Dosage & Administration
The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can be used in select patients at the discretion of the treating healthcare provider
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/m2
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
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed
JEVTANA injection single-dose vial requires
A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider. (
The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can be used in select patients at the discretion of the treating healthcare provider
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/m2
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
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed
JEVTANA injection single-dose vial requires
JEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3
Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported.
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
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/m2arm and 15 patients (3%) on the 25 mg/m2arm died from infection; of these, 4 deaths on the 20 mg/m2arm and 8 deaths on the 25 mg/m2arm occurred within the first 30 days of treatment. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m2arm and 9.2% on 25 mg/m2arm), neutropenic infection/sepsis (2.1% on 20 mg/m2arm and 6.4% on 25 mg/m2arm), and neutropenic deaths (0.3% on 20 mg/m2arm and 0.7% on 25 mg/m2arm).
Fewer patients receiving JEVTANA 20 mg/m2were reported to have infectious adverse reactions. Grade 1–4 infections were experienced by 160 patients (28%) on the 20 mg/m2arm and 227 patients (38%) on the 25 mg/m2arm. Grade 3–4 infections were experienced by 57 patients (10%) on the 20 mg/m2arm and 120 patients (20%) on the 25 mg/m2arm. Noninferiority for overall survival was demonstrated between these two arms
In the CARD trial where JEVTANA 25 mg/m2was 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%)
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/m2.
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
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/m2arm and 1.3% (8/595) patients on the 25 mg/m2arm; all of these patients were >60 years of age.
In PROSELICA, on the 20 mg/m2arm, 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/m2arm, 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
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.
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with 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.
| Adverse Reactions | JEVTANA 25 mg/m2every 3 weeks with prednisone 10 mg daily n=371 | Mitoxantrone 12 mg/m2every 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 | ||||
| AnemiaBased 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 PainIncludes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain. | 17 | 2 | 6 | 0 |
| DyspepsiaIncludes 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 NeuropathyIncludes 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 InfectionIncludes urinary tract infection enterococcal and urinary tract infection fungal. | 8 | 2 | 3 | 1 |
Cardiac Disorders | ||||
| ArrhythmiaIncludes 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 |
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/m2(n=595) or the 20 mg/m2(n=580) dose.
Deaths within 30 days of last study drug dose were reported in 22 (3.8%) patients in the 20 mg/m2and 32 (5.4%) patients in the 25 mg/m2arm. The most common fatal adverse reactions in JEVTANA-treated patients were related to infections, and these occurred more commonly on the 25 mg/m2arm (n=15) than on the 20 mg/m2arm (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/m2versus 20 mg/m2arms 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/m2versus 20 mg/m2arms were leukopenia, neutropenia, and febrile neutropenia.
Treatment discontinuations due to adverse reactions occurred in 17% of patients in the 20 mg/m2group and 20% of patients in the 25 mg/m2group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m2group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2group, 128 patients (22%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3%) had a dose reduced from 20 to 15 mg/m2and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m2, and 9 patients (2%) had a dose reduced from 15 to 12 mg/m2.
| Adverse Reactions | JEVTANA 20 mg/m2every 3 weeks with prednisone 10 mg daily n=580 | JEVTANA 25 mg/m2every 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 | ||||
| AnemiaBased on laboratory values, JEVTANA 20 mg/m2: n=577, JEVTANA 25 mg/m2: 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 infectionIncludes urinary tract infection staphylococcal, urinary tract infection bacterial, urinary tract infection fungal, and urosepsis. | 7 | 2 | 11 | 2 |
| Neutropenic infectionIncludes 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 |
The safety of JEVTANA 25 mg/m2in 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
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.
| Adverse Reactions | JEVTANA 25 mg/m2+ 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 | ||||
| AnemiaBased 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 | ||||
| Fatigueincludes asthenia, fatigue, lethargy, malaise. | 53 | 4 | 36 | 2.4 |
| Edema peripheralincludes lymphoedema, edema peripheral, peripheral swelling. | 11 | 0.8 | 10 | 1.6 |
| Pyrexia | 6 | 0 | 7 | 0 |
| Pain | 6 | 0 | 6 | 0.8 |
Gastrointestinal Disorders | ||||
| Diarrheaincludes colitis, diarrhea, diarrhea hemorrhagic, gastroenteritis. | 40 | 4.8 | 6 | 0 |
| Nausea | 23 | 0 | 23 | 0.8 |
| Constipation | 15 | 0 | 11 | 0 |
| Abdominal painincludes 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 painincludes 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 fractureincludes 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 | ||||
| Infectionsincludes 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 neuropathyincludes 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 | ||||
| Hematuriaincludes hematuria, cystitis hemorrhagic. | 16 | 0.8 | 6 | 1.6 |
| Lower urinary tract symptomsinclude lower urinary tract symptoms, micturition urgency, nocturia, pollakiuria, urinary incontinence, urinary retention, dysuria. | 10 | 0 | 9 | 0 |
| Acute kidney injuryincludes 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 | ||||
| Pneumoniaincludes 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 | ||||
| Hypertensionincludes 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%).
