Jevtana

1 INDICATIONS AND USAGE JEVTANA ® is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. JEVTANA is a microtubule inhibitor indicated in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dose: JEVTANA 20 mg/m 2 administered every three weeks as a one-hour intravenous infusion in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment. ( 2.1 ) A dose of 25 mg/m 2 can be used in select patients at the discretion of the treating healthcare provider. ( 2.1 , 5.1 , 5.2 , 6.1 , 14 ) JEVTANA requires two dilutions prior to administration. ( 2.5 ) Use the entire contents of the accompanying diluent to achieve a concentration of 10 mg/mL JEVTANA. ( 2.5 ) PVC equipment should not be used. ( 2.5 ) Premedication Regimen: Administer intravenously 30 minutes before each dose of JEVTANA: Antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent antihistamine) Corticosteroid (dexamethasone 8 mg or equivalent steroid) H 2 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 ) 2.1 Dosing Information The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m 2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment. A dose of 25 mg/m 2 can be used in select patients at the discretion of the treating healthcare provider [see Warnings and Precautions (5.1 , 5.2) , Adverse Reactions (6.1) , and Clinical Studies (14) ] . Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m 2 [see Contraindications (4) and Warnings and Precautions (5.1 , 5.2) ] . Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous medications to reduce the risk and/or severity of hypersensitivity [see Warnings and Precautions (5.3) ] : antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine), corticosteroid (dexamethasone 8 mg or equivalent steroid), H 2 antagonist. Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed [see Warnings and Precautions (5.3) ] . JEVTANA injection single-dose vial requires two dilutions prior to administration [see Dosage and Administration (2.5) ] . 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 Dosage Modification Prolonged grade ≥3 neutropenia (greater than 1 week) despite appropriate medication including granulocyte-colony stimulating factor (G-CSF) Delay treatment until neutrophil count is >1,500 cells/mm 3 , then reduce dosage of JEVTANA by one dose level. Use G-CSF for secondary prophylaxis. Febrile neutropenia or neutropenic infection Delay treatment until improvement or resolution, and until neutrophil count is >1,500 cells/mm 3 , then reduce dosage of JEVTANA by one dose level. Use G-CSF for secondary prophylaxis. Grade ≥3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement Delay treatment until improvement or resolution, then reduce dosage of JEVTANA by one dose level. Grade 2 peripheral neuropathy Delay treatment until improvement or resolution, then reduce dosage of JEVTANA by one dose level. Grade ≥3 peripheral neuropathy Discontinue JEVTANA. Patients at a 20 mg/m 2 dose who require dose reduction should decrease dosage of JEVTANA to 15 mg/m 2 [see Adverse Reactions (6.1) ] . Patients at a 25 mg/m 2 dose who require dose reduction should decrease dosage of JEVTANA to 20 mg/m 2 . One additional dose reduction to 15 mg/m 2 may be considered [see Adverse Reactions (6.1) ] . 2.3 Dose Modifications for Hepatic Impairment Mild hepatic impairment (total bilirubin >1 to ≤1.5 × Upper Limit of Normal (ULN) or AST >1.5 × ULN)…

5 WARNINGS AND PRECAUTIONS Bone marrow suppression (particularly neutropenia) and its clinical consequences (febrile neutropenia, neutropenic infections, and death): Monitor blood counts frequently to determine if dosage modification or initiation of G-CSF is needed. Closely monitor patients with hemoglobin <10 g/dL. ( 2.2 , 4 , 5.1 ) Increased toxicities in elderly patients: Patients ≥65 years of age were more likely to experience fatal outcomes and certain adverse reactions, including neutropenia and febrile neutropenia. Monitor closely. ( 5.2 , 8.5 ) Hypersensitivity: Severe hypersensitivity reactions can occur. Premedicate with corticosteroids and H 2 antagonists. Discontinue infusion immediately if hypersensitivity is observed and treat as indicated. ( 4 , 5.3 ) Gastrointestinal disorders: Nausea, vomiting, and diarrhea may occur. Mortality related to diarrhea has been reported. Rehydrate and treat with antiemetics and antidiarrheals as needed. If experiencing Grade ≥3 diarrhea, dosage should be modified. ( 2.2 ) Deaths have occurred due to gastrointestinal hemorrhage, perforation and neutropenic enterocolitis. Delay or discontinue JEVTANA and treat as indicated. ( 5.4 ) Renal failure, including cases with fatal outcomes, has been reported. Identify cause and manage aggressively. ( 5.5 ) Urinary disorders including cystitis: Cystitis, radiation cystitis, and hematuria may occur. Monitor patients who previously received pelvic radiation for signs and symptoms of cystitis. Interrupt or discontinue JEVTANA and provide medical or surgical supportive care, as needed, in patients experiencing severe hemorrhagic cystitis. ( 5.6 ) Respiratory disorders: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome, including fatal outcomes, have been reported. Delay or discontinue JEVTANA and treat as indicated. ( 5.7 ) Hepatic impairment: Administer JEVTANA at a dose of 20 mg/m 2 in patients with mild hepatic impairment. Administer JEVTANA at a dose of 15 mg/m 2 in patients with moderate hepatic impairment. ( 2.3 , 5.8 ) Embryo-fetal toxicity: JEVTANA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception. ( 5.9 , 8.1 , 8.3 ) 5.1 Bone Marrow Suppression JEVTANA is contraindicated in patients with neutrophils ≤1,500/mm 3 [see Contraindications (4) ] . Closely monitor patients with hemoglobin <10 g/dL. Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported. TROPIC Trial (JEVTANA 25 mg/m 2 ) In the TROPIC trial with G-CSF administered only at the investigator's discretion, 5 patients (1.3%) died from neutropenic infection (sepsis or septic shock); 4 of these patients died in the first 30 days of treatment. 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. Grade 3–4 neutropenia occurred in 82% of patients treated with JEVTANA in the randomized trial [see Adverse Reactions (6.1) ] . PROSELICA Trial (comparison of JEVTANA 20 mg/m 2 versus 25 mg/m 2 ) In the PROSELICA trial comparing two doses of JEVTANA, primary prophylaxis with G-CSF was not allowed, but could be administered after development of neutropenia at investigators discretion. Eight patients (1%) on the 20 mg/m 2 arm and 15 patients (3%) on the 25 mg/m 2 arm died from infection; of these, 4 deaths on the 20 mg/m 2 arm and 8 deaths on the 25 mg/m 2 arm occurred within the first 30 days of treatment. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m 2 arm and 9.2% on 25 mg/m 2 arm), neutropenic infection/sepsis (2.1% on 20 mg/m 2 arm and 6.4% on 25 mg/m 2 arm), and neutropenic deaths (0.3% on 20 mg/m 2 arm and 0.7% on 25 mg/m 2 arm). Fewer patients receiv…

4 CONTRAINDICATIONS JEVTANA is contraindicated in patients with: neutrophil counts of ≤1,500/mm 3 [see Warnings and Precautions (5.1) ] history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Warnings and Precautions (5.3) ] severe hepatic impairment (total bilirubin >3 × ULN) [see Warnings and Precautions (5.8) ] Neutrophil counts of ≤1,500/mm 3 ( 2.2 , 4 ) History of severe hypersensitivity to JEVTANA or polysorbate 80 ( 4 ) Severe hepatic impairment (Total Bilirubin >3 × ULN) ( 4 )

7 DRUG INTERACTIONS Avoid coadministration of JEVTANA with strong CYP3A inhibitors. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction. ( 2.4 , 7.1 , 12.3 ) 7.1 CYP3A Inhibitors Cabazitaxel is primarily metabolized through CYP3A [see Clinical Pharmacology (12.3) ] . 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 strong CYP3A inhibitors. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary The safety and efficacy of JEVTANA have not been established in females. There are no human data on the use of JEVTANA in pregnant women to inform the drug-associated risk. In animal reproduction studies, intravenous administration of cabazitaxel in pregnant rats during organogenesis caused embryonic and fetal death at doses lower than the maximum recommended human dose [see Data ] . Data Animal data In an early embryonic developmental toxicity study in rats, cabazitaxel was administered intravenously for 15 days prior to mating through day 6 of pregnancy, which resulted in an increase in pre-implantation loss at 0.2 mg/kg/day and an increase in early resorptions at ≥0.1 mg/kg/day (approximately 0.06 and 0.02 times the C max in patients at the recommended human dose, respectively). In an embryo-fetal developmental toxicity study in rats, cabazitaxel caused maternal and embryo-fetal toxicity consisting of increased postimplantation loss, embryolethality, and fetal deaths when administered intravenously at a dose of 0.16 mg/kg/day (approximately 0.06 times the C max in patients at the recommended human dose). Decreased mean fetal birthweight associated with delays in skeletal ossification was observed at doses ≥0.08 mg/kg. Cabazitaxel crossed the placenta barrier within 24 hours of a single intravenous administration of 0.08 mg/kg to pregnant rats at gestational day 17. A dose of 0.08 mg/kg in rats resulted in a C max approximately 0.02 times that observed in patients at the recommended human dose. Administration of cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures.

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) ] Increased Toxicities in Elderly Patients [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.4) ] Renal Failure [see Warnings and Precautions (5.5) ] Urinary Disorders Including Cystitis [see Warnings and Precautions (5.6) ] Respiratory Disorders [see Warnings and Precautions (5.7) ] Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.8) ] Most common all grades adverse reactions and laboratory abnormalities (≥10%) with JEVTANA 20 mg/m 2 or 25 mg/m 2 are neutropenia, anemia, diarrhea, nausea, fatigue, asthenia, vomiting, hematuria, constipation, decreased appetite, back pain, and abdominal pain. ( 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. TROPIC Trial (JEVTANA 25 mg/m 2 compared to mitoxantrone) The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with metastatic castration-resistant prostate cancer treated in the randomized TROPIC trial, compared to mitoxantrone plus prednisone. Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) JEVTANA-treated patients and 3 (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea. The most common (≥10%) grade 1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. The most common (≥5%) grade 3–4 adverse reactions in patients who received JEVTANA were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. Treatment discontinuations due to adverse 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: Adverse Reactions Graded using NCI CTCAE version 3. and Hematologic Abnormalities in ≥5% of Patients in TROPIC Adverse Reactions JEVTANA 25 mg/m 2 every 3 weeks with prednisone 10 mg daily n=371 Mitoxantrone 12 mg/m 2 every 3 weeks with prednisone 10 mg daily n=371 Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Blood and Lymphatic System Disorders Anemia Based on laboratory values, JEVTANA: n=369, mitoxantrone: n=370. 98 11 82 5 Leukopenia 96 69 93 42 Neutropenia 94 82 87 58 Thrombocytopenia 48 4 43 2 Febrile Neutropenia 7 7 1 1 Gastrointestinal Disorders Diarrhea 47 6 11 <1 Nausea 34 2 23 <1 Vomiting 22 2 10 0 Constipation 20 1 15 <1 Abdominal Pain Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain. 17 2 6 0 Dyspepsia Includes gastroesophageal reflux disease and reflux gastritis. 10 0 2 0 General Disorders and Adm…