Adverse reactions : תופעות לוואי

6   ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in another section of the label:
•   Bone Marrow Suppression [see Warnings and Precautions (5.1)].
•   Increased Toxicities in Elderly Patients [see Warnings and Precautions (5.2)].
•   Hypersensitivity Reactions [see Warnings and Precautions (5.3)].

•   Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.4)].
•   Renal Failure [see Warnings and Precautions (5.5)].
•   Urinary Disorders Including Cystitis [see Warnings and Precautions (5.6)].
•   Respiratory Disorders [see Warnings and Precautions (5.7)].
•   Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.8)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
TROPIC Trial (JEVTANA + 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 2: 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       Mitoxantrone 12 mg/m2 every 3 with prednisone 10 mg daily      weeks with prednisone 10 mg daily n=371                               n=371
Grade 1-4           Grade 3-4      Grade 1-4          Grade 3-4 n (%)              n (%)          n (%)              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 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                             6 cycles                                 4 cycles Treatment

*
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.


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 3: 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      JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily         with prednisone 10 mg daily n=580                               n=595
Primary System Organ
Grade 1-4          Grade 3-4        Grade 1-4       Grade 3-4
Class n (%)              n (%)            n (%)           n (%)
Preferred Term
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
38 (7%)                  0         63 (11%)         4 (0.7%) neuropathy
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%) 
JEVTANA 20 mg/m2 every 3 weeks               JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily                  with prednisone 10 mg daily n=580                                        n=595
Primary System Organ
Grade 1-4              Grade 3-4             Grade 1-4              Grade 3-4 Class n (%)                  n (%)                 n (%)                  n (%) Preferred Term
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
2 (0.3%)                   0                 32 (5%)                   0 usage process
* 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.


Table 4: Incidence of Hematologic Laboratory Abnormalities in Patients Receiving JEVTANA 20 mg/m2 or 25 mg/m2 in Combination with Prednisone in Study PROSELICA JEVTANA 20 mg/m2 every 3 weeks       JEVTANA 25 mg/m2 every 3 weeks with prednisone 10 mg daily          with prednisone 10 mg daily n=577                                n=590
Laboratory                Grade 1-4          Grade 3-4        Grade 1-4          Grade 3-4 Abnormality                n (%)              n (%)            n (%)              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%.
6.2 Postmarketing Experience
The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Gastrointestinal: Gastritis, intestinal obstruction.
Respiratory: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome.
Renal and urinary disorders: Radiation recall hemorrhagic cystitis.
Reporting suspected adverse reactions after authorization of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/