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.
The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤1%.
The efficacy and safety of JEVTANA in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen (TROPIC, NCT00417079).
A total of 755 patients were randomized to receive either JEVTANA 25 mg/m2intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.
This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets >100,000 cells/mm3, hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.
Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the JEVTANA group.
Efficacy results for the JEVTANA arm versus the control arm are summarized in Table 5 and Figure 1.
| JEVTANA + Prednisone n=378 | Mitoxantrone + Prednisone n=377 | |
|---|---|---|
Overall Survival | ||
| Number of deaths (%) | 234 (61.9%) | 279 (74.0%) |
| Median survival (month) (95% CI) | 15.1 (14.1–16.3) | 12.7 (11.6–13.7) |
| Hazard RatioHazard ratio estimated using Cox model; a hazard ratio of less than 1 favors JEVTANA.(95% CI) | 0.70 (0.59–0.83) | |
| p-value | <0.0001 | |
Investigator-assessed tumor response of 14.4% (95% CI: 9.6–19.3) was higher for patients in the JEVTANA arm compared to 4.4% (95% CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005.
The efficacy and safety of JEVTANA were evaluated in a noninferiority, multicenter, randomized, open-label study (PROSELICA, NCT01308580). A total of 1200 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen were randomized to receive either JEVTANA 25 mg/m2(n=602) or 20 mg/m2(n=598) dose. Overall survival (OS) was the major efficacy outcome.
Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 45–89) and the racial distribution for all groups was 87% Caucasian, 6.9% Asian, 2.3% Black, and 3.8% Others in the JEVTANA 20 mg/m2group. The median age was 69 years (range 45–88) and the racial distribution for all groups was 88.7% Caucasian, 6.6% Asian, 1.8% Black, and 2.8% Others in the JEVTANA 25 mg/m2group.
The study demonstrated noninferiority in overall survival (OS) of JEVTANA 20 mg/m2in comparison with JEVTANA 25 mg/m2in an intent-to-treat population (see Table 6and Figure 2). Based on the per-protocol population, the estimated median OS was 15.1 months on JEVTANA 20 mg/m2and 15.9 months on JEVTANA 25 mg/m2, the observed hazard ratio (HR) of OS was 1.042 (97.78% CI: 0.886, 1.224). Among the subgroup analyses intended for assessing the heterogeneity, no notable difference in OS was observed on the JEVTANA 25 mg/m2arm compared to the JEVTANA 20 mg/m2arm in subgroups based on the stratification factors of ECOG performance status score, measurability of disease, or region.
| CBZ20+PRED n=598 | CBZ25+PRED n=602 | |
|---|---|---|
| CBZ20=Cabazitaxel 20 mg/m2, CBZ25=Cabazitaxel 25 mg/m2, PRED=Prednisone/Prednisolone. | ||
| CI=confidence interval. | ||
Overall Survival | ||
| Number of deaths, n (%) | 497 (83.1%) | 501 (83.2%) |
| Median survival (95% CI) (months) | 13.4 (12.2 to 14.9) | 14.5 (13.5 to 15.3) |
| Hazard RatioHazard ratio is estimated using a Cox Proportional Hazards regression model. A hazard ratio <1 indicates a lower risk of death for Cabazitaxel 20 mg/m2with respect to 25 mg/m2.(97.78% CIAdjusted for interim OS analyses. The noninferiority margin is 1.214.) | 1.024 (0.886, 1.184) | |
The efficacy and safety of JEVTANA were evaluated in a multinational, randomized, active-controlled, open-label study (CARD: NCT02485691) in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel containing regimen and had progressed within 12 months of initiating either abiraterone or enzalutamide. A total of 255 patients were randomized to receive either JEVTANA 25 mg/m2every 3 week plus prednisone/prednisolone 10 mg daily (n=129), abiraterone 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily depending on prior therapy received (n=126). Primary prophylactic G-CSF was administered at each cycle for patients in the JEVTANA arm. This study included patients over 18 years of age with ECOG performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets >100,000 cells/mm3, hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study. Randomization was stratified by ECOG performance status (0 or 1 vs 2), time from abiraterone acetate or enzalutamide to disease progression, and receipt of abiraterone acetate or enzalutamide before or after docetaxel containing regimen.
