No evidence of dose dumping after administration with food was observed, with C_max for bupropion in both periods occurring at approximately 5 hours, in agreement with t_max observed in the previous single dose and multiple dose studies of WELLBUTRIN XL (AK1BIOVAIL2751 and AK1BIOVAIL2543).

 

The 90% confidence intervals on the geometric means of the C_max and AUC ratios are within the bioequivalence interval of 0.8 to 1.25 for bupropion and for the predominant metabolite hydroxybupropion.  They are outside of the bioequivalence for the Cmax [C_max] and AUC_0-∞ for bupropion erythroamino ([blacked out] and (1.05, 1.27), respectively, and the AUC_0-t for bupropion threoamino alcohol (1.04, 1.26).  This was due to an approximate [blacked out] and 13% increase in bupropion erythroamino Cmax and AUC_0-∞, respectively and an approximate 8% increase in bupropion threoamino AUC_0-t.

 

Although the 90% Confidence interval was not contained in the equivalence limits of 80%-125% for 2 of the metabolites of bupropion, the differences between the fed and fasting states are very small (≤15%).  Therefore, this study demonstrates that there is no appreciable effect of food on exposure to bupropion or its metabolites when bupropion extended release tablets (300 mg) are given with a high fat meal.

 

·         What dosing recommendations should be made, if any, regarding administration of the product in relation to meals or meal types?

 

The sponsor can claim that no food effect on bioavailability is expected, and could state that WELLBUTRIN XL may be taken without regard to meals.

 

4.5.5        When would a fed BE study be appropriate and was one conducted?

 

A fed BE study is not necessary in this case.

 

4.5.6        How do the dissolution conditions and specifications assure in vivo performance and quality of the product?

 

Dissolution method development is reviewed in the Appendix, Section 6.2.6.  In vitro dissolution specifications were based on lots from the proposed commercial formulation that were used in the pharmacokinetic studies AK1BIOVAIL 2543, 2548, and 2571.  The sponsor has proposed the following dissolution method and specifications:

 

Apparatus:         USP Apparatus 1 (Basket)

Medium:            0.1 N HCl

Volume:             900 ml

Rotation Speed: 75 rpm

Specification:     2 hours: [blacked out]

                           4 hours: [blacked out]

                           8 hours: [blacked out]

                           16 hours: [blacked out]

 

 

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