·         Dosage strength equivalence was demonstrated between the 150 mg and 300 mg strengths of WELLBUTRIN XL.

 

·         There is no appreciable effect of food on exposure to bupropion or its metabolites when WELLBUTRIN XL (300 mg) is given with a high fat meal.

 

In addition, recent data in the literature suggest that several SSRIs (sertraline, paroxetine, and fluvoxamine as well as norfluoxetine) and several antiretroviral drugs (ritonavir, efavirenz, and nelfinavir) inhibit the hydroxylation of bupropion in vitro.  The Office of Clinical Pharmacology and Biopharmaceutics recommends that the label be revised with respect to the potential for CYP2B6-mediated interactions.

 

1.1    Recommendations and Comments to Sponsor

 

The Office of Clinical Pharmacology and Biopharmaceutics (OCPB) finds the submitted data in NDA 21-515 for WELLBUTRIN XL acceptable, pending the outcome of the DSI inspection report of the pivotal bioequivalence study AK1BIOVAIL2543.  The OCPB recommends some revisions of the proposed label’s text (please refer to Section 5).

 

1)      The proposed in vitro dissolution method is acceptable.  The OCPB recommends that the specification be changed to the following:

 

2 hours:  [blacked out]

4 hours:  [blacked out]

8 hours:  [blacked out]

16 hours: [blacked out]

 

In addition, it should be noted that the Sponsor has not consistently used [blacked out] tablets for each time point in the dissolution profiles.  In the future, the Sponsor should adhere to the practice of using [blacked out] for each dissolution profile.

 

2)      Bupropion is hydroxylated by CYP2B6.  Recently in vitro studies have identified more substrates and inhibitors of CYP2B6, and the results of recent in vitro studies suggest that several SSRIs and antiretroviral drugs may inhibit the hydroxylation of bupropion by CYP2B6.  It would be useful to characterize the requirement for dosing modifications, if necessary, when such drugs are given with bupropion.  Therefore we recommend that you conduct a thorough search of the literature as well as adverse event reports for bupropion to evaluate the potential for pharmacokinetic and/or pharmacodynamic (adverse event) drug interactions with bupropion and an inhibitor/substrate such as paroxetine, sertraline, fluvoxamine, norfluoxetine, efavirenz, ritonavir, and nelfinavir.  Based on literature results, an in vivo drug-drug interaction study may be necessary.

 

 

Please forward the comments 1 and 2 above and the labeling comments in Section 5 to the Sponsor.

 

 

2

 

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