NDA
21-515
WELLBUTRIN
XL
was reported as the suspect drug. There is no further information provided regarding those reports.
Similarly
there have been case reports of adverse events in patients taking bupropion
with nelfinavir, ritonavir, or efavirenz.
There was one case report of myclonia when bupropion was given with
nelfinavir, and although the reporter stated that there were laboratory results
to indicate a possible pharmacokinetic interaction, the laboratory values were
not provided in the report. There was 1
case of seizure in a patient taking bupropion with ritonavir, although blood
levels were not available. There were no
cases of seizures reported with the concomitant use of bupropion and efavirenz.
In
summary, although there were several cases reports in the Sponsor’s database of
seizures when bupropion was given with SSRIS or protease inhibitors, the
available information cannot be used to determine whether a pharmacokinetic
drug interaction occurred, and cannot be used to rule out the possibility of
clinically significant CYP2B6-mediated rug interactions.
3.2.3 Recommended Labeling
Changes
The
Office of Clinical Pharmacology and Biopharmaceutics previously recommended
some revisions in the proposed label text.
All of the proposed changes were made with the exception of the addition
of information regarding in the in vitro studies regarding CYP2B6-mediated drug
interactions. Based on the discussion
in section 3.2.2 above, and in agreement with the Guidance for Industry
entitled “In Vivo Drug Metabolism/Drug Interaction Studies – Study Design, Data
Analysis, and Recommendations for Dosing and Labeling” that has specific
labeling recommendations when in vitro interaction has been
demonstrated, the Office of Clinical Pharmacology and Biopharmaceutics (OCPB)
recommends inclusion of that information in the labeling in paragraph 2
(beginning at line 382) of the Drug Interactions section of the label. The recommended change language is as
follows (OCPB changes in the labeling are highlighted):
“Because
bupropion is extensively metabolized, the coadministration of other drugs may
affect its clinical activity. In vitro
studies indicate that bupropion is primarily metabolized to hydroxybupropion by
the CYP2B6 isoenzyme. Therefore, the
potential exists for a drug interaction between WELLBUTRIN XL and drugs that
are substrates or inhibitors of the CYO2B6 isoenzyme (e.g., ophenadrine,
thiotepa, and cyclophosphamide). In
addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine,
and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz inhibit the
hydroxylation of bupropion. No clinical
studies have been performed to evaluate this finding. The threohydrobupropion metabolite....
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