The major efficacy outcome measure was radiographic progression free-survival (rPFS) as defined by Prostate Cancer Working Group-2 (PCWG2) assessed by study investigators. Other efficacy outcome measures included overall survival and objective response rate.
Demographics and baseline disease characteristics were balanced between treatment arms. The overall median age was 70 years (range 45 to 88), 95% of patients had an ECOG PS of 0 to 1 and median Gleason score was 8. A majority of the patients (61%) had their prior treatment with abiraterone acetate or enzalutamide after docetaxel. There were 36% of patients on the cabazitaxel arm with visceral disease (liver 8%, lung 8%, other 20%) and 57% with bone-only disease. Race and ethnicity data were not collected. Approximately 92% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy during the first 3 cycles and, overall, 90% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy at each cycle.
Efficacy results from the CARD trial are summarized in Table 7 and Figure 3.
| JEVTANA + prednisone/prednisolone + G-CSF n=129 | Abiraterone + prednisone/prednisolone or Enzalutamide n=126 | |
|---|---|---|
Radiographic Progression Free Survival (rPFS) | ||
| Number of events (%)Investigator assessed. | 95 (73.6%) | 101 (80.2%) |
| Median rPFS (months) (95% CI) | 8.0 (5.7 to 9.2) | 3.7 (2.8 to 5.1) |
| Hazard Ratio (95% CI) | 0.54 (0.40 to 0.73) | |
| p-valueStratified log-rank test, significance threshold = 0.05. | <0.0001 | |
Overall Survival (OS) Overall survival was statistically significant. | ||
| Median OS [95% CI] (months) | 13.6 [11.5; 17.5] | 11.0 [9.2; 12.9] |
| Hazard Ratio (95% CI) | 0.64 [0.46; 0.89] | |
| p-value | 0.0078 | |
In terms of therapy sequence prior to randomization, rPFS was consistent across the subgroups of patients who received abiraterone acetate/enzalutamide prior to docetaxel (HR=0.61, 95% CI: 0.39, 0.96) and those who received abiraterone acetate/enzalutamide after docetaxel (HR=0.48, 95% CI: 0.32, 0.70).
Objective tumor response rate assessed by study investigators was 36.5% (95% CI: 26.6 to 48.4) for JEVTANA arm versus 11.5% (95% CI: 2.9 to 20.2) for abiraterone acetate plus prednisone/prednisolone or enzalutamide arm, p=0.004.
By using PrescriberAI, you agree to the AI Terms of Use.
Jevtana Prescribing Information
WARNING: NEUTROPENIA AND HYPERSENSITIVITY
- Neutropenic deaths have been reported. Obtain frequent blood counts to monitor for neutropenia. JEVTANA is contraindicated in patients with neutrophil counts of ≤1,500 cells/mm3. 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/m2 (,
4 CONTRAINDICATIONSJEVTANA is contraindicated in patients with:
- neutrophil counts of ≤1,500/mm3[see Warnings and Precautions (5.1)]
- history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80[see Warnings and Precautions (5.3)]
- severe hepatic impairment (total bilirubin >3 × ULN)[see Warnings and Precautions (5.8)]
- Neutrophil counts of ≤1,500/mm3
- History of severe hypersensitivity to JEVTANA or polysorbate 80
- Severe hepatic impairment (Total Bilirubin >3 × ULN)
,5.1 Bone Marrow SuppressionJEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3
[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/m2)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/m2versus 25 mg/m2)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/m2arm and 15 patients (3%) on the 25 mg/m2arm died from infection; of these, 4 deaths on the 20 mg/m2arm and 8 deaths on the 25 mg/m2arm occurred within the first 30 days of treatment. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m2arm and 9.2% on 25 mg/m2arm), neutropenic infection/sepsis (2.1% on 20 mg/m2arm and 6.4% on 25 mg/m2arm), and neutropenic deaths (0.3% on 20 mg/m2arm and 0.7% on 25 mg/m2arm).
