling and
`preparing JEVTANA solutions, taking into account the use of containment devices, personal
`protective equipment (e.g., gloves), and preparation procedures. Please refer to Handling and
`Disposal (16.3).
`
`If JEVTANA Injection, first diluted solution, or second (final) dilution for intravenous infusion
`should come into contact with the skin, immediately and thoroughly wash with soap and water.
`
`
`
`Reference ID: 3188106
`
`4
`
`
`
`
`
`If JEVTANA Injection, first diluted solution, or second (final) dilution for intravenous infusion
`should come into contact with mucosa, immediately and thoroughly wash with water.
`
`2.5 Instructions for Preparation
`
`Do not use PVC infusion containers or polyurethane infusions sets for preparation and
`administration of JEVTANA infusion solution.
`
`Read this entire section carefully before mixing and diluting. JEVTANA requires two dilutions
`prior to administration. Please follow the preparation instructions provided below. 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.
`
`The following two-step dilution process must be carried out under aseptic conditions to prepare
`the second (final) infusion solution.
`
`Set aside the JEVTANA Injection and supplied diluent vials. The JEVTANA Injection is a clear
`yellow to brownish-yellow viscous solution, if appropriately stored.
`
`
`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.
`
`
`
`
`Reference ID: 3188106
`
`5
`
`
`
`
`
`JEVTANA should not be mixed with any other drugs.
`
`Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or
`bottle.
`
`JEVTANA final 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 within a total of 24 hours if refrigerated (including the one-hour infusion).
`
`As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this
`occurs and discard.
`
`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.
`
`Discard any unused portion.
`
`2.6 Administration
`
`The final JEVTANA infusion solution should be administered intravenously as a one-hour
`infusion at room temperature.
`
`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 used immediately. However, in-use storage
`time can be longer under specific conditions, i.e. 8 hours under ambient conditions (including the
`one-hour infusion) or for a total of 24 hours if refrigerated (including the one-hour infusion) [see
`
`Dosage and Administration (2.5)].
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL is supplied as a kit consisting of the following:
`
` JEVTANA Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate
`80,
`
` Diluent for JEVTANA Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13%
`(w/w) ethanol in water for injection.
`
`
`
`4 CONTRAINDICATIONS
`
`JEVTANA should not be used in patients with neutrophil counts of ≤ 1,500/mm3.
`
`
`
`
`Reference ID: 3188106
`
`6
`
`
`
`
`
`JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions
`to cabazitaxel or to other drugs formulated with polysorbate 80.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Neutropenia
`
`Five patients experienced fatal infectious adverse events (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.
`
`G-CSF may be administered to reduce the risks of neutropenia complications associated with
`JEVTANA use. 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.
`Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients
`considered to be 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)].
`
`JEVTANA should not be administered to patients with neutrophils ≤ 1,500/mm3 [see
`
`
`Contraindications (4)].
`
`If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week)
`despite appropriate medication (e.g., G-CSF), the dose of JEVTANA should be reduced [see
`Dosage and Administration (2.2)]. Patients can restart treatment with JEVTANA only when
`neutrophil counts recover to a level > 1,500/mm3 [see Contraindications (4)].
`
`5.2 Hypersensitivity Reactions
`
`
`All patients should be premedicated prior to the initiation of the infusion of JEVTANA [see
`Dosage and Administration (2.3)]. 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 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. Severe hypersensitivity reactions require immediate discontinuation of the
`JEVTANA infusion and appropriate therapy. Patients with a history of severe hypersensitivity
`reactions should not be re-challenged with JEVTANA [see Contraindications (4)].
`
`
`
`
`Reference ID: 3188106
`
`7
`
`
`
`
`
`
`
` 5.3 Gastrointestinal Symptoms
`
`Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and
`electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be
`required for severe diarrhea and electrolyte imbalance. Patients should be treated with
`rehydration, anti-diarrheal or anti-emetic medications as needed. Treatment delay or dosage
`reduction may be necessary if patients experience Grade ≥ 3 diarrhea [see Dosage and
`Administration (2.2)].
`
`
`5.4 Renal Failure
`
`Renal failure, including four cases with fatal outcome, was reported in the randomized clinical
`trial. 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.
