`
` Severe hepatic impairment (Total Bilirubin > 3 x ULN) (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`Bone marrow suppression (particularly neutropenia) and its clinical
`
`consequences (febrile neutropenia, neutropenic infections): Monitor
`
`blood counts frequently to determine if dosage modification or initiation
`of G-CSF is needed. Primary prophylaxis with G-CSF should be
`considered in patients with high-risk clinical features. Use caution in
`
`patients with hemoglobin < 10 g/dL. (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 disorders: Nausea, vomiting, and diarrhea may occur.
`
`
`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) Deaths have occurred due to
`
`gastrointestinal hemorrhage, perforation and neutropenic enterocolitis.
`Delay or discontinue JEVTANA. (5.3)
`Renal failure, including cases with fatal outcomes, has been reported.
`
`Identify cause and manage aggressively. (5.4)
`
`Respiratory disorders: Interstitial pneumonia/pneumonitis, interstitial
`
`lung disease and acute respiratory distress syndrome, including fatal
`outcomes, have been reported. Delay or discontinue JEVTANA and
`
`
`treat as indicated. (5.5)
`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. (5.6)(6)(8.5)
`Hepatic impairment: Reduce the JEVTANA dose to 20 mg/m2 in
`patients with mild hepatic impairment and to 15 mg/m2 in patients with
`
`
`moderate hepatic impairment. (2.3)
`
`JEVTANA can cause fetal harm when administered to a pregnant
`
`woman. (5.8)(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------------------------------­
`Avoid coadministration of JEVTANA with strong CYP3A inhibitors. If
`
`patients require co-administration of a strong CYP3A inhibitor, consider a
`25% JEVTANA dose reduction. (2.4)(7.1)(12.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`JEVTANA safely and effectively. See full prescribing information for
`JEVTANA.
`
`JEVTANA® (cabazitaxel) injection, for intravenous use
`
`
`Initial U.S. Approval: 2010
`
`
`WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
`
`See full prescribing information for complete boxed warning.
`
`
` Neutropenic deaths have been reported. Obtain frequent blood counts
`
`to monitor for neutropenia. 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. (2.1)(5.2)
`
`
` Contraindicated if history of severe hypersensitivity reactions to
`JEVTANA or to drugs formulated with polysorbate 80. (4)
`
`
`----------------------------RECENT MAJOR CHANGES------------------------­
` 09/2016
`Warnings and Precautions (5.5)
`
`
`
`
`
`----------------------------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)
`
`
`(2.1)
`
`Antiemetic prophylaxis (oral or intravenous) is recommended as needed.
`(2.1)
`Dosage Modifications: See full prescribing information (2.2, 2.3, 2.4)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Single dose vial 60 mg/1.5 mL, supplied with diluent (5.7 mL) for
`
`
`
`
`JEVTANA (3)
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`2.2 Dose Modifications for Adverse Reactions
`
`2.3 Dose Modifications for Hepatic Impairment
`2.4 Dose Modifications for Use with Strong CYP3A Inhibitors
`
`
`2.5 Preparation and Administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Bone Marrow Suppression
`
`5.2 Hypersensitivity Reactions
`5.3 Gastrointestinal Adverse Reactions
`5.4 Renal Failure
`
`
`
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
` Neutrophil counts of ≤1,500/mm3 (2.2)(4)
`
`
`
`
`
`
`History of severe hypersensitivity to JEVTANA or polysorbate 80 (4)
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`Revised: 09/2016
`
`
`
`
`
`5.5 Respiratory Disorders
`5.6 Use in Elderly Patients
`5.7 Use in Patients with Hepatic Impairment
`5.8 Embryo-Fetal Toxicity
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trial Experience
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`7.1 CYP3A Inhibitors
`
`
`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
`
`
`
`
`
`
`
`Reference ID: 3984498
`
`1
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 1
`
`