Fewer patients receiving JEVTANA 20 mg/m2were reported to have infectious adverse reactions. Grade 1–4 infections were experienced by 160 patients (28%) on the 20 mg/m2arm and 227 patients (38%) on the 25 mg/m2arm. Grade 3–4 infections were experienced by 57 patients (10%) on the 20 mg/m2arm and 120 patients (20%) on the 25 mg/m2arm. Noninferiority for overall survival was demonstrated between these two arms
[see Adverse Reactions (6.1)].CARD Trial (JEVTANA 25 mg/m2+ primary prophylaxis G-CSF)In the CARD trial where JEVTANA 25 mg/m2was 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/m2.
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 PatientsIn 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/m2arm and 1.3% (8/595) patients on the 25 mg/m2arm; all of these patients were >60 years of age.
In PROSELICA, on the 20 mg/m2arm, 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/m2arm, 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.
- neutrophil counts of ≤1,500/mm3
- Severe hypersensitivity can occur and may include generalized rash/erythema, hypotension and bronchospasm. Discontinue JEVTANA immediately if severe reactions occur and administer appropriate therapy. (,
2.1 Dosing InformationThe recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can 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/m2
[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),
- H2antagonist.
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
twodilutions prior to administration[see Dosage and Administration (2.5)].)5.2 Increased Toxicities in Elderly PatientsIn 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/m2arm and 1.3% (8/595) patients on the 25 mg/m2arm; all of these patients were >60 years of age.
In PROSELICA, on the 20 mg/m2arm, 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/m2arm, 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.
- Contraindicated if history of severe hypersensitivity reactions to cabazitaxel or to drugs formulated with polysorbate 80. ()
4 CONTRAINDICATIONSJEVTANA is contraindicated in patients with:
- neutrophil counts of ≤1,500/mm3[see Warnings and Precautions (5.1)]
- history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80[see Warnings and Precautions (5.3)]
- severe hepatic impairment (total bilirubin >3 × ULN)[see Warnings and Precautions (5.8)]
- Neutrophil counts of ≤1,500/mm3
- History of severe hypersensitivity to JEVTANA or polysorbate 80
- Severe hepatic impairment (Total Bilirubin >3 × ULN)
- neutrophil counts of ≤1,500/mm3
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.
The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can be used in select patients at the discretion of the treating healthcare provider
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/m2
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
- antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine),
- corticosteroid (dexamethasone 8 mg or equivalent steroid),
- H2antagonist.
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed
JEVTANA injection single-dose vial requires
A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider. (
The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can be used in select patients at the discretion of the treating healthcare provider
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/m2
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
- antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine),
- corticosteroid (dexamethasone 8 mg or equivalent steroid),
- H2antagonist.
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed
JEVTANA injection single-dose vial requires
JEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3
Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported.
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
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/m2arm and 15 patients (3%) on the 25 mg/m2arm died from infection; of these, 4 deaths on the 20 mg/m2arm and 8 deaths on the 25 mg/m2arm occurred within the first 30 days of treatment. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m2arm and 9.2% on 25 mg/m2arm), neutropenic infection/sepsis (2.1% on 20 mg/m2arm and 6.4% on 25 mg/m2arm), and neutropenic deaths (0.3% on 20 mg/m2arm and 0.7% on 25 mg/m2arm).
Fewer patients receiving JEVTANA 20 mg/m2were reported to have infectious adverse reactions. Grade 1–4 infections were experienced by 160 patients (28%) on the 20 mg/m2arm and 227 patients (38%) on the 25 mg/m2arm. Grade 3–4 infections were experienced by 57 patients (10%) on the 20 mg/m2arm and 120 patients (20%) on the 25 mg/m2arm. Noninferiority for overall survival was demonstrated between these two arms
In the CARD trial where JEVTANA 25 mg/m2was 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%)
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/m2.
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
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/m2arm and 1.3% (8/595) patients on the 25 mg/m2arm; all of these patients were >60 years of age.
In PROSELICA, on the 20 mg/m2arm, 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/m2arm, 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
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.
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with 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.
| Adverse Reactions | JEVTANA 25 mg/m2every 3 weeks with prednisone 10 mg daily n=371 | Mitoxantrone 12 mg/m2every 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 | ||||
| AnemiaBased 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 PainIncludes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain. | 17 | 2 | 6 | 0 |
| DyspepsiaIncludes 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 NeuropathyIncludes 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 InfectionIncludes urinary tract infection enterococcal and urinary tract infection fungal. | 8 | 2 | 3 | 1 |
Cardiac Disorders | ||||
| ArrhythmiaIncludes 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 |
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/m2(n=595) or the 20 mg/m2(n=580) dose.
Deaths within 30 days of last study drug dose were reported in 22 (3.8%) patients in the 20 mg/m2and 32 (5.4%) patients in the 25 mg/m2arm. The most common fatal adverse reactions in JEVTANA-treated patients were related to infections, and these occurred more commonly on the 25 mg/m2arm (n=15) than on the 20 mg/m2arm (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/m2versus 20 mg/m2arms 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/m2versus 20 mg/m2arms were leukopenia, neutropenia, and febrile neutropenia.
Treatment discontinuations due to adverse reactions occurred in 17% of patients in the 20 mg/m2group and 20% of patients in the 25 mg/m2group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m2group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2group, 128 patients (22%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3%) had a dose reduced from 20 to 15 mg/m2and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2group, 58 patients (10%) had a dose reduced from 20 to 15 mg/m2, and 9 patients (2%) had a dose reduced from 15 to 12 mg/m2.
| Adverse Reactions | JEVTANA 20 mg/m2every 3 weeks with prednisone 10 mg daily n=580 | JEVTANA 25 mg/m2every 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 | ||||
| AnemiaBased on laboratory values, JEVTANA 20 mg/m2: n=577, JEVTANA 25 mg/m2: 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 infectionIncludes urinary tract infection staphylococcal, urinary tract infection bacterial, urinary tract infection fungal, and urosepsis. | 7 | 2 | 11 | 2 |
| Neutropenic infectionIncludes 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 |
The safety of JEVTANA 25 mg/m2in 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
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.
| Adverse Reactions | JEVTANA 25 mg/m2+ 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 | ||||
| AnemiaBased 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 | ||||
| Fatigueincludes asthenia, fatigue, lethargy, malaise. | 53 | 4 | 36 | 2.4 |
| Edema peripheralincludes lymphoedema, edema peripheral, peripheral swelling. | 11 | 0.8 | 10 | 1.6 |
| Pyrexia | 6 | 0 | 7 | 0 |
| Pain | 6 | 0 | 6 | 0.8 |
Gastrointestinal Disorders | ||||
| Diarrheaincludes colitis, diarrhea, diarrhea hemorrhagic, gastroenteritis. | 40 | 4.8 | 6 | 0 |
| Nausea | 23 | 0 | 23 | 0.8 |
| Constipation | 15 | 0 | 11 | 0 |
| Abdominal painincludes 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 painincludes 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 fractureincludes 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 | ||||
| Infectionsincludes 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 neuropathyincludes 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 | ||||
| Hematuriaincludes hematuria, cystitis hemorrhagic. | 16 | 0.8 | 6 | 1.6 |
| Lower urinary tract symptomsinclude lower urinary tract symptoms, micturition urgency, nocturia, pollakiuria, urinary incontinence, urinary retention, dysuria. | 10 | 0 | 9 | 0 |
| Acute kidney injuryincludes 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 | ||||
| Pneumoniaincludes 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 | ||||
| Hypertensionincludes 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%).
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.
The incidences of grade 3–4 increased AST, increased ALT, and increased bilirubin were each ≤1%.
The efficacy and safety of JEVTANA in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen (TROPIC, NCT00417079).
A total of 755 patients were randomized to receive either JEVTANA 25 mg/m2intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.
This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets >100,000 cells/mm3, hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.
Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the JEVTANA group.
Efficacy results for the JEVTANA arm versus the control arm are summarized in Table 5 and Figure 1.
| JEVTANA + Prednisone n=378 | Mitoxantrone + Prednisone n=377 | |
|---|---|---|
Overall Survival | ||
| Number of deaths (%) | 234 (61.9%) | 279 (74.0%) |
| Median survival (month) (95% CI) | 15.1 (14.1–16.3) | 12.7 (11.6–13.7) |
| Hazard RatioHazard ratio estimated using Cox model; a hazard ratio of less than 1 favors JEVTANA.(95% CI) | 0.70 (0.59–0.83) | |
| p-value | <0.0001 | |
Investigator-assessed tumor response of 14.4% (95% CI: 9.6–19.3) was higher for patients in the JEVTANA arm compared to 4.4% (95% CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005.
The efficacy and safety of JEVTANA were evaluated in a noninferiority, multicenter, randomized, open-label study (PROSELICA, NCT01308580). A total of 1200 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen were randomized to receive either JEVTANA 25 mg/m2(n=602) or 20 mg/m2(n=598) dose. Overall survival (OS) was the major efficacy outcome.
Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 45–89) and the racial distribution for all groups was 87% Caucasian, 6.9% Asian, 2.3% Black, and 3.8% Others in the JEVTANA 20 mg/m2group. The median age was 69 years (range 45–88) and the racial distribution for all groups was 88.7% Caucasian, 6.6% Asian, 1.8% Black, and 2.8% Others in the JEVTANA 25 mg/m2group.
The study demonstrated noninferiority in overall survival (OS) of JEVTANA 20 mg/m2in comparison with JEVTANA 25 mg/m2in an intent-to-treat population (see Table 6and Figure 2). Based on the per-protocol population, the estimated median OS was 15.1 months on JEVTANA 20 mg/m2and 15.9 months on JEVTANA 25 mg/m2, the observed hazard ratio (HR) of OS was 1.042 (97.78% CI: 0.886, 1.224). Among the subgroup analyses intended for assessing the heterogeneity, no notable difference in OS was observed on the JEVTANA 25 mg/m2arm compared to the JEVTANA 20 mg/m2arm in subgroups based on the stratification factors of ECOG performance status score, measurability of disease, or region.
| CBZ20+PRED n=598 | CBZ25+PRED n=602 | |
|---|---|---|
| CBZ20=Cabazitaxel 20 mg/m2, CBZ25=Cabazitaxel 25 mg/m2, PRED=Prednisone/Prednisolone. | ||
| CI=confidence interval. | ||
Overall Survival | ||
| Number of deaths, n (%) | 497 (83.1%) | 501 (83.2%) |
| Median survival (95% CI) (months) | 13.4 (12.2 to 14.9) | 14.5 (13.5 to 15.3) |
| Hazard RatioHazard ratio is estimated using a Cox Proportional Hazards regression model. A hazard ratio <1 indicates a lower risk of death for Cabazitaxel 20 mg/m2with respect to 25 mg/m2.(97.78% CIAdjusted for interim OS analyses. The noninferiority margin is 1.214.) | 1.024 (0.886, 1.184) | |
The efficacy and safety of JEVTANA were evaluated in a multinational, randomized, active-controlled, open-label study (CARD: NCT02485691) in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel containing regimen and had progressed within 12 months of initiating either abiraterone or enzalutamide. A total of 255 patients were randomized to receive either JEVTANA 25 mg/m2every 3 week plus prednisone/prednisolone 10 mg daily (n=129), abiraterone 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily or enzalutamide 160 mg once daily depending on prior therapy received (n=126). Primary prophylactic G-CSF was administered at each cycle for patients in the JEVTANA arm. This study included patients over 18 years of age with ECOG performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets >100,000 cells/mm3, hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study. Randomization was stratified by ECOG performance status (0 or 1 vs 2), time from abiraterone acetate or enzalutamide to disease progression, and receipt of abiraterone acetate or enzalutamide before or after docetaxel containing regimen.
The major efficacy outcome measure was radiographic progression free-survival (rPFS) as defined by Prostate Cancer Working Group-2 (PCWG2) assessed by study investigators. Other efficacy outcome measures included overall survival and objective response rate.
Demographics and baseline disease characteristics were balanced between treatment arms. The overall median age was 70 years (range 45 to 88), 95% of patients had an ECOG PS of 0 to 1 and median Gleason score was 8. A majority of the patients (61%) had their prior treatment with abiraterone acetate or enzalutamide after docetaxel. There were 36% of patients on the cabazitaxel arm with visceral disease (liver 8%, lung 8%, other 20%) and 57% with bone-only disease. Race and ethnicity data were not collected. Approximately 92% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy during the first 3 cycles and, overall, 90% of the patients on the cabazitaxel arm received primary prophylaxis with G-CSF therapy at each cycle.
Efficacy results from the CARD trial are summarized in Table 7 and Figure 3.
| JEVTANA + prednisone/prednisolone + G-CSF n=129 | Abiraterone + prednisone/prednisolone or Enzalutamide n=126 | |
|---|---|---|
Radiographic Progression Free Survival (rPFS) | ||
| Number of events (%)Investigator assessed. | 95 (73.6%) | 101 (80.2%) |
| Median rPFS (months) (95% CI) | 8.0 (5.7 to 9.2) | 3.7 (2.8 to 5.1) |
| Hazard Ratio (95% CI) | 0.54 (0.40 to 0.73) | |
| p-valueStratified log-rank test, significance threshold = 0.05. | <0.0001 | |
Overall Survival (OS) Overall survival was statistically significant. | ||
| Median OS [95% CI] (months) | 13.6 [11.5; 17.5] | 11.0 [9.2; 12.9] |
| Hazard Ratio (95% CI) | 0.64 [0.46; 0.89] | |
| p-value | 0.0078 | |
In terms of therapy sequence prior to randomization, rPFS was consistent across the subgroups of patients who received abiraterone acetate/enzalutamide prior to docetaxel (HR=0.61, 95% CI: 0.39, 0.96) and those who received abiraterone acetate/enzalutamide after docetaxel (HR=0.48, 95% CI: 0.32, 0.70).
