NDA 21-515

WELLBUTRIN XL

 

IVIVC, the recommended range at any dissolution time point specification is +/- 10% deviation from the meat dissolution profile from bioavailability lots, and although deviations from that range can be accepted, the range should not exceed [blacked out].

 

The Sponsor has proposed a shift in the specification range at 4 hours to [blacked out] reflecting the different dissolution profiles of the 150 mg and 300 mg strengths at that time.  The mean % dissolved at 4 hours is [blacked out] for the 150 mg strength tablets and [blacked out] for the 300 mg strength tablets.  A range of ± 25% would be approximately [blacked out] and [blacked out] for the 150 mg and 300 mg strengths, respectively.  To allow the same dissolution specifications for both strengths of tablets, the proposed range of [blacked out] at 4 hours is acceptable.  The Office of Clinical Pharmacology and Biopharmaceutics recommends that the specification be changed to the following:

 

2 hours:

4 hours: [blacked out]

8 hours:

16 hours:

 

In addition, in the approvable letter, the Office of Clinical Pharmacology and Biopharmaceutics recommended that in the future, the Sponsor should adhere to the practice of using [blacked out] for each dissolution profile.  The Sponsor has requested confirmation of the information provided in that teleconference of July 2, 2003 regarding this recommendation.  It should be noted that this is not necessary for routine QC testing (i.e. standard USP stages apply).  This recommendation refers to the number of tablets that should be tested for the data that should be submitted on pivotal biobatches in the NDA in support of setting the dissolution specification.

 

3.2.2        Evaluation of the Potential for Drug Interactions

 

According to the label for WELLBUTRIN SR (extended to the proposed labeling for WELLBUTRIN XL), in vitro studies suggest that bupropion is primarily metabolized to hydroxybupropion by CYP2B6.  The results of recent in vitro studies,^1,2 suggest that several SSRIs and antiretroviral drugs may inhibit the hydroxylation of bupropion by CYB2B6.  Specifically, the reviewer identified two publications in the literature evaluating in vitro the potential for P450-mediated drug interactions with bupropion.  Hesse et al² evaluated potential drug interactions with other antidepressants in human liver microsomes and reported a mean IC₅₀ value for paroxetine of approximately 1.6 µM.  Sertraline, norfluoxetine, and fluvoxamine also inhibit bupropion metabolism with mean IC₅₀ values of 3.2, 4.2, and 6.1 µM, respectively.  Hesse et al¹ have also reported inhibition of bupropion hydroxylation in human liver microsomes by nelfinavir, ritonavir, and efavirenz with the mean IC₅₀ values of 2.5, 2.2, and 5.5 µM respectively.

 

The Office of Clinical Pharmacology and Biopharmaceutics recommended that the Sponsor conduct a thorough search of the literature as well as adverse event reports for bupropion to evaluate the potential for pharmacokinetic and/or pharmacodynamic

 

 

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