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
`Seefull prescribing information for complete boxed warning.
`9 Neutropenic deaths have been reported. Obtain frequent blood counts
`to monitor for neutropenia. Do not give JEVTANA if neutrophil counts
`are _<_I,50O cells/mm’. (2.2)(4)
`0 Severe hypersensitivity can occur and may include generalized
`rash/erythema, hypotension and bronchospasm. Discontinue
`JEVTANA immediately ifsevere 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 8|). (4)
`
`---------------------INDICATI ONS 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. ( l)
`------—-—-—-~--—--«DOSAGE AND ADMINISTRATION-----——~---~-----«
`Recommended dose: JEVTANA 25 mg/m’ administered every three weeks
`as a one-hour intravenous infusion in combination with oral prednisone l0 mg
`administered daily throughout JEVTANA treatment. (2.1)
`
`-
`-
`
`JEVTANA requires gm dilutions prior to administration (25)
`Use the entire contents of the accompanying diluent to achieve a
`concentration of IO mg/mL JEVTANA. (25)
`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)
`Corticosteroid (dexamethasone 8 mg or equivalent steroid)
`H, antagonist (ranitidine 50 mg or equivalent H; antagonist)
`(2.3)
`Antiemetic prophylaxis (oral or intravenous) is recommended as needed.
`(2.3)
`Dosage Modifications: See full prescribing information (2.2)
`o
`----------------DOSAGE FORMS AND STRENGTHS---—-----—---------
`o
`Single use vial 60 mg/l .5 mL, supplied with diluent (5.7 mL) for
`JEVTANA (3)
`
`o
`o
`
`FULL PRESCRIBING INFORMATION: CONTENTS‘
`
`WARNING
`I
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.l 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
`55 Elderly Patients
`56 Hepatic Impairment
`5.7
`Pregnancy
`
`------------------------—CONTRAINDICATIONS—-———»————-——------»--—-
`-
`Neutrophil counts of Si ,500/mm’ (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»risl< clinical features.
`(2.2)(4)(5.l)
`Hypersensitivity: Severe hypersensitivity reactions can occur.
`Premedicate with conicosteroids 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 2 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 2 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 impainnent is likely
`to increase the cabazitaxel concentrations. JEVTANA should not be
`given to patients with hepatic impainnent. (S.6)(8.7)
`JEVTANA can cause fetal hann when administered to a pregnant
`woman. (5.7)(8.l)
`
`———————————————————--A ovansa REACTIONS-———~-—~—------~-—--------
`Most common all grades adverse reactions (210%) 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 sanoti-aventls
`U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-I088 or
`www.fda.gov/medwatch.
`
`-~~~~~~~~~~~~~~~~~--DRUG INTERACTIONS------------------———-—
`0
`Use with caution in patients taking concomitant medicines that induce or
`inhibit CYP3A. (7)
`
`See I7 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 06/20l0
`
`6 ADVERSE REACTIONS
`6.l Clinical Trial Experience
`7 DRUG INTERACTIONS
`7.] Drugs That May Increase Cabazitaxel Plasma Concentrations
`7.2 Drugs That May Decrease Cabazitaxel Plasma Concentrations
`8 USE IN SPECIFIC POPULATION
`8.]
`Pregnancy
`‘
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`85 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`I0 OVERDOSAGE
`II DESCRIPTION
`I2 CLINICAL PHARMACOLOGY
`l2,l Mechanism of Action
`l2.2
`Pharmacodynamics
`12,3
`Pharrnacokinetics
`I3 NONCLINICALTOXICOLOGY
`l3.l Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`AVENTIS EXHIBIT 2058
`Mylan v. Aventis
`IPR2016-00627
`
`

`
`I4 CLINICAL STUDIES
`15 REFERENCES
`I6 HOW SUPPLIED/STORAGE AND HANDLING
`I6.l Howsupplied
`162
`Storage
`
`16.3 Handling and Disposal
`l7 PATIENT COUNSELING INFORMATION
`‘Sections or subsections omitted from the full prescribing infonnation are not
`listed.
`
`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING
`
` 1
`
`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/mm’.
`
`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
`
`JEV'l‘ANA® 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
`
`0 The individual dosage ofJEVTANA is based on calculation ofthe 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.
`
`o
`
`0
`0
`
`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.
`I
`JEVTANA Injection single-use vial requires fig dilutions prior to administration [see
`Dosage and Administration (2.5)] .
`0 Do not use PVC infusion containers and polyurethane infusions sets for preparation and
`administration of JEVTANA infusion solution [see Dosage and Administration (2. 5)].
`0 Both the JEVTANA Injection and the diluent vials contain an overfill to compensate for
`liquid loss during preparation.
`
`

