The most commonly observed adverse events associated with the use of ZONEGRAN in controlled clinical trials that were not seen at an equivalent frequency among placebo-treated patients were somnolence, anorexia, dizziness, headache, nausea, and agitation/irritability.
In controlled clinical trials, 12% of patients receiving ZONEGRAN as adjunctive therapy discontinued due to an adverse event compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received ZONEGRAN in clinical studies discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse events were dose-related (see WARNINGS and PRECAUTIONS).
Adverse Event Incidence in Controlled Clinical Trials
Table 3 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with ZONEGRAN in controlled clinical trials that were numerically more common in the ZONEGRAN group. In these studies, either ZONEGRAN or placebo was added to the patient's current AED therapy. Adverse events were usually mild or moderate in intensity.
The prescriber should be aware that these figures, obtained when ZONEGRAN was added to concurrent AED therapy, cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
Table 3. Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Trials (Events that occurred in at least 2% of ZONEGRAN-treated patients and occurred more frequently in ZONEGRAN-treated than placebo-treated patients)
|BODY SYSTEM/PREFERRED TERM||ZONEGRAN(n=269)|
| BODY AS A WHOLE |
|Headache ||10 ||8 |
|Abdominal Pain ||6 ||3 |
|Flu Syndrome ||4 ||3 |
| DIGESTIVE |
|Anorexia ||13 ||6 |
|Nausea ||9 ||6 |
|Diarrhea ||5 ||2 |
|Dyspepsia ||3 ||1 |
|Constipation ||2 ||1 |
|Dry Mouth ||2 ||1 |
| HEMATOLOGIS AND LYMPHATIC |
|Ecchymosis ||2 ||1 |
| METABOLIC AND NUTRITIONAL |
|Weight Loss ||3 ||2 |
| NERVOUS SYSTEM |
|Dizziness ||13 ||7 |
|Ataxia ||6 ||1 |
|Nystagmus ||4 ||2 |
|Paresthesia ||4 ||1 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-ALTERED COGNITIVE FUNCTION |
|Confusion ||6 ||3 |
|Difficulty Concentrating ||6 ||2 |
|Difficulty with Memory ||6 ||2 |
|Mental Slowing ||4 ||2 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-BEHAVIORAL ABNORMALITIES (NON-PYSCHOSIS-RELATED) |
|Agitation/Irritability ||9 ||4 |
|Depression ||6 ||3 |
|Insomnia ||6 ||3 |
|Anxiety ||3 ||2 |
|Nervousness ||2 ||1 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-BEHAVIORAL ABNORMALITIES (PYSCHOSIS-RELATED) |
|Schizophrenic/Schizophreniform Behavior ||2 ||0 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-CNS DEPRESSION |
|Somnolence ||17 ||7 |
|Fatigue ||8 ||6 |
|Tiredness ||7 ||5 |
| NEUROPSYCHIATRIC AND COGNITIVE DYSFUNCTION-SPEECH AND LANGUAGE ABNORMALITIES |
|Speech Abnormalities ||5 ||2 |
|Difficulties in Verbal Expression ||2 ||<1 |
| RESPIRATORY |
|Rhinitis ||2 ||1 |
| SKIN AND APPENDAGES |
|Rash ||3 ||2 |
| SPECIAL SENSES |
|Diplopia ||6 ||3 |
Other Adverse Events Observed During Clinical Trials
ZONEGRAN has been administered to 1,598 individuals during all clinical trials, only some of which were placebo-controlled. During these trials, all events were recorded by the investigators using their own terms. To provide a useful estimate of the proportion of individuals having adverse events, similar events have been grouped into a smaller number of standardized categories using a modified COSTART dictionary. The frequencies represent the proportion of the 1,598 individuals exposed to ZONEGRAN who experienced an event on at least one occasion. All events are included except those already listed in the previous table or discussed in WARNINGS or PRECAUTIONS, trivial events, those too general to be informative, and those not reasonably associated with ZONEGRAN.
Events are further classified within each category and listed in order of decreasing frequency as follows: frequent occurring in at least 1:100 patient; infrequent occurring in 1:100 to 1:1000 patients; rare occurring in fewer than 1:1000 patients.
Body as a Whole: Frequent: Accidental injury, asthenia. Infrequent: Chest pain, flank pain, malaise, allergic reaction, face edema, neck rigidity. Rare: Lupus erythematosus.
Cardiovascular: Infrequent: Palpitation, tachycardia, vascular insufficiency, hypotension, hypertension, thrombophlebitis, syncope, bradycardia. Rare: Atrial fibrillation, heart failure, pulmonary embolus, ventricular extrasystoles.
Digestive: Frequent: Vomiting. Infrequent: Flatulence, gingivitis, gum hyperplasia, gastritis, gastroenteritis, stomatitis, cholelithiasis, glossitis, melena, rectal hemorrhage, ulcerative stomatitis, gastro-duodenal ulcer, dysphagia, gum hemorrhage. Rare: Cholangitis, hematemesis, cholecystitis, cholestatic jaundice, colitis, duodenitis, esophagitis, fecal incontinence, mouth ulceration.
Hematologic and Lymphatic: Infrequent: Leukopenia, anemia, immunodeficiency, lymphadenopathy. Rare: Thrombocytopenia, microcytic anemia, petechia.
Metabolic and Nutritional: Infrequent: Peripheral edema, weight gain, edema, thirst, dehydration. Rare: Hypoglycemia, hyponatremia, lactic dehydrogenase increased, SGOT increased, SGPT increased.
Musculoskeletal: Infrequent: Leg cramps, myalgia, myasthenia, arthralgia, arthritis.
Nervous System: Frequent: Tremor, convulsion, abnormal gait, hyperesthesia, incoordination. Infrequent: Hypertonia, twitching, abnormal dreams, vertigo, libido decreased, neuropathy, hyperkinesia, movement disorder, dysarthria, cerebrovascular accident, hypotonia, peripheral neuritis, parathesia, reflexes increased. Rare: Circumoral paresthesia, dyskinesia, dystonia, encephalopathy, facial paralysis, hypokinesia, hyperesthesia, myoclonus, oculogyric crisis.
Behavioral Abnormalities —Non-Psychosis-Related: Infrequent: Euphoria.
Respiratory: Frequent: Pharyngitis, cough increased. Infrequent: Dyspnea. Rare: Apnea, hemoptysis.
Skin and Appendages: Frequent: Pruritus. Infrequent: Maculopapular rash, acne, alopecia, dry skin, sweating, eczema, urticaria, hirsutism, pustular rash, vesiculobullous rash.
Special Senses: Frequent: Amblyopia, tinnitus. Infrequent: Conjunctivitis, parosmia, deafness, visual field defect, glaucoma. Rare: Photophobia, iritis.
Urogenital: Infrequent: Urinary frequency, dysuria, urinary incontinence, hematuria, impotence, urinary retention, urinary urgency, amenorrhea, polyuria, nocturia. Rare: Albuminuria, enuresis, bladder pain, bladder calculus, gynecomastia, mastitis, menorrhagia.