Jevtana Drug Information

® 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.

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. 99.8 10 99.7 14 Leukopenia 80 29 95 60 Neutropenia 67 42 89 73 Thrombocytopenia 35 3 43 4 Febrile Neutropenia 2 2 9 9 Gastrointestinal Disorders Diarrhea 31 1 40 4 Nausea 25 0.7 32 1 Constipation 18 0.3 18

Vomiting 15 1.2 18 1 Abdominal pain 6 0.5 9 1 Stomatitis

5 0 5

General Disorders and

Administration Site Conditions Fatigue 25 3 27 4 Asthenia 15 2 20 2 Edema peripheral 7 0.2 9

Pyrexia 5 0.2 6 0.2 Renal and Urinary Disorders Hematuria 14 2

21 4 Dysuria 5 0.3 4 0 Metabolism and Nutrition Disorders Decreased appetite 13 0.7 19 1 Musculoskeletal and Connective Tissue Disorders Back pain 11 0.9 14 1 Bone pain 8 2 8 2 Arthralgia 8 0.5 7

Pain in extremity 5 0.2 7 0.5 Nervous System Disorders Dysgeusia 7

0 11 0 Peripheral sensory neuropathy 7 0 11

Dizziness 4 0 5 0 Headache 5 0.2 4 0.2 Infections and

Infestations Urinary tract infection Includes urinary tract infection staphylococcal, urinary tract infection bacterial, urinary tract infection fungal, and urosepsis. 7 2 11 2 Neutropenic infection Includes neutropenic sepsis. 3 2 7 6 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 5 0.9 8

Cough 6 0 6 0 Investigations Weight decreased 4 0.2 7 0

Skin and Subcutaneous Tissue Disorders Alopecia 3 0 6.1 0 Injury, Poisoning and Procedural Complications Wrong technique in drug usage process 0.3 0 5 0 CARD Trial (JEVTANA 25 mg/m 2 + primary prophylaxis with G-CSF) The safety of JEVTANA 25 mg/m 2 in combination with prednisone/prednisolone and primary prophylaxis G-CSF was evaluated in a randomized, open-label study (CARD) in patients with metastatic castration-resistant prostate cancer who progressed after receiving prior docetaxel-containing regimens and abiraterone acetate or enzalutamide . This study compared JEVTANA 25 mg/m 2 in combination with prednisone/prednisolone and primary prophylaxis with G-CSF to either abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily. Among patients receiving JEVTANA, 35% remained on treatment at 6 months and 4.7% remained on treatment at 12 months. Serious adverse reactions occurred in 39% of patients receiving JEVTANA. Serious adverse reactions in ≥3% of patients included neutropenia (6%), infections (4.8%), and diarrhea, fatigue, pneumonia, and spinal cord compression (3.2% each). Deaths due to causes other than disease progression were reported in 2.4% of JEVTANA treated patients.

Fatal adverse reactions in JEVTANA-treated patients were septic shock, urinary tract infection (UTI), and aspiration (0.8% each). Treatment discontinuations due to adverse drug reactions occurred in 20% of patients who received JEVTANA and 8% of patients who received abiraterone acetate plus prednisone/prednisolone or enzalutamide. The adverse reactions leading to treatment discontinuation in >1% of patients in JEVTANA arm were nervous system disorders, infections/infestations, and gastrointestinal disorders. Dose interruptions (alone or in combination with dose reduction) due to an adverse reaction occurred in 31% of patients receiving JEVTANA. Dose reductions were reported in 18% of JEVTANA-treated patients.

The most frequent adverse reactions leading to dose interruption of JEVTANA were fatigue (7%) and hypersensitivity reaction (3.2%); the most frequent adverse reaction leading to reduction of JEVTANA were neutropenia and peripheral neuropathy (3.9% each). Table 4 summarizes the adverse reactions and laboratory hematologic abnormalities in patients in CARD. The most common (≥10%) adverse reactions were fatigue, diarrhea, musculoskeletal pain, nausea, infections, peripheral neuropathy, hematuria, constipation, abdominal pain, decreased appetite, vomiting, dysgeusia, edema peripheral and lower urinary tract symptoms. The most common (≥10%) hematologic abnormalities were anemia, lymphopenia, neutropenia and thrombocytopenia. Table 4: Adverse Reactions Grade from NCI CTC version 4.0. and Hematologic Abnormalities in ≥5% of Patients in CARD Trial Adverse Reactions JEVTANA 25 mg/m 2 + prednisone/prednisolone + G-CSF Abiraterone + prednisone/prednisolone or Enzalutamide (N=126) (N=124) Grade 1–4 % Grade 3–4 % Grade 1–4 % Grade 3–4 % Blood and Lymphatic System Disorders Anemia Based on laboratory values - % calculated using the number of patients with at least one event(n) over the number of patients assessed for each parameter during the on-treatment period. 99 8 95