Objective tumor response rate assessed by study investigators was 36.5% (95% CI: 26.6 to 48.4) for JEVTANA arm versus 11.5% (95% CI: 2.9 to 20.2) for abiraterone acetate plus prednisone/prednisolone or enzalutamide arm, p=0.004.
- JEVTANA requires twodilutions prior to administration. ()
2.5 Preparation and AdministrationJEVTANA is a hazardous anticancer drug. Follow applicable special handling and disposal procedures
[see References (15)]. If JEVTANA first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin or mucous, immediately and thoroughly wash with soap and water.Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of JEVTANA infusion solution.
JEVTANA should not be mixed with any other drugs.
PreparationRead this
entiresection carefully before mixing and diluting. JEVTANA requirestwodilutions prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to overdose[see Overdosage (10)].Note:Both the JEVTANA injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with theentire contentsof the accompanying diluent, there is an initial diluted solution containing 10 mg/mL JEVTANA.Inspect the JEVTANA injection and supplied diluent vials. The JEVTANA injection is a clear yellow to brownish-yellow viscous solution.
Step 1 – first dilution
Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the
entire contentsof supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake.
Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process.
The resulting initial diluted JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2.
Step 2 – second (final) dilution
Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL JEVTANA is not exceeded. The concentration of the JEVTANA final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.
Fully prepared JEVTANA infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions.
Discard any unused portion.
AdministrationInspect visually for particulate matter, any crystals and discoloration prior to administration. If the JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.
Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.
The final JEVTANA infusion solution should be administered intravenously as a one-hour infusion at room temperature.
- Use the entire contentsof the accompanying diluent to achieve a concentration of 10 mg/mL JEVTANA. ()
2.5 Preparation and AdministrationJEVTANA is a hazardous anticancer drug. Follow applicable special handling and disposal procedures
[see References (15)]. If JEVTANA first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin or mucous, immediately and thoroughly wash with soap and water.Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of JEVTANA infusion solution.
JEVTANA should not be mixed with any other drugs.
PreparationRead this
entiresection carefully before mixing and diluting. JEVTANA requirestwodilutions prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to overdose[see Overdosage (10)].Note:Both the JEVTANA injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with theentire contentsof the accompanying diluent, there is an initial diluted solution containing 10 mg/mL JEVTANA.Inspect the JEVTANA injection and supplied diluent vials. The JEVTANA injection is a clear yellow to brownish-yellow viscous solution.
Step 1 – first dilution
Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the
entire contentsof supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake.
Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process.
The resulting initial diluted JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2.
Step 2 – second (final) dilution
Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL JEVTANA is not exceeded. The concentration of the JEVTANA final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.
Fully prepared JEVTANA infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions.
Discard any unused portion.
AdministrationInspect visually for particulate matter, any crystals and discoloration prior to administration. If the JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.
Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.
The final JEVTANA infusion solution should be administered intravenously as a one-hour infusion at room temperature.
- PVC equipment should not be used. ()
2.5 Preparation and AdministrationJEVTANA is a hazardous anticancer drug. Follow applicable special handling and disposal procedures
[see References (15)]. If JEVTANA first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin or mucous, immediately and thoroughly wash with soap and water.Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of JEVTANA infusion solution.
JEVTANA should not be mixed with any other drugs.
PreparationRead this
entiresection carefully before mixing and diluting. JEVTANA requirestwodilutions prior to administration. Follow the preparation instructions provided below, as improper preparation may lead to overdose[see Overdosage (10)].Note:Both the JEVTANA injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with theentire contentsof the accompanying diluent, there is an initial diluted solution containing 10 mg/mL JEVTANA.Inspect the JEVTANA injection and supplied diluent vials. The JEVTANA injection is a clear yellow to brownish-yellow viscous solution.
Step 1 – first dilution
Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the
entire contentsof supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake.
Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process.
