8.0                            Safety Findings

 

8.1                            Methods

 

The bupropion sustained-release NDA integrated safety summary provided the foundation for the safety assessment which follows.  The Burroughs-Wellcome integrated safety database included data from Phase 2 and Phase 3 studies: the Phase 1 safety findings were considered separately.  the Phase 1 Clinical Pharmacology trials involved 131 subjects who received bupropion sustained-release.  The sponsor’s pooled Phase 2-3 integrated summary of safety database incorporates data from 928 patients who were exposed to bupropion sustained-release or placebo in studies 203 and 205, with the exception of 36 patients for whom no treatment phase assessments were available.  Of this group, 693 patients received bupropion sustained-release and 235 patients received placebo.  In addition, the sponsor performed a phase 3 study (Protocol 208) designed to measure seizure incidence.  This study consisted of an open-label trial of bupropion sustained-release in 3100 patients in a treatment phase for eight weeks, and in an optional continuation phase extending indefinitely beyond the eight weeks.

 

Safety issues were evaluated on the basis of these data sets and case report forms.  Uncommon, severe adverse events were assessed using premature discontinuations from clinical trials and “serious” adverse events (as defined below), while more common but less grave adverse reactions were identified through routinely collected safety data.  Treatment emergent changes in vital signs and clinical laboratory tests were examined and are described in section 8.5.  Section 8.6 contains a discussion of those adverse events deemed both significant and potentially drug-related.

 

8.2                            Deaths

 

None were reported from the pooled safety database from the placebo-controlled 203 and 205.  Six deaths did occur during the open trial (208): three due to suicide, one due to homicide, and two due to cardiac illness.  None of these deaths were considered attributable to bupropion sustained-release.  Patient 021-016 was a 75-year-old female who died of cardiac arrest 45 days after starting bupropion sustained-release.  She had a history of hypertension.  Patient 034-021 was a 39-year-old male who killed himself with a gun 11 days after discontinuing bupropion sustained-release prematurely, after having taken the medication for nine days total.  Patient 053-028 was a 32-year-old male who died of a multiple drug overdose, without ever having taken a single dose of bupropion sustained-release.  As of July 14, 1994, three patients had died in the continuation phase of the study.  Patient 045-015 was a 36-year-old female who killed herself with a gun after approximately three months of bupropion sustained-release intake.  Patient 074-013 was a 32-year-old male who was killed by a gunshot following an argument at his workplace after approximately twelve weeks of bupropion sustained-release intake.  Patient 078-066 was a 66-year-old male with a history of hypertension and hyperlipidemia who died of a presumed myocardial infarction after 130 days of bupropion sustained-release intake.  He had complained of chest pain to his primary physician six weeks before death.

 

8.3                            Assessment of Dropouts

 

8.3.1                       Overall Pattern of Dropouts

 

Table 8.3.1.1 summarizes reasons for premature discontinuation among patients who were randomly assigned to receive treatment under protocols 203 and 205.  Because 36 patients assigned to received treatment dropped out between point of randomization and first ingestion of medication, the total number of subjects in this table is larger by 36 than the number of subjects in the integrated summary of safety database.  This table was compiled by reviewing the reasons assigned by the individual investigators for each subject who dropped out.  In several cases where “Consent Withdrawn” was assigned by the investigator as a reason for withdrawal, but where the case reports or narrative case summaries suggested to this reviewer that “Lack of Efficacy” or “Adverse Experiences” better captured the reason for dropping out, one of the later two explanations was used in the table.

 

 

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