NDA
21-515
WELLBUTRIN
XL
concomitant
treatment with either sertraline or fluoxetine. On patient’s bupropion concentration rose from [blacked out]. No other details are available. The Sponsor cites a case series in the
literature describing the combination of bupropion with nelfinavir, ritonavir,
or efavirenz given to 10 patients, eight of whom had predisposing risk factors
for seizures. No seizures were
reported.
In
summary, there has not been a systematic evaluation of drug literature with
bupropion and protease inhibitors or SSRIs reported in the literature. There were several reports of seizures, as
well as 1 case in which a pharmacokinetic interaction occurred. Thus there is not enough information to draw
a conclusion about the clinical relevance of potential CYP2B6-mediated drug
interactions.
· Do the results of the
Sponsor’s event database rule out the likelihood of clinically significant drug
interactions between
bupropion and either SSRIs or protease inhibitors?
The
Sponsor has provided a summary of case reports in the adverse event database of
Global clinical [Clinical] Safety and
Pharmacovigilance. These included all
indications and formulations for the use of bupropion up to and including May
31, 2003. Particular attention was
given to reports of seizures and those will be addressed here. Cases of seizures when bupropion was used
with SSRIs were reported as follows.
Plasma concentration data was not available. For paroxetine,
there were seizures in 6 cases reported as suspected drug interactions although
the role of concomitant use was unclear in these cases. There were 42 other cases in which seizure
was reported in patients on bupropion and paroxetine concomitantly. In 9 of those, time to onset was reported
and was typically after addition of bupropion to pre-existing paroxetine
therapy. In 9 cases, other risk factors
for seizure were reported. For fluoxetine
there were 6 cases reported as possible interactions, in which seizure was
reported. These occurred either shortly
after stopping fluoxetine (1), shortly after increasing the bupropion dose to
450 mg on a stable dose of fluoxetine (1), shortly after adding fluoxetine to a
stable regimen of bupropion with possible involvement of paroxetine (1), or
with an unknown time course of co-administration. There were 91 other cases in which seizure was reported in
patients on bupropion and fluoxetine concomitantly. In more than half of those cases, seizure occurred following
overdose of either bupropion of fluoxetine, in the setting of other medications
known to lower seizure threshold, or in patients with risk factors for seizure,
with insufficient information in the remaining cases. For fluvoxamine, there were 5 cases reported as possible
interactions, in which seizure was reported.
In one case the time course for co-administration was not clear, in the
others it occurred after fluvoxamine was added to the bupropion regimen, after
bupropion to the regimen, or after the dose of fluvoxamine was increased. There were 8 other cases in which seizure
was reported in patients on bupropion and fluvoxamine concomitantly. In 6 of those cases the patients had other
risk factors for seizures, and 1 case occurred in a breastfeeding infant of a
mother receiving bupropion and fluvoxamine, with apparently confounding factors
in the other case. For sertraline,
there was one case reported as a possible interaction in which a seizure
occurred after adding to a regimen of bupropion. There were 33 other cases of seizures in patients taking
sertraline with bupropion in which bupropion
9
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