The resulting initial diluted JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2.
Step 2 – second (final) dilution
Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL JEVTANA is not exceeded. The concentration of the JEVTANA final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.
As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.
Fully prepared JEVTANA infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions.
Discard any unused portion.
AdministrationInspect visually for particulate matter, any crystals and discoloration prior to administration. If the JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.
Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.
The final JEVTANA infusion solution should be administered intravenously as a one-hour infusion at room temperature.
- 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)
- H2 antagonist ()
2.1 Dosing InformationThe recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can 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/m2
[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),
- H2antagonist.
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
twodilutions prior to administration[see Dosage and Administration (2.5)].
)2.1 Dosing InformationThe recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m2administered 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/m2can 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/m2
[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),
- H2antagonist.
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
twodilutions prior to administration[see Dosage and Administration (2.5)]. - Dosage Modifications:See full prescribing information (,
2.2 Dose Modifications for Adverse ReactionsReduce 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/mm3, 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/mm3, 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/m2dose who require dose reduction should decrease dosage of JEVTANA to 15 mg/m2
[see Adverse Reactions (6.1)].Patients at a 25 mg/m2dose who require dose reduction should decrease dosage of JEVTANA to 20 mg/m2. One additional dose reduction to 15 mg/m2may 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): Administer JEVTANA at a dose of 20 mg/m2.
- Moderate hepatic impairment (total bilirubin >1.5 to ≤3 × ULN and AST = any): Administer JEVTANA at a dose of 15 mg/m2based on tolerability data in these patients; however, the efficacy of this dose is unknown.
- Severe hepatic impairment (total bilirubin >3 × ULN): JEVTANA is contraindicated in patients with severe hepatic impairment[see Warning and Precautions (5.8)and Clinical Pharmacology (12.3)].
)2.4 Dose Modifications for Use with Strong CYP3A InhibitorsConcomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel. Avoid the coadministration of JEVTANA with these drugs. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction
[see Drug Interactions (7.1)and Clinical Pharmacology (12.3)].
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
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
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 Cmaxin 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 Cmaxin 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 Cmaxapproximately 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.
JEVTANA is contraindicated in patients with:
- neutrophil counts of ≤1,500/mm3[see]
5.1 Bone Marrow SuppressionJEVTANA is contraindicated in patients with neutrophils ≤1,500/mm3
[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/m2)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/m2versus 25 mg/m2)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/m2arm and 15 patients (3%) on the 25 mg/m2arm died from infection; of these, 4 deaths on the 20 mg/m2arm and 8 deaths on the 25 mg/m2arm occurred within the first 30 days of treatment. Clinically important neutropenia-related events occurred and included febrile neutropenia (2.1% on 20 mg/m2arm and 9.2% on 25 mg/m2arm), neutropenic infection/sepsis (2.1% on 20 mg/m2arm and 6.4% on 25 mg/m2arm), and neutropenic deaths (0.3% on 20 mg/m2arm and 0.7% on 25 mg/m2arm).
Fewer patients receiving JEVTANA 20 mg/m2were reported to have infectious adverse reactions. Grade 1–4 infections were experienced by 160 patients (28%) on the 20 mg/m2arm and 227 patients (38%) on the 25 mg/m2arm. Grade 3–4 infections were experienced by 57 patients (10%) on the 20 mg/m2arm and 120 patients (20%) on the 25 mg/m2arm. Noninferiority for overall survival was demonstrated between these two arms
[see Adverse Reactions (6.1)].CARD Trial (JEVTANA 25 mg/m2+ primary prophylaxis G-CSF)In the CARD trial where JEVTANA 25 mg/m2was 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/m2.
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)]. - history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see]
5.3 Hypersensitivity ReactionsHypersensitivity reactions may occur within a few minutes following the initiation of the infusion of JEVTANA, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm.
Premedicate all patients prior to the initiation of the infusion of JEVTANA
[see Dosage and Administration (2.1)]. Observe patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and appropriate therapy. JEVTANA is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80[see Contraindications (4)]. - severe hepatic impairment (total bilirubin >3 × ULN) [see]
5.8 Use in Patients with Hepatic ImpairmentCabazitaxel is extensively metabolized in the liver.
JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN)
[see Contraindications (4)]. Dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) and moderate (total bilirubin >1.5 to ≤3.0 × ULN and any AST) hepatic impairment, based on tolerability data in these patients[see Dosage and Administration (2.3)and Use in Specific Populations (8.7)]. Administration of JEVTANA to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety.