Adverse reactions : תופעות לוואי

ADVERSE REACTIONS
Adverse reactions for the trials are described in the tables below.

Primary Surgery
The following data are the most frequently occurring adverse events observed in 5% or more of the newly-diagnosed malignant glioma patients during the trial.



COMMON ADVERSE EVENTS OBSERVED IN > 5% OF PATIENTS
RECEIVING GLIADEL WAFER AT INITIAL SURGERY
Body System                             GLIADEL® Wafer N=120   Placebo N=120 Adverse event                           n (%)               n (%)

Body as a whole
Aggravation reaction*                  98 (82)            95 (79)
Headache                               33 (28)            44 (37)
Asthenia                               26 (22)            18 (15)
Infection                              22 (18)            24 (20)
Fever                                  21 (18)            21 (18)
Pain                                   16 (13)            18 (15)
Abdominal pain                          10 (8)             2 (2)
Back pain                                8 (7)             4 (3)
Face edema                               7 (6)             6 (5)
Abscess                                  6 (5)             3 (3)
Accidental injury                        6 (5)             8 (7)
Chest pain                               6 (5)               0
Allergic reaction                        2 (2)             6 (5)

Cardiovascular system
Deep thrombophlebitis                   12 (10)             11 (9)
Pulmonary embolus                        10 (8)             10 (8)
Hemorrhage                                8 (7)              7 (6)
Digestive system
Nausea                                 26 (22)            20 (17)
Vomiting                               25 (21)            19 (16)
Constipation                           23 (19)            14 (12)
Diarrhea                                6 (5)              5 (4)
Liver function tests abnormal           1 (1)              6 (5)

Endocrine system
Diabetes mellitus                        6 (5)              5 (4)
Cushings syndrome                        4 (3)              6 (5)

Metabolic and nutritional disorders
Healing abnormal                        19 (16)            14 (12)
Peripheral edema                         11 (9)             11 (9)
Musculoskeletal system
Myasthenia                               5 (4)              6 (5)

Nervous system
Hemiplegia                              49 (41)            53 (44)
Convulsion                              40 (33)            45 (38)
Confusion                               28 (23)            25 (21)
Brain edema                             27 (23)            23 (19)
Aphasia                                 21 (18)            22 (18)
Depression                              19 (16)            12 (10)
Somnolence                              13 (11)            18 (15)
Speech disorder                         13 (11)             10 (8)
Amnesia                                  11 (9)            12 (10)



COMMON ADVERSE EVENTS OBSERVED IN > 5% OF PATIENTS
RECEIVING GLIADEL WAFER AT INITIAL SURGERY
Body System                               GLIADEL® Wafer N=120        Placebo N=120 Adverse event                             n (%)                    n (%) *Adverse events coded to the COSTART term “aggravation reaction” were usually events involving tumor/disease progression or general deterioration of condition (e.g.
condition/health/Karnofsky/neurological/physical deterioration).


Nervous system (continued)
Intracranial hypertension                  11 (9)                    2 (2) Personality disorder                       10 (8)                    9 (8) Anxiety                                     8 (7)                    5 (4) Facial paralysis                            8 (7)                    5 (4) Neuropathy                                  8 (7)                  12 (10) Ataxia                                      7 (6)                    5 (4) Hypesthesia                                 7 (6)                    6 (5) Paresthesia                                 7 (6)                   10 (8) Thinking abnormal                           7 (6)                   10 (8) Abnormal gait                               6 (5)                    6 (5) Dizziness                                   6 (5)                   11 (9) Grand mal convulsion                        6 (5)                    5 (4) Hallucinations                              6 (5)                    4 (3) Insomnia                                    6 (5)                    7 (6) Tremor                                      6 (5)                    8 (7) Coma                                        5 (4)                    6 (5) Incoordination                              3 (3)                    8 (7) Hypokinesia                                 2 (2)                    8 (7) 
Respiratory system
Pneumonia                                 10 (8)                   9 (8) Dyspnea                                    4 (3)                   8 (7) 
Skin and appendages
Rash                                      14 (12)                 13 (11) Alopecia                                  12 (10)                 14 (12) 
Special senses
Conjunctival edema                        8 (7)                   8 (7) Abnormal vision                           7 (6)                   7 (6) Visual field defect                       6 (5)                   8 (7) Eye disorder                              3 (3)                   6 (5) Diplopia                                  1 (1)                   6 (5) 
Urogenital system
Urinary tract infection                    10 (8)                  13 (11) Urinary incontinence                        9 (8)                   9 (8) 


Surgery for Recurrent Disease
The following post-operative adverse events were observed in 4% or more of the patients receiving GLIADEL Wafer at recurrent surgery. Except for nervous system effects, where there is a possibility that the placebo wafers could have been responsible, only events more common in the GLIADEL Wafer group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.


COMMON ADVERSE EVENTS OBSERVED IN >4% OF PATIENTS
RECEIVING GLIADEL WAFER AT SURGERY FOR RECURRENT DISEASE
GLIADEL Wafer          PLACEBO Wafer with Carmustine        without Carmustine
Body System                                       [N=110]                 [N=112] Adverse Event                               n (%)                   n (%) 
Body as a Whole
Fever                                     13 (12)                  9 (8) Pain*                                      8 (7)                   1 (1) 
Digestive System
Nausea and Vomiting                        9 (8)                   7 (6) 
Metabolic and Nutritional Disorders
Healing Abnormal*                          15 (14)                  6 (5) 
Nervous System
Convulsion                                 21 (19)                 21 (19) Hemiplegia                                 21 (19)                 22 (20) Headache                                   16 (15)                 14 (13) Somnolence                                 15 (14)                 12 (11) Confusion                                  11 (10)                  9 (8) Aphasia                                     10 (9)                 12 (11) Stupor                                       7 (6)                  7 (6) Brain Edema                                  4 (4)                  1 (1) Intracranial Hypertension                    4 (4)                  7 (6) Meningitis or Abscess                        4 (4)                  1 (1) Skin and Appendages
Rash                                       6 (5)                   4 (4) 
Urogenital System
Urinary Tract Infection                    23 (21)                 19 (17) 
*p < 0.05 for comparison of GLIADEL Wafer versus placebo groups

Post-marketing experience includes spontaneous reports of cyst formation after Gliadel ®wafer implantation. These occurred at varying time intervals post-implantation.
Cyst formation has also been reported in patients following resection of malignant glioma who have not had Gliadel® implanted.

The following four categories of adverse events are possibly related to treatment with GLIADEL Wafer. The frequency with which they occurred in the randomized trials along with descriptive detail is provided below.
1. Seizures: In the initial surgery trial, the incidence of seizures was 33.3% in patients receiving GLIADEL Wafer and 37.5% in patients receiving placebo. Grand mal seizures occurred in 5% of GLIADEL Wafer-treated patients and 4.2% of placebo treated patients.
The incidence of seizures within the first 5 days after wafer implantation was 2.5% in the GLIADEL Wafer group and 4.2% in the placebo group. The time from surgery to the onset of the first post-operative seizure did not differ between the GLIADEL Wafer and placebo treated patients.

In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in both patients receiving GLIADEL Wafer and placebo. In this study, 12/22 (54%) of patients treated with GLIADEL Wafer and 2/22 (9%) of placebo patients experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL Wafer and 61 days in placebo patients.

2. Brain Edema: In the initial surgery trial, brain edema was noted in 22.5% of patients treated with GLIADEL Wafer and in 19.2% of patients treated with placebo.
Development of brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of GLIADEL Wafer or its remnants.

3. Healing Abnormalities: The following healing abnormalities have been reported in clinical trials of GLIADEL Wafer: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak. In the initial surgery trial, healing abnormalities occurred in 15.8% of GLIADEL Wafer treated patients and in 11.7% of placebo recipients. Cerebrospinal fluid leaks occurred in 5% of GLIADEL Wafer recipients and 0.8% of those given placebo. During surgery, a water-tight dural closure should be obtained to minimize the risk of cerebrospinal fluid leak.

In the surgery for recurrent disease trial, the incidence of healing abnormalities was 14% in GLIADEL Wafer treated patients and 5% in patients receiving placebo wafers.

4. Intracranial Infection: In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL Wafer and 6% in patients receiving placebo. In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL Wafer and 1% in patients receiving placebo.

The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with GLIADEL Wafer in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL Wafer caused these events cannot be determined.



Body as a Whole: peripheral edema (2%); neck pain (2%); accidental injury (1%); back pain (1%); allergic reaction (1%); asthenia (1%); chest pain (1%); sepsis (1%) 
Cardiovascular System: hypertension (3%); hypotension (1%)

Digestive System: diarrhea (2%); constipation (2%); dysphagia (1%); gastrointestinal hemorrhage (1%); fecal incontinence (1%)

Hemic and Lymphatic System: thrombocytopenia (1%); leukocytosis (1%) 
Metabolic and Nutritional Disorders: hyponatremia (3%); hyperglycemia (3%); hypokalemia (1%)

Musculoskeletal System: infection (1%)

Nervous System: hydrocephalus (3%); depression (3%); abnormal thinking (2%); ataxia (2%); dizziness (2%); insomnia (2%); monoplegia (2%); coma (1%); amnesia (1%); diplopia (1%); paranoid reaction (1%). In addition, cerebral hemorrhage and cerebral infarct were each reported in less than 1% of patients treated with GLIADEL Wafer.

Respiratory System: infection (2%); aspiration pneumonia (1%)

Skin and Appendages: rash (2%)
Special Senses: visual field defect (2%); eye pain (1%)

Urogenital System: urinary incontinence (2%)