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warnings
WARNINGS Patients undergoing craniotomy for malignant glioma and implantation of GLIADEL ® Wafer should be monitored closely for known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema. Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with GLIADEL ® Wafer, including one case leading to brain herniation. Pregnancy: There are no studies assessing the reproductive toxicity of GLIADEL ® Wafer. Carmustine, the active component of GLIADEL ® Wafer, can cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic and teratogenic in rats at i.p. doses of 0.5, 1, 2, 4, or 8 mg/kg/day when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 1/6 the recommended human dose (eight wafers of 7.7 mg carmustine/wafer) on a mg/m 2 basis). Carmustine was embryotoxic in rabbits at i.v. doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m 2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes. There are no studies of GLIADEL ® Wafer in pregnant women. If GLIADEL ® Wafer is used during pregnancy, or if the patient becomes pregnant after GLIADEL ® Wafer implantation, the patient must be warned of the potential hazard to the fetus.
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 Adverse Event GLIADEL ® Wafer [N=120] n (%) Placebo [N=120] 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). 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) 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 Body System Adverse Event GLIADEL ® Wafer with Carmustine [N=110] n (%) PLACEBO Wafer without Carmustine [N=112] n (%) *p < 0.05 for comparison of GLIADEL ® Wafer versus placebo groups 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) 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%)