discontinued
participation because of an allergic reaction.
The divergence between incidence of allergic phenomena in drug- vs.
placebo-treated controls, and the previous description of allergic phenomena in
bupropion immediate-release-treated patients makes it likely that these adverse
events are directly related to bupropion sustained-release.
8.6.3
Anxious States
Six
patients (0.9% of 693 total bupropion sustained-release-treated patients) in
protocols 203 and 205 discontinued bupropion sustained-release due to anxious
phenomenona, including agitation, nervousness, anxiety, and panic attacks. In protocol 208, 43 patients (1.4% of 3100
bupropion sustained-treated patients) discontinued due to these anxious
phenomena. None of the 245 patients in
the placebo-treated groups of protocols 203 and 205 discontinued participation
because of an anxious state. Panic
attacks were also clearly associated as an adverse event with higher doses of
bupropion sustained-release. None of
the patients treated with placebo or doses of bupropion sustained-release less
than 200 mg/day experienced a panic attack in protocols 203 and 205. In contrast, the relative proportions of 200
mg/day, 300 mg/day, and 400 mg/day bupropion sustained-release-treated patients
experiencing panic attacks were 0.9% (1 of 115), 1.3% (3 of 229), and 1.8% (2
of 114), respectively. Panic attacks in
patients taking bupropion sustained-release in protocol 203 and 205 all
occurred between the 5th and 18th days of treatment and
were likely associated with increasing drug levels. (Two patients in protocol 208 experienced panic attacks: one
patient was on 100 mg/day bupropion sustained-release and experienced the
attack on the 4th day of treatment, the other was on 200 mg/day
bupropion sustained-release and experienced the attack on the 22nd
day of treatment). The divergence
between incidence of anxious phenomena in drug- vs. placebo-treated controls,
and the previous description of similar phenomena (bupropion
immediate-release-treated patients makes it likely that these adverse events
are directly related to bupropion sustained-release.
8.6.4
Theoretical Risk of Treatment-Emergent Mania
Although
mania was not reported as a treatment-emergent adverse effect of bupropion
sustained-release in any of the three protocols considered in this review,
antidepressants are considered to pose theoretical risks of inducing
mania. In the data concerning bupropion
immediate-release that supported NDA 18,644, “manic reaction” was noted as an
adverse event affecting 0.23% (3 of 1315) patients in the safety database for
that formulation. Placebo-treated
patients were noted as experiencing a similarly low rate (0 of 140) of
treatment-emergent mania in that NDA. A
recent report on the use of bupropion immediate-release in 11 patients with
bipolar disorder (Fogelson, Bystristsky, and Pasnau. J Clin Psychiatry
(1992) 53:443-446) noted that 6 of the patients experienced manic or hypomanic
episodes that necessitated discontinuation of the medication.
8.7
Summary of Important Adverse Events Considered Not Drug Related
During
clinical trials involving significant numbers of patients, serious untoward
events may occur incidentally. No
deaths occurred in the course of the controlled clinical trials for bupropion
sustained-release; six deaths that were probably not drug-related in protocol
208 were described in section 8.2.
Three serious events that were probably not drug-related occurred in
protocols 203 and 205 to subjects taking bupropion sustained-release: urinary
tract infection with prostatitis, cholelithiasis, and myocardial
infarction. The conclusion of lack of
causality between the myocardial infarction and bupropion sustained-release
treatment (patient 2045) is predicted upon the sponsor’s statement that
post-infarction catheterization documented the existence of pre-existing
coronary artery disease. In protocol
208 non-drug-related important events included nine patients with suicide
attempts or overdoses, eight patients with cardiac disease or events, six
patients with coincidental surgeries, four patients with infections, and three
patients with cerebrovascular disease or events. Two patients (008-004 and 022-032) who experienced seizures not
considered drug-related are referred to above in section 8.5.5. All treatment-emergent serious events from
protocols 203, 205, and 208 and that are considered to be unlikely to be
related to bupropion sustained-release are listed in Appendix 8.7.
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