`These highlights do not include all the information needed to use
`JEVTANA safely and efl'eetively. See full preserlbing information for
`JEVTANA.
`
`JEVTANA (<abazitaxel) Injection, 60 mg/1.5 mL,
`for intravenous infusion only
`Initial U.S. Approval: 2010
`
`WARNING
`See foil prescribing information for complete boxed warning.
`• Neutropenic deaths have been reported. ObtaiD. frequent blood counts
`to monitor for neutropeu.ia. Do not give JEVTANA ifneutrophll counts
`are :9,500 cells/JDJD'. (2.2)(4)
`• Severe hypersensitivity can occur and may include generalized
`rash/erythema, hypotension and bronchospasm. Discontinue
`JEVTANA immediately if severe reaedons occur and administer
`appropriate therapy. (2.3)(5.2)
`• Contraindicated if history of severe hypenensiti.vity reactions to
`JEVTANA or to dngs formulated with polysorbate 80. (4)
`
`,------INDICATIONS AND USAGE-
`JEVT.ANA 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. (I)
`
`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 mglmL JEVTANA. (2.5)
`PVC equipment should not be used (2.5)
`Premedication Regimen: Administer intravenously 30 minutes before
`each dose of JEVTANA:
`Antihistamine (dexchloropheniramine S mg or
`o
`diphenhydramine 25 mg or equivalent antihistamine)
`Corticosteroid (dexamethasone 8 mg or equivalent steroid)
`H2 antagonist (:ranitidine 50 mg or equivalent H 2 antagonist)
`(2.3)
`Antiemetic prophylaxis (oral or intravenous) is recommended as needed
`(2.3)
`Dosage Modifications: See full prescribing information (2.2)
`
`o
`o
`
`----------:DOSAGEFORMSANDSTRENG~
`•
`Single use vial60 mg/1.5 mL, supplied with diluent (5.7 mL) for
`JEVTANA(3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING
`1
`INDICATIONS AND USAGE
`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 STRENGmS
`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
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`·-----CONTRAINDICATIONS.
`Neutrophil counts of:::;I,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 ifhypersensitivity is observed and treat as
`indicated. (4)(5.2)
`Gastrointestinal symptoms (nausea, vomiting, diarrhea): Mortality
`related to diarrhea has been reported. Rehydrate and 1reat with anti(cid:173)
`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---------(cid:173)
`Most common all grades adverse reactions ~100/o) are neutropenia, anemia,
`leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting,
`constipation, asthenia, abdominal pain, hematuria, back pain, anorexia,
`peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, artbralgia, and
`alopecia. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis
`U.S. LLC at 1-li00-633-1610 or FDA at 1-l!OO-FDA-1088 or
`www.fda.guvlmedwatch.
`
`, ___ , , ___ ,_DRUG INTERACTIONS-------
`Use with caution in patients taking concomitant medicines that induce or
`inhibit CYP3A. (7)
`
`•
`
`See17 for PATIENT COUNSELING INFORMATION and FDA(cid:173)
`approved patient labeling.
`
`Revised: 0612010
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`7 DRUG INTERACTIONS
`7 .I 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 Impainnent
`8.7 Hepatic Impairment
`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 ofFertility
`
`1
`
`MYLAN - EXHIBIT 1067
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`
`
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 s-g•
`
`16.3 Handling and Disposal
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`2
`
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING
`
`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::51,500 cells/mm3
`
`•
`
`Severe hypersensitivity reactions can occur and may include generalized rash/erythema,
`hypotension and bronchospasm. Severe hypersensitivity reactions require immediate
`discontinuation of the JEVT ANA 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)].
`
`1
`
`INDICATIONS AND USAGE
`
`JEVT 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
`
`• The individual dosage of JEVT ANA 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 JEVT ANA
`treatment.
`• Premedication is recommended prior to treatment [see Dosage and Administration (2.3)].
`•
`JEVT ANA 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.
`
`•
`
`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
`
`Febrile neutropenia
`
`Toxicity
`Dosa2e Modification
`Prolonged grade 2': 3 neutropenia (greater thao Delay treatment until neutrophil count is
`> 1,500 cells/mm3
`, then reduce dosage of
`1 week) despite appropriate medication
`JEVTANA to 20 mg/m2
`including G-CSF
`• 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 JEVT ANA to
`20m!Vm2
`•
`
`Grade 2': 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
`20mg/m2
`•
`
`2.3 Premedication
`
`Premedicate at least 30 minutes prior to each dose of JEVT ANA with the following intravenous
`medications to reduce the risk and/or severity of hypersensitivity:
`antihistamine (dexchlorpheuiramine 5 mg, or diphenhydramine 25 mg or equivalent
`•
`antihistamine),
`corticosteroid (dexamethasone 8 mg or equivalent steroid),
`•
`• Hz antagouist (ranitidine 50 mg or equivalent Hz antagouist).
`
`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 JEVT ANA 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.
`
`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 JEVT ANA ( 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 (cabazitaxellO 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 reco=ended 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 JEVT ANA is required, use a larger volume of the infusion vehicle so that
`a concentration of0.26 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.
`
`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 of24 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 of0.22 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 of24 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 :S 1 ,500/mm3
`
`•
`
`JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions
`to cabazitaxel or to other drugs formulated with polysorbate 80.
`
`6
`
`
`
`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 JEVT ANA [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)].
`
`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
`
`7
`
`
`
`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 131 (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 2': 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 2': 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 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 JEVT ANA [see Use in
`Specific Populations (8.1)].
`
`8
`
`
`
`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) offatal 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% ofmitoxantrone-treatedpatients.
`
`9
`
`
`
`Table 2 - Incidence of Reported Adverse Reactions1 and Hematologic Abnormalities in
`~ 5% of Patients Receiving JEVTANA in Combination witb Prednisone or Mitoxantrone in
`Combination with Prednisone
`
`Mitoxantrone 12 mglm1 every 3
`JEVTANA 25 mglm1 every 3
`weeks with prednisone 10 mg daily weeks with prednisone 10 mg daily
`n=371
`n=371
`
`Grade 1-4
`n(%}
`
`Grade3-4
`n(%}
`
`Grade 1-4
`n(%}
`
`Grade3-4
`n (%}
`
`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
`Arrhythmia'
`Gastrointestinal Disorders
`173 (47%)
`Diarrhea
`Nausea
`127 (34%)
`83 (22%)
`Vomiting
`76 (20%)
`Constipation
`Abdominal Pain4
`64 (17%)
`Dyspepsia5
`36 (10%)
`General Disorders and Administration Site Conditions
`Fatigue
`136 (37%)
`76 (20%)
`Asthenia
`Pyrexia
`45 (12%)
`Peripheral Edema
`34 {9%)
`Mucosal Inflammation
`22 (6%)
`20 {5%)
`Pain
`Infections and Infestations
`Urinary Tract Infection•
`Investigations
`32 (9%)
`Weight Decreased
`Metabolism and Nutrition Disorders
`Anorexia
`59 (16%)
`18 {5%)
`Dehydration
`Musculoskeletal and Connective Tissue Disorders
`Back Pain
`60 (16%)
`Arthralgia
`39 (11%)
`Muscle Spasms
`27 (7%)
`Nervous System Disorders
`Peripheral Neuropathy7
`Dysgeusia
`Dizziness
`Headache
`Renal and Urinary Tract Disorders
`Hematuria
`
`303 (82%)
`27 (7%)
`39 (11%)
`253 (69%)
`15 (4%)
`
`325 (87%)
`5 {I%)
`302 (82%)
`343 (93%)
`160 (43%)
`
`215 (58%)
`5 {I%)
`18 (5%)
`157 (42%)
`6(2%)
`
`4(1%)
`
`6(2%)
`
`1 {< 1%)
`
`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%)
`1 {< 1%)
`2 {< 1%)
`1 {< 1%)
`7 {2%)
`
`6(2%)
`
`12 (3%)
`
`4(1%)
`
`0
`
`28 (8%)
`
`1 {< 1%)
`
`3 {< 1%)
`8 {2%)
`
`14 (4%)
`4(1%)
`0
`
`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
`
`7(2%)
`
`13 (4%)
`
`1 {< 1%)
`
`10
`
`18 (5%)
`
`29 (8%)
`
`50 (13%)
`41 (11%)
`30 (8%)
`28 {8%)
`
`62 (17%)
`
`
`
`25 (7%)
`Dysuria
`Respiratory, Thoracic and Mediastinal Disorders
`Dyspnea
`43 (12%)
`40 (11%)
`Cough
`Skin and Subcutaneous Tissue Disorders
`Alopecia
`37 (10%)
`Vascular Disorders
`Hypotension
`
`20 (5%)
`
`0
`
`4(1%)
`0
`
`0
`
`2 (<1 %)
`
`5 (1%)
`
`16 (4%)
`22 (6%)
`
`18 (5%)
`
`9(2%)
`
`0
`
`2 (< 1%)
`0
`
`0
`
`1 (< 1%)
`
`6 cycles
`
`Median Duration of
`Treatment
`Graded using NCI CTCAE version 3
`1Based on laboratory values, cabazitaxel: n ~369, mitoxantrone: n ~ 370.
`'Includes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia,
`jlalpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia.
`"'ncludes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain.
`'Includes gastroesophageal reflux disease and reflux gastritis.
`"'ncludes urinary tract infection enterococcal and urinary tract infection fungal.
`7Includes peripheral motor neuropathy and peripheral sensory neuropathy.
`
`4 cycles
`
`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': 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 AL T, and increased bilirubin were each
`:0:::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.
`
`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)].
`
`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, nelfinavir, ritonavir, saquinavir,
`telithromycin, voriconazole) is expected to increase concentrations of cabazitaxel. Therefore, co(cid:173)
`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 JEVT ANA 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/k.g 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/k.g/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/k.g
`(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.
`
`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 oflactating 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 mglk:g (approximately 0.02 times
`the maximum reco=ended 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 JEVT ANA 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= 1 00) 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
`~ 65 years of age and younger patients. Elderly patients ~ 65 years of age) may be more likely
`to experience certain adverse reactions. The incidence of neutropenia, fatigne, asthenia, pyrexia,
`dizziness, urinary tract infection and dehydration occurred at rates ~ 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 :<::;creatinine clearance (CLcr) < 80 mL/min) and moderate renal impairment
`(30 mL/min :<::; CLcr< 50 mL/mi