Lymphopenia 72 27 55 17 Neutropenia 66 45 7 3.2 Thrombocytopenia 41

3.2 16

General Disorders and

Administration Site Conditions Fatigue includes asthenia, fatigue, lethargy, malaise. 53 4 36

Edema peripheral includes lymphoedema, edema peripheral, peripheral swelling. 11 0.8 10 1.6

Pyrexia 6 0 7 0 Pain 6 0 6

Gastrointestinal Disorders Diarrhea includes colitis, diarrhea, diarrhea hemorrhagic, gastroenteritis. 40 4.8 6

0 Nausea 23 0 23

Constipation 15 0 11 0 Abdominal pain includes abdominal pain, abdominal pain

lower, abdominal pain upper, flank pain, gastrointestinal pain. 14 1.6 6

Vomiting 13 0 12 1.6 Stomatitis 8 0 1.6 0 Dyspepsia 4.8

0 2.4 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, noncardiac chest pain. 27 1.6 40 6 Pain in extremity 4.8 0 11

Bone fracture includes femoral neck fracture, pathological fracture, rib fracture, spinal compression

fracture, sternal fracture, thoracic vertebral fracture. 3.2 1.6 8

Infections and Infestations Infections includes bacteremia, bacteriuria, cellulitis, device related sepsis, Enterobacter

sepsis, erysipelas, furuncle, influenza, influenza like illness, localized infection, oral fungal infection, perineal cellulitis, pulmonary sepsis, pyelocaliectasis, pyelonephritis, pyelonephritis acute, respiratory tract infection, respiratory tract infection viral, sepsis, septic shock, subcutaneous abscess, upper respiratory tract infection, ureteritis, urinary tract infection, urinary tract infection bacterial, urosepsis, viral infection. 19 4 14 6 Nervous System Disorders Peripheral neuropathy includes neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy. 18 1.6 4.8 0 Dysgeusia 11 0 4 0 Polyneuropathy 6 1.6 0 0 Dizziness 0.8 0 4.8 0 Renal and Urinary Disorders Hematuria includes hematuria, cystitis hemorrhagic. 16 0.8 6

Lower urinary tract symptoms include lower urinary tract symptoms, micturition urgency, nocturia

pollakiuria, urinary incontinence, urinary retention, dysuria. 10 0 9 0 Acute kidney injury includes acute kidney injury, blood creatinine increased, renal failure, renal impairment. 5 2.4 10 4 Metabolism and Nutrition Disorders Decreased appetite 14 0.8 15

Hypokalemia 3.2 0 6 0 Neoplasms Benign, Malignant and Unspecified (incl cysts

and polyps) Cancer pain 8 1.6 9

Cardiac disorders includes aortic valve incompetence, aortic valve stenosis, atrial fibrillation, atrial

flutter, atrioventricular block complete, atrioventricular block second degree, bradycardia, sinus bradycardia, tachycardia, cardiac failure, acute coronary syndrome, angina pectoris. 6 0.8 6

Respiratory, Thoracic and Mediastinal Disorders Pneumonia includes lower respiratory tract infection, lung

infection, lung infiltration, pneumonia. 6 1.6 3.2

Dyspnea 6 0 2.4 0 Skin and Subcutaneous Tissue Disorders Alopecia 6

0 0 0 Injury, Poisoning and Procedural Complications Fall 4.8 0 0 0 Vascular Disorders Hypertension includes hypertension, hypertensive crisis. 4 2.4 8

Investigations Weight decreased 4 0 6 0 Psychiatric Disorders Insomnia 3.2 0

4.8 0 Clinically relevant ≥ Grade 3 adverse reactions in <5% of patients who received JEVTANA in combination with prednisone and primary prophylaxis G-CSF: febrile neutropenia (3.2%), pulmonary embolism (1.6%), and neutropenic infection (0.8%). Hematuria In study TROPIC, adverse reactions 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.

In study PROSELICA, hematuria of all grades was observed in 18% of patients overall. In CARD, hematuria of all grades was observed in 16% of patients receiving JEVTANA. Hepatic Laboratory Abnormalities The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤1%.

Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made. Gastrointestinal: Gastritis, intestinal obstruction.

Respiratory: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome. Renal and urinary disorders: Radiation recall hemorrhagic cystitis.

CYP3A Inhibitors Cabazitaxel is primarily metabolized through

CYP3A . 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.

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 . 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.

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.

is contraindicated in patients with: neutrophil counts of ≤1,500/mm 3 history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 severe hepatic impairment (total bilirubin >3 × ULN) Neutrophil counts of ≤1,500/mm 3 History of severe hypersensitivity to JEVTANA or polysorbate 80 Severe hepatic impairment (Total Bilirubin >3 × ULN)

There is no known antidote for JEVTANA overdose. Overdose has resulted from improper preparation . Read the entire section Dosage and Administration carefully before mixing or diluting. Complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders.

Overdose has led to fatal outcome. In case of overdose, the patient should be kept in a specialized unit where vital signs, chemistry and particular functions can be closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose.

Other appropriate symptomatic measures should be taken, as needed.