ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in another section of the label:
- Neutropenia [see Warnings and Precautions].
- Hypersensitivity Reactions [see Warnings and Precautions].
- Gastrointestinal Symptoms [see Warnings and Precautions].
- Renal Failure [see Warnings and Precautions].
Clinical Trial 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.
The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized 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 14 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia.
The most common (≥ 5%) grade 34 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 2 Incidence of Reported Adverse ReactionsGraded using NCI CTCAE version 3 and Hematologic Abnormalities in ≥ 5% of Patients Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in Combination with Prednisone
|
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 |
|
Grade 14 n (%) |
Grade 34 n (%) |
Grade 14 n (%) |
Grade 34 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
|
ArrhythmiaIncludes atrial fibrillation, atrial flutter, atrial tachycardia, atrioventricular block complete, bradycardia, palpitations, supraventricular tachycardia, tachyarrhythmia, and tachycardia.
|
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 PainIncludes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and GI pain.
|
64 (17%) |
7 (2%) |
23 (6%) |
0 |
DyspepsiaIncludes gastroesophageal reflux disease and reflux gastritis.
|
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 InfectionIncludes urinary tract infection enterococcal and urinary tract infection fungal.
|
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 NeuropathyIncludes peripheral motor neuropathy and peripheral sensory neuropathy.
|
50 (13%) |
3 (< 1%) |
12 (3.2%) |
3 (< 1%) |
Dysgeusia |
41 (11%) |
0 |
15 (4%) |
0 |
Dizziness |
30 (8%) |
0 |
21 (6%) |
2 (< 1%) |
Headache |
28 (8%) |
0 |
19 (5%) |
0 |
Renal and Urinary Tract Disorders
|
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
|
Neutropenia and Associated Clinical Events:
Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. 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. The most common adverse reaction leading to treatment discontinuation in the JEVTANA group was neutropenia (2%).
Hematuria:
Adverse events 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.
Hepatic Laboratory Abnormalities:
The incidences of grade 34 increased AST, increased ALT, and increased bilirubin were each ≤ 1%.
Elderly Population:
The following grade 14 adverse reactions were reported at rates ≥ 5% higher in patients 65 years of age or greater compared to younger patients: fatigue (40% vs. 30%), neutropenia (97% vs. 89%), asthenia (24% vs. 15%), pyrexia (15% vs. 8%), dizziness (10% vs. 5%), urinary tract infection (10% vs. 3%) and dehydration (7% vs. 2%), respectively.
The incidence of the following grade 34 adverse reactions were higher in patients ≥ 65 years of age compared to younger patients; neutropenia (87% vs. 74%), and febrile neutropenia (8% vs. 6%) [see Use in Specific Populations].
|