`
`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
`
`
`
`
`
`
`
`Dosae Modification
`Prolonged grade 2 3 neutropenia (greater than
`Delay treatment until neutrophil count is
`
`1 week) despite appropriate medication
`> 1,500 cells/mm3, then reduce dosage of
`including G-CSF
`JEVTANA to 20 mg/m2. Use G-CSF for
`
`-
`seconda
`roh laxis.
`
`Delay treatment until improvement or
` Febrile neutropenia
`resolution, and until neutrophil count is
`
`> 1,500 cells/mm3, then reduce dosage of
`JEVTANA to 20 mg/m’. Use G-CSF for
`secondary prophylaxis.
`Delay treatment until improvement or
`Grade 2 3 diarrhea or persisting diarrhea
`resolution, then reduce dosage of JEVTANA to
`despite appropriate medication, fluid and
`
`
`electrol
`es relacement
`20 m /m2.
`
`
`
`
`
`
`
`
`
`
`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:
`0
`antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent
`antihistamine),
`corticosteroid (dexamethasone 8 mg or equivalent steroid),
`0
`0 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
`
`J EVTANA 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.
`
`

`
`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 ofJEVTANA 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 l0 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 fiJll mixing ofthe 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.
`
`

`
`J EVTANA 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 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 ofthe following:
`
`— JEVTANA Injection 60 mg/l.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 5 1,500/mm3.
`
`JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions
`to cabazitaxel or to other drugs fonnulated 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 5 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 infiision of JEVTANA [see
`Dosage andAdmim'stration (2. 3)]. Patients should be observed closely for hypersensitivity
`reactions, especially during the first and second infiisions. Hypersensitivity reactions may occur
`within a few minutes following the initiation ofthe infiision 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 reschallenged with JEVTANA [see Contraindications (4)] .
`
`5.3 Gastrointestinal Symptoms
`
`Nausea, vomiting and severeidiarrhea, 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 2 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 I31 (2%) patients < 65 years of age and 15 of 240 (6%)
`2 65 years of age died of causes other than disease progression within 30 days of the last
`cabazitaxel dose. Patients 2 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 2 ULN, or AST and/or ALT _>_ 1.5 X 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 2 ULN, or AST and/or ALT _>_ 1.5 X 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.
`
`There are no adequate and well—controlled studies in pregnant women using JEVTANA. If this
`drug is used during pregnancy, or ifthe 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 reacti_ons are discussed in greater detail in another section of the
`label:
`
`0 Neutropenia [see Warnings and Precautions (5.1)].
`o Hypersensitivity Reactions [see Warnings and Precautions (5. 2)].
`0 Gastrointestinal Symptoms [see Warnings and Precautions (5. 3)].
`0 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 (2 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 (2 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
`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 Reactions‘ and Hematologic Abnormalities in
`2 5% of Patients Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in
`Combination with Prednisone
`
`
`Mitoxantrone 12 mg/ml every 3
`JEVTANA 25 mg/m2 every 3
`weeks with prednisone 10 mg daily
`weeks with prednisone 10 mg daily
`
`n=371
`n=371
`
`Grade 3-4
`Grade 1-4
`Grade 3-4
`Grade 1-4
`in
`°/o
`n %
`n %
`n %
`
`Any Adverse Reaction
`Blood and Lymphatic System Disorders
`Neutropeniaz
`347 (94%)
`Febrile Neutropenia
`27 (7%)
`Anemia’
`361 (98%)
`Leukopeniaz
`355 (96%)
`Thrombocytopeniaz
`176 (48%)
`Cardiac Disorders
`
`303 (82%)
`27 (7%)
`39 (11%)
`253 (69%)
`15 (4%)
`
`325 (87%)
`5 (1%)
`302 (82%)
`343 (93%)
`160 (43%)
`
`215 (53%)
`S (1%)
`18 (5%)
`157 (42%)
`6 (2%)
`
`Arrhythmia’
`Gastrointestinal Disorders
`
`18 (5%)
`
`4 (1%)
`
`6 (2%)
`
`1 (< 1%)
`
`173 (47%)
`Diarrhea
`127 (34%)
`Nausea
`83 (22%)
`Vomiting
`76 (20%)
`Constipation
`64 (17%)
`Abdominal Pain‘
`36 (10%)
`Dyspepsias
`General Disorders and Administration Site Conditions
`
`Fatigue
`Asthenia
`Pyrexia
`Peripheral Edema
`Mucosal Inflammation
`Pain
`lnfections and lnfestations
`
`Urinary Tract Infections
`Investigations
`
`136 (37%)
`76 (20%)
`45 (12%)
`34 (9%)
`22 (6%)
`20 (5%)
`
`23 (6%)
`7 (2%)
`6 (2%)
`4 (1%)
`7 (2%)
`0
`
`18 (5%)
`17 (5%)
`4 (1%)
`2 (< 1%)
`1 (< 1%)
`4 (1%)
`
`39 (11%)
`85 (23%)
`38 (10%)
`57 (15%)
`23 (6%)
`9 (2%)
`
`102 (27%)
`46 (12%)
`23 (6%)
`34 (9%)
`10 (3%)
`18 (5%)
`
`1 (< 1%)
`1 (< 1%)
`0
`2 (< 1%)
`0
`0
`
`11 (3%)
`9 (2%)
`I (< 1%)
`2 (< 1%)
`1 (< 1%)
`7 (2%)
`
`29 (8%)
`
`6 (2%)
`
`12 (3%)
`
`4 (1%)
`
`Weight Decreased
`Metabolism and Nutrition Disorders
`
`32 (9%)
`
`Anorexia
`
`59 (16%)
`
`18 (5%)
`Dehydration
`Musculoskeletal and Connective Tissue Disorders
`Back Pain
`60 (16%)
`Anhralgia
`39(11%)
`Muscle Spasms
`27 (7%)
`Nervous System Disorders
`
`Peripheral Neuropathy7
`Dysgeusia
`Dizziness
`
`Headache '
`
`50 (13%)
`41 (11%)
`30 (8%)
`
`28 (8%)
`
`0
`
`28 (8%)
`
`1 (< 1%)
`
`3 (< 1%)
`
`8 (2%)
`
`14 (4%)
`4 (1%)
`O
`
`3 (< 1%)
`0
`0
`
`0
`
`39 (11%)
`
`10 (3%)
`
`45 (12%)
`31 (8%)
`10 (3%)
`
`12 (3.2%)
`15 (4%)
`21 (6%)
`
`19 (5%)
`
`3 (< 1%)
`
`3 (< 1%)
`
`11 (3%)
`4 (1%)
`0
`
`3 (< 1%)
`0
`2 (< 1%)
`
`0
`
`Renal and Urinary Tract Disorders
`1-lematuria
`
`62 (17%)
`
`7 (2%)
`
`13 (4%)
`
`1 (< 1%)
`
`10
`
`

`
`25 (7%)
`Dysuria
`Respiratory, Thoracic and Mediastinal Disorders
`Dyspnea
`43 (12%)
`Cough
`40 (11%)
`Skin and Subcutaneous Tissue Disorders
`
`0
`
`4 (1%)
`O
`
`0
`
`5 (1%)
`
`16 (4%)
`22 (6%)
`
`18 (5%)
`
`9 (2%)
`
`0
`
`2 (< 1%)
`0
`
`0
`
`1 (< 1%)
`
`37 (10%)
`
`20 (5%)
`
`2 (<1 %)
`
`Alopecia
`Vascular Disorders
`
`Hypotension
`
`Median Duration of
`Treatment
`
`6 cycles
`
`4 cycles
`
`'Graded using NCI CTCAE version 3
`'Based on laboratory values, cabazitaxel: n =369, mitoxantrone: n = 370.
`Jlncludes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia,
`palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia.
`“Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain.
`slncludes gastroesophageal reflux disease and reflux gastritis.
`“includes urinary tract infection enterococcal and urinary tract infection fungal.
`7lnc1udes 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 withouta 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 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
`51%.
`
`Elderly Population:
`The following grade 1-4 adverse reactions were reported at rates 2 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.
`
`The incidence of the following grade 3-4 adverse reactions were higher in patients 2 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)].
`
`11
`
`

`
`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, nelfmavir, 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 lnducers: Though no formal drug interaction trials have been conducted for
`J EVTANA, 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.
`
`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 2 0.08 mg/kg
`(approximately 0.02 times the Cmax at the MRHD). In utero exposure to cabazitaxel did not
`
`12
`
`

`
`result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the
`expected human exposures.
`
`Ifthis drug is used during pregnancy or ifthe 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 mother was calculated to be delivered in the maternal milk.
`Because many drugs are excreted in human milk and because of the potential for serious adverse
`reactions in nursing infants from JEVTANA, a decision should be made whether to discontinue
`nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`
`The safety and effectiveness of JEVTANA in pediatric patients have not been established.
`
`8.5 Geriatric Use
`
`Based on a population pharmacokinetic analysis, no significant difference was observed in the
`pharmacokinetics of cabazitaxel between patients < 65 years (n=100) and older (n=70).
`
`Of the 371 patients with prostate cancer treated with JEVTANA every three weeks plus
`prednisone, 240 patients (64.7%) were 65 years of age and over, while 70 patients (18.9%) were
`75 years of age and over. No overall differences in effectiveness were observed between patients
`2 65 years of age and younger patients. Elderly patients (2 65 years of age) may be more likely
`to experience certain adverse reactions. The incidence of neutropenia, fatigue, asthenia, pyrexia,
`dizziness, urinary tract infection and dehydration occurred at rates 2 5% higher in patients who
`were 65 years of age or greater compared to younger patients [see Adverse Reactions (6. 1)].
`
`8.6 Renal Impairment
`
`No dedicated renal impairment trial for JEVTANA has been conducted. Based on the population
`pharmacokinetic analysis, no significant difference in clearance was observed in patients with
`mild (50 mL/min S creatinine clearance (CLcr) < 80 mL/min) and moderate renal impairment
`(30 mL/min 5 CLcr< 50 mL/min). No data are available for patients with severe renal
`impairment or end-stage renal disease [see Clinical Pharmacology (1 2. 3)] . Caution should be
`used in patients with severe renal impairment (CLcr < 30 mL/min) and patients with end-stage
`renal diseases.
`
`13
`
`

`
`8.7 Hepatic Impairment
`
`No dedicated hepatic impairment trial for JEVTANA has been conducted. The safety of
`JEVTANA has not been evaluated in patients with hepatic impairment [see Warnings and
`Precautions (5.6)] .
`
`As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to i