JEVTANA SIDE EFFECTS
- Generic Name: cabazitaxel injection
- Brand Name: Jevtana
- Drug Class: Antineoplastics, Antimicrotubular
SIDE EFFECTS
The following serious adverse reactions are discussed in greater detail in another section of the label:
- Bone Marrow Suppression
- Increased Toxicities in Elderly Patients
- Hypersensitivity Reactions
- Gastrointestinal Adverse Reactions
- Renal Failure
- Urinary Disorders Including Cystitis
- Respiratory Disorders
- Use in Patients with Hepatic Impairment
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
TROPIC Trial (JEVTANA + Prednisone Compared To Mitoxantrone)
The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with metastatic castration-resistant prostate cancer treated in the randomized TROPIC trial, compared to mitoxantrone plus prednisone.
Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) JEVTANA-treated patients and 3 (<1%) mitoxantrone-treated patients. The most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.
The most common (≥10%) grade 1-4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia.
The most common (≥5%) grade 3-4 adverse reactions in patients who received JEVTANA were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.
Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received JEVTANA and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and renal failure. Dose reductions were reported in 12% of JEVTANA-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of JEVTANA-treated patients and 15% of mitoxantrone-treated patients.
Table 1: Incidence of Adverse Reactions* and Hematologic Abnormalities in ≥5% of Patients Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in Combination with Prednisone in TROPIC
| JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily n=371 |
Mitoxantrone 12 mg/m2 every 3 weeks with prednisone 10 mg daily n=371 |
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| Grade 1-4 n (%) |
Grade 3-4 n (%) |
Grade 1-4 n (%) |
Grade 3-4 n (%) |
|
| Any Adverse Reaction | ||||
| Blood and Lymphatic System Disorders | ||||
| Neutropenia† | 347 (94%) | 303 (82%) | 325 (87%) | 215 (58%) |
| Febrile Neutropenia | 27 (7%) | 27 (7%) | 5 (1%) | 5 (1%) |
| Anemia† | 361 (98%) | 39 (11%) | 302 (82%) | 18 (5%) |
| Leukopenia† | 355 (96%) | 253 (69%) | 343 (93%) | 157 (42%) |
| Thrombocytopenia† | 176 (48%) | 15 (4%) | 160 (43%) | 6 (2%) |
| Cardiac Disorders | ||||
| Arrhythmia‡ | 18 (5%) | 4 (1%) | 6 (2%) | 1 (<1%) |
| Gastrointestinal Disorders | ||||
| Diarrhea | 173 (47%) | 23 (6%) | 39 (11%) | 1 (<1%) |
| Nausea | 127 (34%) | 7 (2%) | 85 (23%) | 1 (<1%) |
| Vomiting | 83 (22%) | 6 (2%) | 38 (10%) | 0 |
| Constipation | 76 (20%) | 4 (1%) | 57 (15%) | 2 (<1%) |
| Abdominal Pain§ | 64 (17%) | 7 (2%) | 23 (6%) | 0 |
| Dyspepsia¶ | 36 (10%) | 0 | 9 (2%) | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 136 (37%) | 18 (5%) | 102 (27%) | 11 (3%) |
| Asthenia | 76 (20%) | 17 (5%) | 46 (12%) | 9 (2%) |
| Pyrexia | 45 (12%) | 4 (1%) | 23 (6%) | 1 (<1%) |
| Peripheral Edema | 34 (9%) | 2 (<1%) | 34 (9%) | 2 (<1%) |
| Mucosal Inflammation | 22 (6%) | 1 (<1%) | 10 (3%) | 1 (<1%) |
| Pain | 20 (5%) | 4 (1%) | 18 (5%) | 7 (2%) |
| Infections and Infestations | ||||
| Urinary Tract Infection# | 29 (8%) | 6 (2%) | 12 (3%) | 4 (1%) |
| Investigations | ||||
| Weight Decreased | 32 (9%) | 0 | 28 (8%) | 1 (<1%) |
| Metabolism and Nutrition Disorders | ||||
| Anorexia | 59 (16%) | 3 (<1%) | 39 (11%) | 3 (<1%) |
| Dehydration | 18 (5%) | 8 (2%) | 10 (3%) | 3 (<1%) |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Back Pain | 60 (16%) | 14 (4%) | 45 (12%) | 11 (3%) |
| Arthralgia | 39 (11%) | 4 (1%) | 31 (8%) | 4 (1%) |
| Muscle Spasms | 27 (7%) | 0 | 10 (3%) | 0 |
| Nervous System Disorders | ||||
