NDA 20-358

Page 6

 

The critical issue here is not whether or not bupropion works, or whether or not the SR formulation works, but rather, what is the effective dose range that should be recommended to clinicians.  The data from the early bupropion immediate release studies supported the effectiveness and acceptable safety of the currently recommended bupropion dose range of 300 to 450 mg/day, albeit with the recognized problem of a fairly steep dose response curve for seizures.  The clinical data for the SR formulation fail overall to support the 150-300 mg/day range, although we believe our meta-analysis provides some additional support for the view that the approved dose of 300 mg/day is at the low end of the effective dose range.

 

Deficiencies in the Chemistry and Manufacturing

 

1.                    The stability data for the drug product are insufficient to support the proposed 24 month expiry date, and additional data at 30°C is needed that includes 24 month data.  An expiry data of 18 months is suggested until further confirmatory data is available.  In addition, the label storage statement “Store at 15°-30°C (59°-86°F)” is acceptable only for expiry dates of less than 24 months.

 

2.                    The proposed “individual unidentified compound” specification for the drug product of 0.2% should be lowered to 0.1%.

 

Deficiencies in the Environmental Assessment

 

Item 4. description of the proposed action:

 

a.        Requested Approval:  The description of the request should mention the NDA number.

 

b.       Need of action:  The added benefit of sustained-release tablets over the presently marketed immediate-release tablets should be stated.

 

c.        Production Locations:

 

                                 i.       Proprietary Intermediates:  It should be confirmed that none of the input materials are proprietary intermediates that are manufactured at another location.  If proprietary intermediates are used, information about their manufacture must be provided.

 

                                ii.       The exact addresses for the facilities used in production of the drug substance and drug product should be provided.

 

                              iii.       Disposal Locations:  The license number of the off-site incineration facility used by the Wellcome Foundation Limited, and the dates of expiration for the licenses of the incineration facility and the landfill site, should be given.  In addition, the application should state that disposition of drug product in a landfill is appropriate based on the toxicity of the drug substance.

 

 

 

 

 

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