NDA 21-515

WELLBUTRIN XL

 

The Office of Clinical Pharmacology and Biopharmaceutics agrees with the Sponsor’s proposed dissolution specifications, and recommends that those specifications be adapted.

 

• The Sponsor has provided a literature review and adverse event review to evaluate the potential for drug interactions with CYP2B6 substrates/inhibitors.  The Sponsor suggests that clinically significant interactions are unlikely.  Their rationale is that 1) bupropion is metabolized by multiple pathways so that other pathways can compensate, 2) multiple P450 isozymes catalyze the hydroxylation of bupropion to hydroxybupropion, and 3) low unbound plasma concentrations of these highly protein bound substrates/inhibitors relative to the in vitro IC₅₀ make the in vitro observations clinically insignificant.  In addition the Sponsor suggests that neither the case reports in the literature nor the case reports in the Sponsor’s adverse events database support a clinically significant CYP2B6-mediated drug interaction.

 

However, although bupropion is metabolized by multiple pathways to multiple metabolites so that other metabolites may be formed if formation of hydroxybupropion is blocked, the contributions to efficacy and safety of the various other metabolites, at concentrations which cannot be predicted at this point, is unknown.  In addition the actual role of other P450s in catalyzing the hydroxylation of bupropion if CYP2B6 were blocked in humans is unknown.  The literature is unclear as to how to extrapolate data from in vitro binding studies with drugs that are highly protein bound and the effect of protein binding on P450 inhibition in humans is difficult to predict.  Finally, while the case reports do not necessarily confirm clinically relevant drug interactions, they do not rule out the possibility.

 

The in vitro studies suggest that specific SSRIs as well as specific protease inhibitors can inhibit CYP2B6-medicated hydroxylation of bupropion.  However, the clinical significance is unknown.

 

• The Sponsor has made all of the labeling changes that were recommended by the OCPB,  [blacked out].  The OCPB recommends that the labeling reflect this interaction.

 

 

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