| Peripheral NeuropathyÞ | 50 (13%) | 3 (<1%) | 12 (3%) | 3 (<1%) |
| Dysgeusia | 41 (11%) | 0 | 15 (4%) | 0 |
| Dizziness | 30 (8%) | 0 | 21 (6%) | 2 (<1%) |
| Headache | 28 (8%) | 0 | 19 (5%) | 0 |
| Hematuria | 62 (17%) | 7 (2%) | 13 (4%) | 1 (<1%) |
| Dysuria | 25 (7%) | 0 | 5 (1%) | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Dyspnea | 43 (12%) | 4 (1%) | 16 (4%) | 2 (<1%) |
| Cough | 40 (11%) | 0 | 22 (6%) | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Alopecia | 37 (10%) | 0 | 18 (5%) | 0 |
| Vascular Disorders | ||||
| Hypotension | 20 (5%) | 2 (<1 %) | 9 (2%) | 1 (<1%) |
| Median Duration of Treatment | 6 cycles | 4 cycles | ||
| * Graded using NCI CTCAE version 3. † Based on laboratory values, JEVTANA: n=369, mitoxantrone: n=370. ‡ Includes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia, palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia. § Includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain. ¶ Includes gastroesophageal reflux disease and reflux gastritis. # Includes urinary tract infection enterococcal and urinary tract infection fungal. Þ Includes peripheral motor neuropathy and peripheral sensory neuropathy. |
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PROSELICA Trial (Comparison Of Two Doses Of JEVTANA)
In a noninferiority, multicenter, randomized, open-label study (PROSELICA), 1175 patients with metastatic castration-resistant prostate cancer, previously treated with a docetaxel-containing regimen, were treated with either JEVTANA 25 mg/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/m2 and 32 (5.4%) patients in the 25 mg/m2 arm. The most common fatal adverse reactions in JEVTANA-treated patients were related to infections, and these occurred more commonly on the 25 mg/m2 arm (n=15) than on the 20 mg/m2 arm (n=8). Other fatal adverse reactions in JEVTANA-treated patients included cerebral hemorrhage, respiratory failure, paralytic ileus, diarrhea, acute pulmonary edema, disseminated intravascular coagulation, renal failure, sudden death, cardiac arrest, ischemic stroke, diverticular perforation, and cardiorenal syndrome.
Grade 1-4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2 arms were leukopenia, neutropenia, thrombocytopenia, febrile neutropenia, decreased appetite, nausea, diarrhea, asthenia, and hematuria.
Grade 3-4 adverse reactions occurring ≥5% more commonly in patients on the 25 mg/m2 versus 20 mg/m2 arms were leukopenia, neutropenia, and febrile neutropenia.
Treatment discontinuations due to adverse drug reactions occurred in 17% of patients in the 20 mg/m2 group and 20% of patients in the 25 mg/m2 group. The most common adverse reactions leading to treatment discontinuation were fatigue and hematuria. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 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/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 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.
Table 2: Incidence of Adverse Reactions* in ≥5% of Patients Receiving JEVTANA 20 mg/m2 or 25 mg/m2 in Combination with Prednisone in PROSELICA
| JEVTANA 20 mg/m2 every 3 weeks with prednisone 10 mg daily n=580 |
JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily n=595 |
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| Primary System Organ Class Preferred Term | Grade 1-4 n (%) |
Grade 3-4 n (%) |
Grade 1-4 n (%) |
Grade 3-4 n (%) |
| Blood and Lymphatic System Disorders | ||||
| Febrile Neutropenia | 12 (2%) | 12 (2%) | 55 (9%) | 55 (9%) |
| Neutropenia† | 18 (3%) | 14 (2%) | 65 (11%) | 57 (10%) |
| Infections and Infestations | ||||
| Urinary tract infection‡ | 43 (7%) | 12 (2%) | 66 (11%) | 14 (2%) |
| Neutropenic infection§ | 15 (3%) | 13 (2%) | 42 (7%) | 36 (6%) |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 76 (13%) | 4 (0.7%) | 110 (19%) | 7 (1%) |
| Nervous System Disorders | ||||
| Dysgeusia | 41 (7%) | 0 | 63 (11%) | 0 |
| Peripheral sensory neuropathy | 38 (7%) | 0 | 63 (11%) | 4 (0.7%) |
| Dizziness | 24 (4%) | 0 | 32 (5%) | 0 |
| Headache | 29 (5%) | 1 (0.2%) | 24 (4%) | 1 (0.2%) |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Dyspnea | 30 (5%) | 5 (0.9%) | 46 (8%) | 4 (0.7%) |
| Cough | 34 (6%) | 0 | 35 (6%) | 0 |
| Gastrointestinal Disorders | ||||
| Diarrhea | 178 (31%) | 8 (1%) | 237 (40%) | 24 (4%) |
| Nausea | 142 (25%) | 4 (0.7%) | 191 (32%) | 7 (1%) |
| Vomiting | 84 (15%) | 7 (1.2%) | 108 (18 %) | 8 (1%) |
| Constipation | 102 (18%) | 2 (0.3%) | 107 (18%) | 4 (0.7%) |
| Abdominal pain | 34 (6%) | 3 (0.5%) | 52 (9%) | 7 (1%) |
| Stomatitis | 27 (5%) | 0 | 30 (5%) | 2 (0.3%) |
| Skin and Subcutaneous Tissue Disorders | ||||
| Alopecia | 15 (3%) | 0 | 36 (6.1%) | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Back pain | 64 (11%) | 5 (0.9%) | 83 (14%) | 7 (1%) |
| Bone pain | 46 (8%) | 10 (2%) | 50 (8%) | 13 (2 %) |
| Arthralgia | 49 (8%) | 3 (0.5%) | 41 (7%) | 5 (0.8%) |
| Pain in extremity | 30 (5%) | 1 (0.2%) | 41 (7%) | 3 (0.5%) |
| Renal and Urinary Disorders | ||||
| Hematuria | 82 (14%) | 11 (2%) | 124 (21%) | 25 (4%) |
| Dysuria | 31 (5%) | 2 (0.3%) | 24 (4%) | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 143 (25%) | 15 (3%) | 161 (27%) | 22 (4%) |
| Asthenia | 89 (15%) | 11 (2%) | 117 (20%) | 12 (2%) |
| Edema peripheral | 39 (7%) | 1 (0.2%) | 53 (9%) | 1 (0.2%) |
| Pyrexia | 27 (5%) | 1 (0.2%) | 38 (6 %) | 1 (0.2%) |
| Investigations | ||||
| Weight decreased | 24 (4%) | 1 (0.2%) | 44 (7%) | 0 |
| Injury, Poisoning and Procedural Complications | ||||
| Wrong technique in drug usage process | 2 (0.3%) | 0 | 32 (5%) | 0 |
| * Grade from NCI CTCAE version 4.03. † Based on adverse event reporting. ‡ Includes urinary tract infection staphylococcal, urinary tract infection bacterial, urinary tract infection fungal, and urosepsis. § Includes neutropenic sepsis. |
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Table 3: Incidence of Hematologic Laboratory Abnormalities in Patients Receiving JEVTANA 20 mg/m2 or 25 mg/m2 in Combination with Prednisone in Study PROSELICA
| Laboratory Abnormality | JEVTANA 20 mg/m2 every 3 weeks with prednisone 10 mg daily n=577 |
JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily n=590 |
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| Grade 1-4 n (%) |
Grade 3-4 n (%) |
Grade 1-4 n (%) |
Grade 3-4 n (%) |
|
| Neutropenia | 384 (67%) | 241 (42%) | 522 (89%) | 432 (73%) |
| Anemia | 576 (99.8%) | 57 (10%) | 588 (99.7%) | 81 (14%) |
| Leukopenia | 461 (80%) | 167 (29%) | 560 (95%) | 351 (60%) |
| Thrombocytopenia | 202 (35%) | 15 (3%) | 251 (43%) | 25 (4%) |
Hematuria
In study TROPIC, adverse reactions of hematuria, including those requiring medical intervention, were more common in JEVTANA-treated patients. The incidence of grade ≥2 hematuria was 6% in JEVTANA-treated patients and 2% in mitoxantrone-treated patients. Other factors associated with hematuria were well-balanced between arms and do not account for the increased rate of hematuria on the JEVTANA arm.
In study PROSELICA, hematuria of all grades was observed in 18% of patients overall.
Hepatic Laboratory Abnormalities
The incidences of grade 3-4 increased AST, increased ALT, and increased bilirubin were each ≤1%.
Postmarketing Experience
The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Gastrointestinal: Gastritis, intestinal obstruction.
Respiratory: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome.
Renal and urinary disorders: Radiation recall hemorrhagic cystitis.
SRC: NLM .