Cabazitaxel

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 )

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 Single dose vial 60 mg/1.5 mL, supplied with diluent (5.7 mL) for JEVTANA ( 3 )

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 )

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 receiving JEVTANA 20 mg/m 2 were reported to have infectious adverse reactions. Grade 1–4 infections were experienced by 160 patients (28%) on the 20 mg/m 2 arm and 227 patients (38%) on the 25 mg/m 2 arm. Grade 3–4 infections were experienced by 57 patients (10%) on the 20 mg/m 2 arm and 120 patients (20%) on the 25 mg/m 2 arm. Noninferiority for overall survival was demonstrated between these two arms [see Adverse Reactions (6.1) ] . CARD Trial (JEVTANA 25 mg/m 2 + primary prophylaxis G-CSF) In the CARD trial where JEVTANA 25 mg/m 2 was administered with primary prophylaxis of G-CSF, 1 patient (0.8%) died from sepsis within the first 30 days of treatment. Grade 1–4 neutropenia-related adverse reactions were experienced in 33 patients (26%). Grade 3–4 neutropenias were experienced by 26 patients (21%). Clinically important neutropenia-related events occurred and included febrile neutropenia (3.2%), neutropenic infection/sepsis (0.8%) and neutropenic deaths (0.8%) [see Adverse Reactions (6.1) ] . Based on guidelines for the use of G-CSF and the adverse reactions profile of JEVTANA, primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features (older patients, 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. Consider primary prophylaxis with G-CSF in all patients receiving JEVTANA 25 mg/m 2 . 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) ] .

5.2 Increased Toxicities in Elderly Patients In a randomized trial (TROPIC), 2% of patients (3/131) <65 years of age and 6% (15/240) ≥65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose. Patients ≥65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia. The incidence of the following grade 3–4 adverse reactions was higher in patients ≥65 years of age compared to younger patients; neutropenia (87% vs 74%), and febrile neutropenia (8% vs 6%). In a randomized clinical trial (PROSELICA) comparing two doses of JEVTANA, deaths due to infection within 30 days of starting JEVTANA occurred in 0.7% (4/580) patients on the 20 mg/m 2 arm and 1.3% (8/595) patients on the 25 mg/m 2 arm; all of these patients were >60 years of age. In PROSELICA, on the 20 mg/m 2 arm, 3% (5/178) of patients <65 years of age and 2% (9/402) ≥65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose. On the 25 mg/m 2 arm, 2% (3/175) patients <65 years of age and 5% (20/420) ≥65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose [see Adverse Reactions (6) and Use in Specific Populations (8.5) ] . In CARD, a death due to infection within 30 days of starting JEVTANA occurred in 0.8% (1/126) patient who was >75 years of age. There were 2.4% (3/126) of patients who died of causes other than disease progression within 30 days of the last JEVTANA dose; all of these patients were >75 years of age.

5.3 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. […]

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 Administration Site Conditions Fatigue 37 5 27 3 Asthenia 20 5 12 2 Pyrexia 12 1 6 <1 Peripheral Edema 9 <1 9 <1 Mucosal Inflammation 6 <1 3 <1 Pain 5 1 5 2 Renal and Urinary Tract Disorders Hematuria 17 2 4 <1 Dysuria 7 0 1 0 Musculoskeletal and Connective Tissue Disorders Back Pain 16 4 12 3 Arthralgia 11 1 8 1 Muscle Spasms 7 0 3 0 Metabolism and Nutrition Disorders Anorexia 16 <1 11 <1 Dehydration 5 2 3 <1 Nervous System Disorders Peripheral Neuropathy Includes peripheral motor neuropathy and peripheral sensory neuropathy. 13 <1 3 <1 Dysgeusia 11 0 4 0 Dizziness 8 0 6 <1 Headache 8 0 5 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 12 1 4 <1 Cough 11 0 6 0 Skin and Subcutaneous Tissue Disorders Alopecia 10 0 5 0 Investigations Weight Decreased 9 0 8 <1 Infections and Infestations Urinary Tract Infection Includes urinary tract infection enterococcal and urinary tract infection fungal. 8 2 3 1 Cardiac Disorders Arrhythmia Includes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia, palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia. 5 1 2 <1 Vascular Disorders Hypotension 5 <1 2 <1 PROSELICA Trial (comparison of two doses of JEVTANA) In a noninferiority, multicenter, randomized, open-label study (PROSELICA), 1175 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen, were treated with either JEVTANA 25 mg/m 2 (n=595) or the 20 mg/m 2 (n=580) dose. Deaths within 30 days of last study drug dose were reported in 22 (3.8%) patients in the 20 mg/m 2 and 32 (5.4%) patients in the 25 mg/m 2 arm. The most common fatal adverse reactions in JEVTANA-treated patients were related to infections, and these occurred more commonly on the 25 mg/m 2 arm (n=15) than on the 20 mg/m 2 arm (n=8). Other fatal adverse reactions in JEVTANA-treated patients included cerebral hemorrhage, respiratory failure, paralytic ileus, diarrhea, acute pulmonary edema, disseminated intravascular coagulation, renal failure, sudden death, cardiac arrest, ischemic stroke, diverticular perforation, and cardiorenal syndrome. Grade 1–4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m 2 versus 20 mg/m 2 arms were leukopenia, neutropenia, thrombocytopenia, febrile neutropenia, decreased appetite, nausea, diarrhea, asthenia, and hematuria. Grade 3–4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m 2 versus 20 mg/m 2 arms were leukopenia, neutropenia, and febrile neutropenia. Treatment discontinuations due to adverse reactions occurred in 17% of patients in the 20 mg/m 2 group and 20% of patients in the 25 mg/m 2 group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m 2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m 2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m 2 group, 128 patients (22%) had a dose reduced from 25 to 20 mg/m 2 , 19 patients (3%) had a dose reduced from 20 to 15 mg/m 2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m 2 . In the 20 mg/m 2 group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m 2 , and 9 patients (2%) had a dose reduced from 15 to 12 mg/m 2 . Table 3: Adverse Reactions Grade from NCI CTCAE version 4.03. and Hematologic Abnormalities in ≥5% of Patients in PROSELICA Adverse Reactions JEVTANA 20 mg/m 2 every 3 weeks with prednisone 10 mg daily n=580 JEVTANA 25 mg/m 2 every 3 weeks with prednisone 10 mg daily n=595 Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Blood and Lymphatic System Disorders Anemia Based on laboratory values, JEVTANA 20 mg/m 2 : n=577, JEVTANA 25 mg/m 2 : n=590. […]

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.

8.2 Lactation Risk Summary The safety and efficacy of JEVTANA have not been established in females. There is no information available on the presence of cabazitaxel in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Cabazitaxel or cabazitaxel metabolites are excreted in maternal milk of lactating rats [see Data ] . Data Animal data In a milk excretion study, radioactivity related to cabazitaxel was detected in the stomachs of nursing pups 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 C max in patients at the recommended human dose). This was detectable 24 hours post dose. Approximately 1.5% of the dose delivered to the mother was calculated to be delivered in the maternal milk.

8.3 Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of JEVTANA [see Use in Specific Populations (8.1) ] . Infertility Males Based on animal toxicology studies, JEVTANA may impair human fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of JEVTANA in pediatric patients have not been established. JEVTANA was evaluated in 39 pediatric patients (ages 3 to 18 years) receiving prophylactic G-CSF. The maximum tolerated dose (MTD) was 30 mg/m 2 intravenously over 1 hour on Day 1 of a 21 day cycle in pediatric patients with solid tumors based on the dose-limiting toxicity (DLT) of febrile neutropenia. No objective responses were observed in 11 patients with refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). One patient had a partial response among the 9 patients with ependymoma. Infusion related/hypersensitivity reactions were seen in 10 patients (26%). Three patients experienced serious adverse events of anaphylactic reaction. The incidence of infusion related/hypersensitivity reactions decreased with steroid premedication. The most frequent treatment-emergent adverse events were similar to those reported in adults. Based on the population pharmacokinetics analysis conducted with data from 31 pediatric patients with cancer (ages 3 to 18 years), the clearances by body surface area were comparable to those in adults.

8.5 Geriatric Use In the TROPIC study, 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 death due to causes other than disease progression within 30 days of the last cabazitaxel dose were higher in patients who were 65 years of age or greater compared to younger patients [see Warnings and Precautions (5.2) ] . The incidence of grade 3–4 neutropenia and febrile neutropenia were higher in patients who were 65 years of age or greater compared to younger patients. The following grade 1–4 adverse reactions were reported at rates ≥5% higher in patients 65 years of age or older 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. In the PROSELICA study, the grade 1–4 adverse reactions reported at rates of at least 5% higher in patients 65 years of age or older compared to younger patients were diarrhea (43% vs 33%), fatigue (30% vs 19%), asthenia (22% vs 13%), constipation (20% vs 13%), clinical neutropenia (13% vs 6%), febrile neutropenia (11% vs 5%), and dyspnea (10% vs 3%). In the CARD study, the grade 1–4 adverse reactions reported at rates of at least 5% higher in patients 65 years of age or older compared to younger patients were decreased appetite (16% vs 7%), hypertension (5% vs 0), constipation (18% vs 7%), paresthesia (6% vs 0), stomatitis (10% vs 3%), musculoskeletal pain (5% vs 0), fatigue (31% vs 23%), asthenia (30% vs 19%), and edema peripheral (11% vs 0). 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).

8.6 Renal Impairment No dose adjustment is necessary in patients with renal impairment not requiring hemodialysis. Patients presenting with end-stage renal disease (creatinine clearance CL CR <15 mL/min/1.73 m 2 ), should be monitored carefully during treatment [see Clinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment Cabazitaxel is extensively metabolized in the liver. Patients with mild hepatic impairment (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) should have JEVTANA dose of 20 mg/m 2 . Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety [see Clinical Pharmacology (12.3) ]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to ≤3.0 × ULN and AST = any) was 15 mg/m 2 , however, the efficacy at this dose level was unknown. JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN) [see Contraindications (4) ] .

Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions.