In
the placebo-controlled studies, there was a dose-dependent association between
medication-intake and risk of allergic event causing discontinuation: allergic
events occurred in 1 of 115 patients (0.9%) who received 100 mg/d bupropion
sustained-release, in 4 of 235 patients (1.7%) who received 150 to 200 mg/d of
bupropion sustained-release, and in 13 of 343 (3.8%) patients who received 300
mg/d or more of bupropion sustained-release.
It
should be noted that the above profile of adverse events leading to study
discontinuation is similar to that established in the initial product
development of bupropion immediate-release.
In that form of the drug, the more common events causing discontinuation
were neuropsychiatric disturbances (3.0%) (primarily agitation and abnormal
mental status), digestive tract disorders (2.1%) (primarily nausea and
vomiting), neurological disturbances (1.7%) (primarily seizures, headaches, and
sleep disturbances), and dermatological problems (1.4%) (primarily rashes). The similar profiles are seen despite use of
lower total levels of drug and, presumably, fewer fluctuations of blood level
of bupropion in the bupropion sustained-release trials.
8.4
Safety Findings Discovered with Other Specific Search Strategies/Search
for Serious Events
The
sponsor conducted a manual search of the available clinical data from the two
Phase 2-3 placebo-controlled studies for events that it considered “serious.” The criteria for “serious” were fatal,
life-threatening, permanently disabling, requiring or prolonging
hospitalization, congenital abnormality, overdose, cancer, other – as determined
by the investigators. Six such events
were identified in the placebo-controlled trials. Four of these occurred in subjects who received bupropion
sustained-release and two occurred in subjects receiving placebo. Attribution of cause of serious events was
left at the discretion of the individual investigators. None of the adverse events was attributed to
the medication by the sponsor. In
patients #2043 of protocol 205, however, the development of a severe “stomach
flu” with nausea, vomiting, diarrhea, and dehydration requiring hospitalization
within six days of commencing intake of bupropion sustained-release – which is
associated with nausea and vomiting – in this reviewer’s opinion may have been
associated with the drug. In patient
#2045, “cramp-like” chest pain began within two days after commencing intake of
bupropion sustained-release and persisted for three days. An EKG the day after the pain resolved was
negative. Chest pain did not recur
until six weeks further into the study; at that time it evolved into a
myocardial infarction. Although the
case report form for this subject makes no mention of underlying disease, the
summary table in the sponsor’s integrated safety summary records that coronary
artery disease was found to be present in this patient in this patient at
post-MI catheterization. No patient
taking the medication overdosed or attempted suicide during the course of the
controlled studies. Although seizure
incidence was a major concern with the immediate-release form of bupropion, no
patient experienced a seizure during the course of the placebo-controlled
studies of bupropion sustained-release.
An
additional 55 serious events were noted as of July 14, 1994 as having occurred
during the course of open bupropion sustained-release trial 208. Seven of these were considered by the
sponsor as being possibly or reasonably attributable to bupropion
sustained-release: three patients experienced seizures, two patients
experienced panic attacks, one patient experienced facial edema consistent with
an allergic response, and one patient experienced severe somnolence. Ten patients experienced serious suicidal ideation,
overdosed, or otherwise attempted suicide.
Eight patients experienced angina pectoris or a myocardial infarction.
All
events that the sponsor categorized as serious that were thought by the sponsor
or this reviewer as being possibly or reasonably attributable to bupropion
sustained-release are listed in Appendix 8.4.
Bupropion
Sustained-Release Clinical Review 28
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