NDA 20-358

19

 

 

EVALUATION:

 

The sponsor has adequately performed the preclinical studies requested by us and this NDA is approvable.  The findings were generally similar to those in studies performed under the NDA for the immediate release formulation (NDA 18-644).  (One exception to this was a lack of an increased in chromosomal aberrations in the new rat study).  In studies where they were compared, there were no clear differences between “undegraded” and “degraded” (i.e., containing degradation products/impurities at or above their limits in the human sustained released formulation) bupropion.  (Particular attention was paid to effect on the liver, which was identified as the primary target organ for toxicity in the original studies.  Since long term administration of bupropion caused hyperplastic nodules in rat liver, it was deemed important to compare the early effects of “degraded” and “undegraded” bupropion in the 90 day rat study.  Both preparations caused increased in liver weights and hepatocellular hypertrophy with no apparent differences between them).

 

It is noted that whereas the sponsor listed the amounts of impurities in the “degraded” bupropion which was tested, the amounts of impurities in the “undegraded” bupropion were not given.  Since a crucial concern in these studies was to compare the results obtained with the “new” bupropion with the bupropion used in the original preclinical studies (performed under NDA 18-644) it is important that the “undegraded” bupropion tested in the comparative studies be the same or very similar to that used in the original studies.  The sponsor should be requested to verify this.

 

The proposed labelling contains numerous differences from the labelling originally approved for the immediate release formulation under NDA 18-644.  My comments on the sections based on animal data are discussed under “Labelling”.  (Note that most of the proposed animal data-based changes are not specific to the sustained release formulation and would thus presumably also apply to the labelling of the immediate release formulation.)  I have not been able to locate the studies used to support some of the proposed changes; the sponsor should be requested to submit (or indicate if and when previously submitted) these studies (see “Recommendations” section for specifics).

 

 

 

 

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