`

`
` 10 OVERDOSAGE
`
` 11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`Reference ID: 3984498
`
`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.
`
`2
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: NEUTROPENIA AND HYPERSENSITIVITY
`
`
`
`
`
`
`
` Neutropenia: 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 is contraindicated in patients with neutrophil counts of ≤1,500 cells/mm3 [see
`Contraindications (4) and Warnings and Precautions (5.1)].
`
`Severe hypersensitivity: Severe hypersensitivity reactions can occur and may include generalized
`rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require
`immediate discontinuation of the JEVTANA infusion and administration of appropriate therapy.
`Patients should receive premedication. JEVTANA is contraindicated in patients who have a
`history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with
`polysorbate 80 [see Dosage and Administration (2.1), Contraindications (4), and Warnings and
`
`Precautions (5.2)].
`
`
`
`
`
`
`1
`INDICATIONS AND USAGE
`
`
` 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 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.
`
`Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous
`
`medications to reduce the risk and/or severity of hypersensitivity [see Warnings and Precautions (5.2)]:
`
` antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent
`
`antihistamine),
` corticosteroid (dexamethasone 8 mg or equivalent steroid),
` H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist).
`
`Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see
`Warnings and Precautions 5.3)].
`
`
`
`
`
`
`JEVTANA injection single-use vial requires two dilutions prior to administration [see Dosage and
`Administration (2.5)].
`
`Reference ID: 3984498
`
`
`3
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 3
`
`

`

`
`
`2.2 Dose Modifications for Adverse Reactions
`
`Reduce or discontinue JEVTANA dosing for adverse reactions as described in Table 1.
`
`Table 1: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with
`JEVTANA
`
`
`
`Toxicity
`Prolonged grade ≥ 3 neutropenia (greater than
`1 week) despite appropriate medication
`including granulocyte-colony stimulating
`
`factor (G-CSF)
`
`Febrile neutropenia or neutropenic infection
`
`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 .
`
`Delay treatment until improvement or
`resolution, then reduce dosage of JEVTANA to
`20 mg/m2 .
`Discontinue JEVTANA
`
`Grade ≥ 3 diarrhea or persisting diarrhea
`despite appropriate medication, fluid and
`
`electrolytes replacement
`Grade 2 peripheral neuropathy
`
`
`Grade ≥3 peripheral neuropathy
`
`
`
`Discontinue JEVTANA treatment if a patient continues to experience any of these reactions at
`the 20 mg/m2 dosage.
`
`2.3 Dose Modifications for Hepatic Impairment
`
` Mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x Upper Limit of Normal (ULN) or AST
`
`>1.5 x ULN): Reduce JEVTANA starting dose to 20 mg/m2 .
`
` Moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 x ULN and AST = any): Reduce
`
`JEVTANA starting dose to 15 mg/m2 based on tolerability data in these patients; however, the
`efficacy of this dose is unknown.
`
` Severe hepatic impairment (total bilirubin > 3 X ULN): JEVTANA is contraindicated in patients
`
`with severe hepatic impairment [see Warning and Precautions (5.6) and Clinical Pharmacology
`(12.3)].
`
`
`
`2.4 Dose Modifications for Use with Strong CYP3A Inhibitors
`
`
`Concomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole,
`clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
`
`voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of
`JEVTANA with these drugs. If patients require co-administration of a strong CYP3A inhibitor,
`consider a 25% JEVTANA dose reduction [see Drug Interactions (7.1) and Clinical
`
`Reference ID: 3984498
`
`
`4
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 4
`
`

`

`
`
`
`
` Pharmacology (12.3)].
`
`2.5 Preparation and Administration
`
`
`JEVTANA is a cytotoxic anticancer drug. Follow applicable special handling and disposal procedures
`[see References (15)].1 If JEVTANA first diluted solution, or second (final) dilution for intravenous
`infusion should come into contact with the skin or mucous, immediately and thoroughly wash with soap
`and water.
`
`Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of
`JEVTANA infusion solution.
`
`JEVTANA should not be mixed with any other drugs.
`
`
`
`Preparation
`Read this entire section carefully before mixing and diluting. JEVTANA requires two dilutions prior to
`administration. Follow the preparation instructions provided below, as improper preparation may lead to
`overdose [see Overdosage (10)].
`
`
`Note: Both the JEVTANA injection and the diluent vials contain an overfill to compensate for liquid
`loss during preparation. This overfill ensures that after dilution with the entire contents of the
`
`accompanying diluent, there is an initial diluted solution containing 10 mg/mL JEVTANA.
`
`
`
`Inspect the JEVTANA injection and supplied diluent vials. The JEVTANA injection is a clear yellow to
`brownish-yellow viscous solution.
`
`
`Step 1 – First Dilution
`
`Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents of
`
`supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.
`
`When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject slowly
`to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated
`inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake.
`
`Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is
`homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to
`continuing the preparation process.
`
`The resulting initial diluted JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution before
`administration. The second dilution should be done immediately (within 30 minutes) to obtain the final
`infusion as detailed in Step 2.
`
`
`
`Reference ID: 3984498
`
`
`5
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 5
`
`

`

`
`
`
`
` Step 2 – Second (Final) Dilution
`
` Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as prepared in Step
`
`
` 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9%
`sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of
`JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL
`JEVTANA is not exceeded. The concentration of the JEVTANA final infusion solution should be
`between 0.10 mg/mL and 0.26 mg/mL.
`
`Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
`
`As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and
`discard.
`
`
`
`Fully prepared JEVTANA infusion solution (in either 0.9% sodium chloride solution or 5% dextrose
`solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a
`
`total of 24 hours (including the one-hour infusion) under the refrigerated conditions.
`
`Discard any unused portion.
`
`
`
`Administration
`Inspect visually for particulate matter, any crystals and discoloration prior to administration. If the
`JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have
`precipitation, it should be discarded.
`Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during
`administration.
`
`
`
`The final JEVTANA infusion solution should be administered intravenously as a one-hour infusion at
`room temperature.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`JEVTANA (cabazitaxel) injection is supplied as a kit consisting of the following:
` Cabazitaxel injection: 60 mg/1.5 mL; a clear yellow to brownish-yellow viscous solution
` Diluent: 5.7 mL of 13% (w/w) ethanol in water; a clear colorless solution
`
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`JEVTANA is contraindicated in patients with:
` neutrophil counts of ≤ 1,500/mm3 [see Warnings and Precautions (5.1)]
`
`
`
` history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with
`polysorbate 80 [see Warnings and Precautions (5.2)]
`
`severe hepatic impairment (total bilirubin > 3 x ULN) [see Warnings and Precautions (5.7)]
`
`
`
`
`Reference ID: 3984498
`
`
`6
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 6
`
`

`

`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Bone Marrow Suppression
`
`Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia
`may occur. Neutropenic deaths have been reported. In the randomized trial, five patients (1.3%)
`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. Grade 3-4 neutropenia has been observed in 82% of patients treated with
`JEVTANA in the randomized trial.
`
`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 is contraindicated in patients with neutrophils ≤ 1,500/mm3 [see Contraindications (4)].
`
`
`Caution is recommended in patients with hemoglobin < 10 g/dl.
`
`
`
`5.2 Hypersensitivity Reactions
`
`
`Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of
`JEVTANA, thus facilities and equipment for the treatment of hypotension and bronchospasm should be
`available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema,
`hypotension and bronchospasm.
`
`
`Premedicate all patients prior to the initiation of the infusion of JEVTANA [see Dosage and
`Administration (2.1)]. Observe patients closely for hypersensitivity reactions, especially during the first
`and second infusions. Severe hypersensitivity reactions require immediate discontinuation of the
`JEVTANA infusion and appropriate therapy. JEVTANA is contraindicated in patients with a history of
`severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see
`Contraindications (4)].
`
`
`
`5.3 Gastrointestinal Adverse Reactions
`
`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
`
`Reference ID: 3984498
`
`
`7
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 7
`
`

`

`
`
`diarrhea and electrolyte imbalance. Antiemetic prophylaxis is recommended. Treat patients 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)].
`
`
`Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including
`fatal outcome, have been reported in patients treated with JEVTANA [see Adverse Reactions (6.2)].
`Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet
`therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration
`and GI bleeding.
`
`Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may
`be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.
`JEVTANA treatment delay or discontinuation may be necessary.
`
`5.4 Renal Failure
`
`
`
`In the randomized clinical trial, renal failure of any grade occurred in 4% of the patients being treated
`with JEVTANA, including four cases with fatal outcome. Most cases occurred in association with
`sepsis, dehydration, or obstructive uropathy [see Adverse Reactions (6.1)]. Some deaths due to renal
`failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal
`failure and treat aggressively.
`
`5.5 Respiratory Disorders
`
`
`
`Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have
`been reported and may be associated with fatal outcome [see Adverse Reactions (6.2)]. Patients with
`underlying lung disease may be at higher risk for these events. Acute respiratory distress syndrome may
`occur in the setting of infection.
`
`
`
`Interrupt JEVTANA if new or worsening pulmonary symptoms develop. Closely monitor, promptly
`investigate, and appropriately treat patients receiving JEVTANA. Consider discontinuation. The benefit
`of resuming JEVTANA treatment must be carefully evaluated.
`
`
`
`5.6 Use in 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)].
`
`
`
`
`5.7 Use in Patients with Hepatic Impairment
`
`Cabazitaxel is extensively metabolized in the liver.
`
`Reference ID: 3984498
`
`
`8
`
`MYLAN PHARMS. INC. EXHIBIT 1138 PAGE 8
`
`