`
`5.5 Elderly Patients
`
`
`In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 65
`years of age died of causes other than disease progression within 30 days of the last cabazitaxel
`dose. Patients ≥ 65 years of age are more likely to experience certain adverse reactions,
`including neutropenia and febrile neutropenia [see Adverse Reactions (6) and Use in Specific
`Populations (8.5)].
`
`
`5.6 Hepatic Impairment
`
`No dedicated hepatic impairment trial for JEVTANA has been conducted. Patients with
`impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were
`excluded from the randomized clinical trial.
`
`Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase
`cabazitaxel concentrations.
`
`Hepatic impairment increases the risk of severe and life-threatening complications in patients
`receiving other drugs belonging to the same class as JEVTANA. JEVTANA should not be given
`to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN).
`
`5.7 Pregnancy
`
`
`Pregnancy category D.
`
`JEVTANA can cause fetal harm when administered to a pregnant woman. In non-clinical
`studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures
`significantly lower than those expected at the recommended human dose level.
`
`
`
`
`Reference ID: 3188106
`
`8
`
`
`
`
`
`There are no adequate and well-controlled studies in pregnant women using JEVTANA. If this
`drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the
`patient should be apprised of the potential hazard to the fetus. Women of childbearing potential
`should be advised to avoid becoming pregnant during treatment with JEVTANA [see Use in
`Specific Populations (8.1)].
`
`
`6 ADVERSE REACTIONS
`
`The following serious adverse reactions are discussed in greater detail in another section of the
`
`label:
`
`
` Neutropenia [see Warnings and Precautions (5.1)].
`
`
` Hypersensitivity Reactions [see Warnings and Precautions (5.2)].
`
`
` Gastrointestinal Symptoms [see Warnings and Precautions (5.3)].
`
`
` Renal Failure [see Warnings and Precautions (5.4)].
`
`
`6.1 Clinical Trial 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.
`
`The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with
`hormone-refractory metastatic prostate cancer treated in a single randomized 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, dysguesia, cough,
`arthralgia, and alopecia.
`
`The most common (≥ 5%) grade 3-4 adverse reactions in patients who received JEVTANA were
`neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.
`
`Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who
`received JEVTANA and 8% of patients who received mitoxantrone. The most common adverse
`reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and
`renal failure. Dose reductions were reported in 12% of JEVTANA-treated patients and 4% of
`
`
`
`Reference ID: 3188106
`
`9
`
`
`
`
`
`
`
`
`
`Grade 1-4
`
`n (%)
`
`
`Grade 3-4
`n (%)
`
`
`303 (82%)
`27 (7%)
`39 (11%)
`
`253 (69%)
`15 (4%)
`
`
`
`4 (1%)
`
`23 (6%)
`
`7 (2%)
`6 (2%)
`4 (1%)
`7 (2%)
`0
`
`
`
`Any Adverse Reaction
`
`Blood and Lymphatic System Disorders
`
`Neutropenia2
`347 (94%)
`
`Febrile Neutropenia
`27 (7%)
`
` Anemia2
`361 (98%)
`Leukopenia2
`355 (96%)
`
`Thrombocytopenia2
`176 (48%)
`
`Cardiac Disorders
`Arrhythmia3
`18 (5%)
`
`Gastrointestinal Disorders
`
`Diarrhea
`173 (47%)
`Nausea
`127 (34%)
`Vomiting
`83 (22%)
`Constipation
`76 (20%)
`
`Abdominal Pain4
`64 (17%)
`Dyspepsia5
`36 (10%)
`General Disorders and Administration Site Conditions
`
`136 (37%)
`Fatigue
`Asthenia
`76 (20%)
`
`45 (12%)
`Pyrexia
`
`34 (9%)
`Peripheral Edema
`
`
`22 (6%)
`Mucosal Inflammation
`
`20 (5%)
`Pain
`
`Infections and Infestations
`
`Urinary Tract Infection6
`29 (8%)
`Investigations
`
`
`32 (9%)
`Weight Decreased
`
`Metabolism and Nutrition Disorders
`
`59 (16%)
`Anorexia
`
`
`Dehydration
`18 (5%)
`
`Musculoskeletal and Connective Tissue Disorders
`Back Pain
`60 (16%)
`
`Arthralgia
`39 (11%)
`
`Muscle Spasms
`27 (7%)
`
`Nervous System Disorders
`
`Peripheral Neuropathy7
`50 (13%)
`
`41 (11%)
`Dysgeusia
`30 (8%)
`Dizziness
`
`
`mitoxantrone-treated patients. Dose delays were reported in 28% of JEVTANA-treated patients
`and 15% of mitoxantrone-treated patients.
