NDA 21-515                                         Approval Letter                                                 3

 

 

 

3.       The relative response factors associated with each impurity/degradant should be incorporated into the formulas used for calculating the impurity/degradant levels.  The impurity/degradant levels should be recalculated using the relative response factors.  In addition, the impurity/degradant limits should be recalculated for the drug product.

4.       Provide a complete and detailed description of the secondary packaging systems for the [blacked out] bottles [blacked out].  Your response should include specifications and in-process controls.

5.       Please provide updated product stability formulation.

 

We have also incorporated the revised storage statement (previously agreed upon between yourselves and our chemistry review team) into the overall revised labeling (package insert) appended to this letter.  Please address this change in all labeling elements, including container and carton labeling as well as the package insert, when submitting your complete response.

 

CMC: Methods Validation

We have not completed validation of the regulatory methods for this application.  We expect your continued cooperation to resolve any problems that may be identified.

 

CMC: Categorical Exclusion

We have completed our review of the Environmental Assessment information provided by your firm, and we agree with your request for a Categorical Exclusion from the requirement to perform a full Environmental Assessment for this application.

 

Clinical Pharmacology and Biopharmaceutics

1.       Please adopt the following dissolution method and specifications for both strengths of Wellbutrin XL tablets.  Note change in specifications at 4 and 8 hours:

 

Apparatus:                          UPS Apparatus 1 (Basket) at 75RPM

Medium:                             900 mL of 0.1N hydrochloric acid at 37±0.5°C

Specifications:                     2 hours:             [blacked out]

                                          4 hours:             [blacked out]

                                          8 hours:             [blacked out]

                                          16 hours:           [blacked out]

 

Sample size:                        12 tablets for each time point in the 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 concomitantly with bupropion.  Therefore we recommend that you conduct a thorough search of the literature, as well as searching adverse event reports for bupropion, to evaluate the potential for pharmacokinetic and/or pharmacodynamic (adverse event) drug interactions with bupropion and inhibitors/substrates such as paroxetine, sertraline, fluvoxamine, norfluoxetine, efavirenz, ritonavir, and

 

 

 

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