Jevtana
Generic: CABAZITAXEL
Basic Information
Manufacturer
Sanofi-Aventis U.S. LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
FDA Set ID
de3d9c26-572b-4ea4-9b2d-dd58a2b3e8fa
Indications & Usage
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 )
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 )
Adverse Reactions
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 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 0.7 Vomiting 15 1.2 18 1 Abdominal pain 6 0.5 9 1 Stomatitis 5 0 5 0.3 General Disorders and Administration Site Conditions Fatigue 25 3 27 4 Asthenia 15 2 20 2 Edema peripheral 7 0.2 9 0.2 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 0.8 Pain in extremity 5 0.2 7 0.5 Nervous System Disorders Dysgeusia 7 0 11 0 Peripheral sensory neuropathy 7 0 11 0.7 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 0.7 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 [see Clinical Studies 14.3 ] .
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 4.8 Lymphopenia 72 27 55 17 Neutropenia 66 45 7 3.2 Thrombocytopenia 41 3.2 16 1.6 General Disorders and Administration Site Conditions Fatigue includes asthenia, fatigue, lethargy, malaise.
53 4 36 2.4 Edema peripheral includes lymphoedema, edema peripheral, peripheral swelling.
11 0.8 10 1.6 Pyrexia 6 0 7 0 Pain 6 0 6 0.8 Gastrointestinal Disorders Diarrhea includes colitis, diarrhea, diarrhea hemorrhagic, gastroenteritis.
40 4.8 6 0 Nausea 23 0 23 0.8 Constipation 15 0 11 0 Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, flank pain, gastrointestinal pain.
14 1.6 6 0.8 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 2.4 Bone fracture includes femoral neck fracture, pathological fracture, rib fracture, spinal compression fracture, sternal fracture, thoracic vertebral fracture.
3.2 1.6 8 2.4 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 1.6 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 2.4 Hypokalemia 3.2 0 6 0 Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) Cancer pain 8 1.6 9 2.4 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 3.2 Respiratory, Thoracic and Mediastinal Disorders Pneumonia includes lower respiratory tract infection, lung infection, lung infiltration, pneumonia.
6 1.6 3.2 0.8 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 2.4 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%.
6.2 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.
( 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.
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 0.7 Vomiting 15 1.2 18 1 Abdominal pain 6 0.5 9 1 Stomatitis 5 0 5 0.3 General Disorders and Administration Site Conditions Fatigue 25 3 27 4 Asthenia 15 2 20 2 Edema peripheral 7 0.2 9 0.2 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 0.8 Pain in extremity 5 0.2 7 0.5 Nervous System Disorders Dysgeusia 7 0 11 0 Peripheral sensory neuropathy 7 0 11 0.7 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 0.7 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 [see Clinical Studies 14.3 ] .
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 4.8 Lymphopenia 72 27 55 17 Neutropenia 66 45 7 3.2 Thrombocytopenia 41 3.2 16 1.6 General Disorders and Administration Site Conditions Fatigue includes asthenia, fatigue, lethargy, malaise.
53 4 36 2.4 Edema peripheral includes lymphoedema, edema peripheral, peripheral swelling.
11 0.8 10 1.6 Pyrexia 6 0 7 0 Pain 6 0 6 0.8 Gastrointestinal Disorders Diarrhea includes colitis, diarrhea, diarrhea hemorrhagic, gastroenteritis.
40 4.8 6 0 Nausea 23 0 23 0.8 Constipation 15 0 11 0 Abdominal pain includes abdominal pain, abdominal pain lower, abdominal pain upper, flank pain, gastrointestinal pain.
14 1.6 6 0.8 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 2.4 Bone fracture includes femoral neck fracture, pathological fracture, rib fracture, spinal compression fracture, sternal fracture, thoracic vertebral fracture.
3.2 1.6 8 2.4 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 1.6 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 2.4 Hypokalemia 3.2 0 6 0 Neoplasms Benign, Malignant and Unspecified (incl cysts and polyps) Cancer pain 8 1.6 9 2.4 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 3.2 Respiratory, Thoracic and Mediastinal Disorders Pneumonia includes lower respiratory tract infection, lung infection, lung infiltration, pneumonia.
6 1.6 3.2 0.8 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 2.4 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%.
6.2 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.