`
`Table 2 – Incidence of Reported Adverse Reactions1 and Hematologic Abnormalities in
`≥ 5% of Patients Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in
`Combination with Prednisone
`
`JEVTANA 25 mg/m2 every 3
`
`
`weeks with prednisone 10 mg daily
`n=371
`
`Mitoxantrone 12 mg/m2 every 3
`
`
`weeks with prednisone 10 mg daily
`n=371
`
`Grade 1-4
`n (%)
`
`
`325 (87%)
`5 (1%)
`302 (82%)
`343 (93%)
`160 (43%)
`
`6 (2%)
`
`39 (11%)
`
`85 (23%)
`
`38 (10%)
`57 (15%)
`
`23 (6%)
`9 (2%)
`
`Grade 3-4
`n (%)
`
`
`215 (58%)
`5 (1%)
`18 (5%)
`
`157 (42%)
`6 (2%)
`
`
`1 (< 1%)
`
`1 (< 1%)
`1 (< 1%)
`0
`2 (< 1%)
`0
`0
`
`18 (5%)
`
`17 (5%)
`4 (1%)
`2 (< 1%)
`1 (< 1%)
`4 (1%)
`
`6 (2%)
`
`0
`
`3 (< 1%)
`8 (2%)
`
`14 (4%)
`4 (1%)
`0
`
`3 (< 1%)
`0
`0
`
`102 (27%)
`46 (12%)
`23 (6%)
`
`34 (9%)
`
`
`10 (3%)
`
`18 (5%)
`
`12 (3%)
`
`28 (8%)
`
`
`39 (11%)
`
`10 (3%)
`
`
`45 (12%)
`31 (8%)
`10 (3%)
`
`12 (3.2%)
`
`15 (4%)
`21 (6%)
`
`
`11 (3%)
`
`9 (2%)
`1 (< 1%)
`2 (< 1%)
`1 (< 1%)
`7 (2%)
`
`4 (1%)
`
`1 (< 1%)
`
`3 (< 1%)
`3 (< 1%)
`
`11 (3%)
`4 (1%)
`0
`
`3 (< 1%)
`0
`2 (< 1%)
`
`
`
`Reference ID: 3188106
`
`10
`
`
`
`Headache
`Renal and Urinary Tract Disorders
`
`
`Hematuria
`62 (17%)
`
`Dysuria
`25 (7%)
`
`
`Respiratory, Thoracic and Mediastinal Disorders
`
`43 (12%)
`Dyspnea
`
`40 (11%)
`Cough
`
`Skin and Subcutaneous Tissue Disorders
`37 (10%)
`Alopecia
`Vascular Disorders
`
`
`20 (5%)
`Hypotension
`
`
`6 cycles
`
`
`
`
`28 (8%)
`
`0
`
`7 (2%)
`0
`
`4 (1%)
`0
`
`19 (5%)
`
`
`13 (4%)
`5 (1%)
`
`
`16 (4%)
`22 (6%)
`
`0
`
`1 (< 1%)
`0
`
`2 (< 1%)
`0
`
`0
`
`
`2 (<1 %)
`
`
`
`18 (5%)
`
`9 (2%)
`
`
`0
`
`1 (< 1%)
`
`
`4 cycles
`
`
`
`
`Median Duration of
`Treatment
`1Graded using NCI CTCAE version 3
`
`
`2Based on laboratory values, cabazitaxel: n =369, mitoxantrone: n = 370.
`
`
`
`
`3Includes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia,
`
`palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia.
`
`4Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain.
`
`
`5Includes gastroesophageal reflux disease and reflux gastritis.
`
`6Includes urinary tract infection enterococcal and urinary tract infection fungal.
`
`
`7Includes peripheral motor neuropathy and peripheral sensory neuropathy.
`
`
`
`
` Neutropenia and Associated Clinical Events:
`
`Five patients experienced fatal infectious adverse events (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%).