`

`
`
`JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin > 3 x ULN) [see
`Contraindications (4)]. Dose should be reduced for patients with mild (total bilirubin > 1 to ≤ 1.5 x ULN
`or AST > 1.5 x ULN) and moderate (total bilirubin > 1.5 to ≤ 3.0 x ULN and any AST) hepatic
`
`impairment, based on tolerability data in these patients [see Dosage and Administration (2.3) and Use in
`
` Specific Populations (8.7)]. Administration of cabazitaxel to patients with mild and moderate hepatic
`impairment should be undertaken with caution and close monitoring of safety.
`
`5.8 Embryo-Fetal Toxicity
`
`
`JEVTANA is not indicated for use in female patients.
`
`
`
`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. Females 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:
` Bone Marrow Suppression [see Warnings and Precautions (5.1)].
` Hypersensitivity Reactions [see Warnings and Precautions (5.2)].
` Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.3)].
` Renal Failure [see Warnings and Precautions (5.4)].
`
` Respiratory Disorders [see Warnings and Precautions (5.5)].
` Use in Elderly Patients [see Warnings and Precautions (5.6)].
` Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.7)].
` Embryo-Fetal Toxicity [see Warnings and Precautions (5.8)].
`
`
`
`
`
`
`
`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
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`Reference ID: 3984498
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`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.
`
`
`
`
`
`
`
`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
`
`
`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
`
`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 Reactions1 and Hematologic Abnormalities in
`≥ 5% of Patients Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in
`Combination with Prednisone
`
`Mitoxantrone 12 mg/m2 every 3
`JEVTANA 25 mg/m2 every 3
`
`
`
`
`weeks with prednisone 10 mg daily weeks with prednisone 10 mg daily
`n=371
`n=371
`
`
`
`
`
`
`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%)
`
`76 (20%)
`Constipation
`
`
`
`Abdominal Pain4
`64 (17%)
`
`Dyspepsia5
`36 (10%)
`
`
`
`General Disorders and Administration Site Conditions
`
`
`136 (37%)
`Fatigue
`
`
`Asthenia
`76 (20%)
`
`
`
`45 (12%)
`Pyrexia
`
`
`Peripheral Edema
`34 (9%)
`
`
`22 (6%)
`Mucosal Inflammation
`
`
`20 (5%)
`Pain
`
`
`
`18 (5%)
`
`17 (5%)
`
`4 (1%)
`
`2 (< 1%)
`
`1 (< 1%)
`
`4 (1%)
`
`
`102 (27%)
`
`46 (12%)
`
`
`23 (6%)
`
`
`34 (9%)
`
`
`10 (3%)
`
`18 (5%)
`
`
`
`11 (3%)
`
`9 (2%)
`
`1 (< 1%)
`
`2 (< 1%)
`
`1 (< 1%)
`
`7 (2%)
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`Reference ID: 3984498
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`6 (2%)
`
`
`0
`
`
`3 (< 1%)
`
`8 (2%)
`
`
`14 (4%)
`
`4 (1%)
`
`0
`
`3 (< 1%)
`
`0
`
`0
`
`0
`
`
`7 (2%)
`
`0
`
`
`4 (1%)
`
`0
`
`
`
`12 (3%)
`
`
`28 (8%)
`
`
`
`39 (11%)
`
`
`10 (3%)
`
`
`45 (12%)
`
`31 (8%)
`
`10 (3%)
`
`12 (3.2%)
`
`
`15 (4%)
`
`21 (6%)
`
`19 (5%)
`
`
`13 (4%)
`
`
`5 (1%)
`
`
`16 (4%)
`
`
`22 (6%)
`
`
`
`4 (1%)
`
`
`1 (< 1%)
`
`
`3 (< 1%)
`
`3 (< 1%)
`
`
`11 (3%)
`
`4 (1%)
`
`0
`
`3 (< 1%)
`
`0
`
`2 (< 1%)
`
`0
`
`
`1 (< 1%)
`
`0
`
`
`2 (< 1%)
`
`0
`
`
`0
`
`
`
`2 (<1 %)
`
`
`
`18 (5%)
`
`
`9 (2%)
`
`
`
`0
`
`
`1 (< 1%)
`
`
`4 cycles
`
`
`
`
`
`
`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
`
`
`28 (8%)
`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
`
`
`
`
`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%).
`
`
`Reference ID: 3984498
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`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.
`
`The incidence of the following grade 3-4 adverse reactions were higher in patients  65