acknowledge truthfully that we don’t know the mechanism of action.  Consequently, I have deleted this language and replaced it with a more neutral description of  bupropion’s pharmacology.  I have also deleted some animal toxicology data suggestive of a difference between the IR and SR formulations, however, at doses far in excess of those relevant to human experience.

 

Pharmacokinetics

 

The sponsor’s proposed PK section heavily emphasized the PK for bupropion SR, but failed, in my view, to adequately compare the PK for the SR and IR formulations.  Since we are basing our efficacy judgement [judgment] solely on the bioequivalence of these 2 formulations, I felt it was important to describe the steady state findings for these different formulations.  The other reason for emphasizing the bioequivalence of the SR and IR is to justify the inclusion in later sections of adverse event data for the IR, often occurring at somewhat higher doses than used in the SR program, but at doses that are necessarily recommended for the SR, considering the clinical trials upon which efficacy is based.

 

Clinical Trials

 

In recent years, we have added clinical trials subsections to provide some detail on the clinical trials supporting the effectiveness of a drug, and I felt that was particularly important here.  The subsection I have added describes the 2 relevant IR studies, and also notes truthfully that the effectiveness of the SR is based on a link to these IR studies through the bioequivalence of these products, and not on independent data.

 

INDICATIONS AND USAGE

 

The sponsor had deleted the cautionary statement about seizures that is in current labeling, based on the lower seizure incidence observed in current labeling, based on the lower seizure incidence observed in the SR study involving patients dosed in a bupropion range of 100-300 mg/day.  Of course, we are recommending a dosing range of 300-400 mg/day, a range for which bupropion IR has been shown to have a seizure risk about 4-fold higher than that seen in this lower dose range.  Given the bioequivalence of these formulations, I consider the seizure caution equally pertinent to the SR labeling, and I have added it back in.

 

WARNINGS

 

The sponsor’s proposed Warning section significantly de-emphasizes the risk of seizure with Wellbutrin SR, and adds, mostly as an afterthought, the IR data at the higher doses still being recommended for the SR product.  In the absence of any directly relevant data in this higher dose range for the SR product, coupled with the demonstrated bioequivalence for these products, I think it is essential to more strongly emphasize the dose-relatedness for

 

 

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