·         Prior treatment with any form of bupropion;

·         History or current diagnosis of bulimia or anorexia nervosa;

·         Known predisposition to seizure (e.g., history of seizure, significant head trauma, family history of idiopathic seizure disorder, concurrent treatment with medication that lowered seizure threshold, or clinical history of alcohol or substance abuse within the last year);

·         Receipt of any neuroleptic or antidepressant within one week of treatment phase (two weeks for MAOI’s, clemipramine, maprotiline, or protyiptyline, and four weeks for fluoxetine);

·         Unstable medical disorder or a disorder that would interfere with the pharmacokinetics of bupropion, or interfere with the accurate assessment of depression;

·         Pregnancy, lactation, or unwillingness to employ contraceptive methods acceptable to the investigator during the study (females only);

·         Active suicidality.

 

 

During the eight-week treatment phase of the study, bupropion sustained-release in doses up to 300 mg/day was associated with an observed seizure rate of 0.06% (2/3094) with an upper one-sided 95% confidence limit of 0.14%.  Including patients who remained in the continuation phase of the study beyond the eight-week standard treatment who remained in the continuation phase of the study beyond the eight-week standard treatment period, bupropion sustained-release in doses up to 300 mg/day was associated with an observed seizure rate of 0.10% (3/3094) with an upper one-sided 95% confidence limit of 0.19%.  A survival analysis of the 2958 patients in the 100-300 mg cohort population yielded a cumulative seizure rate of 0.08% with an upper one-sided 95% confidence limit of 0.18% for the treatment phase.

 

Fifty-one of the 2958 patients in the 100–300 mg cohort experienced an adverse event that the sponsor termed “serious” of which seven were considered to be possibly or reasonably attributable to bupropion sustained-release: three patients had generalized convulsive seizures, two patients experienced panic attacks, one patient experienced hypersomnolence, and one patient experienced facial edema consistent with an allergic reaction.  All three of the patients who had seizures possibly or reasonably attributable to bupropion sustained-release were males between the ages of 43 and 49 years old; patient 011-004 had a history of alcohol dependence and had been drinking alcohol prior to a seizure on the 54^th day of treatment; patient 073-024 had a past history of alcohol abuse and experienced a seizure on the third day of treatment at 100 mg/day; and patient 054-004 was

 

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