`
`Hematuria:
`Adverse events of hematuria, including those requiring medical intervention, were more
`common in JEVTANA-treated patients. The incidence of grade ≥ 2 hematuria was 6% in
`JEVTANA-treated patients and 2% in mitoxantrone-treated patients. Other factors associated
`with hematuria were well-balanced between arms and do not account for the increased rate of
`hematuria on the JEVTANA arm.
`
`Hepatic Laboratory Abnormalities:
`The incidences of grade 3-4 increased AST, increased ALT, and increased bilirubin were each
`≤ 1%.
`
`Elderly Population:
`The following grade 1-4 adverse reactions were reported at rates 5% higher in patients 65 years
`of age or greater compared to younger patients: fatigue (40% vs. 30%), neutropenia (97% vs.
`89%), asthenia (24% vs. 15%), pyrexia (15% vs. 8%), dizziness (10% vs. 5%), urinary tract
`infection (10% vs. 3%) and dehydration (7% vs. 2%), respectively.
`
`
`
`
`Reference ID: 3188106
`
`11
`
`
`
`
`
`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%) [see Use in Specific Populations (8.5)].
`
`
`7 DRUG INTERACTIONS
`
`No formal clinical drug-drug interaction trials have been conducted with JEVTANA.
`
`Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of
`cabazitaxel.
`
`
`7.1 Drugs That May Increase Cabazitaxel Plasma Concentrations
`
`CYP3A4 Inhibitors: Cabazitaxel is primarily metabolized through CYP3A [see Clinical
`
`
`Pharmacology (12.3)]. Though no formal drug interaction trials have been conducted for
`JEVTANA, concomitant administration of strong CYP3A inhibitors (e.g., ketoconazole,
`itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
`telithromycin, voriconazole) is expected to increase concentrations of cabazitaxel. Therefore,
`co-administration with strong CYP3A inhibitors should be avoided. Caution should be exercised
`with concomitant use of moderate CYP3A inhibitors.
`
`7.2 Drugs That May Decrease Cabazitaxel Plasma Concentrations
`
`CYP3A4 Inducers: Though no formal drug interaction trials have been conducted for
`
`JEVTANA, the concomitant administration of strong CYP3A inducers (e.g., phenytoin,
`carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) is expected to decrease cabazitaxel
`concentrations. Therefore, co-administration with strong CYP3A inducers should be avoided. In
`addition, patients should also refrain from taking St. John’s Wort.
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy category D. See ‘Warnings and Precautions’ section.
`
`JEVTANA can cause fetal harm when administered to a pregnant woman. There are no
`adequate and well-controlled studies of JEVTANA in pregnant women.
`
`Non-clinical studies in rats and rabbits have shown that cabazitaxel is embryotoxic, fetotoxic,
`and abortifacient. Cabazitaxel was shown to cross the placenta barrier within 24 hours of a
`single intravenous administration of a 0.08 mg/kg dose (approximately 0.02 times the maximum
`recommended human dose-MRHD) to pregnant rats at gestational day 17.
`
`
`
`
`Reference ID: 3188106
`
`12
`
`
`
`
`
`Cabazitaxel administered once daily to female rats during organogenesis at a dose of 0.16
`mg/kg/day (approximately 0.02-0.06 times the Cmax in patients with cancer at the recommended
`human dose) caused maternal and embryofetal toxicity consisting of increased post-implantation
`loss, embryolethality, and fetal deaths. Decreased mean fetal birth weight associated with delays
`in skeletal ossification were observed at doses ≥ 0.08 mg/kg (approximately 0.02 times the Cmax
`at the MRHD). In utero exposure to cabazitaxel did not result in fetal abnormalities in rats or
`
`rabbits at exposure levels significantly lower than the expected human exposures.
`
`If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug,
`the patient should be apprised of the potential hazard to the fetus. Women of childbearing
`potential should be advised to avoid becoming pregnant while taking JEVTANA.
`
`8.3 Nursing Mothers
`
`Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats. It is not
`known whether this drug is excreted in human milk. Within 2 hours of a single intravenous
`administration of cabazitaxel to lactating rats at a dose of 0.08 mg/kg (approximately 0.02 times
`the maximum recommended human dose), radioactivity related to cabazitaxel was detected in
`the stomachs of nursing pups. This was detectable for up to 24 hours post-dose. Approximately
`1.5% of the dose delivered to the mot