provided.  Since bupropion and its metabolites are secreted in human milk, and the potential exists for serious adverse reactions in nursing infants, the label states that a decision should be made whether to discontinue nursing or discontinuing the drug, depending on the importance of the drug to the mother.

 

4.4   Extrinsic Factors

 

4.4.1        What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence exposure and/or response and what is the impact of any differences in exposure on pharmacodynamics?

 

 

According to the label for WELLBUTRIN SR (and extended to WELLBUTRIN XL) the effects of cigarette smoking on the pharmacokinetics of bupropion have been studied in healthy volunteers.  The study found no statistically difference in Cmax, half-life, tmax, AUC, or clearance of bupropion or its metabolites between smokers and nonsmokers after a single 150 mg dose of bupropion.

 

4.4.2        Based upon what is known about exposure-response relationships and their variability, what dosage regimen adjustments, if any, do you recommend for each of these factors:  If dosage regimen adjustments across factors are not based on the exposure-response relationships, describe the basis for the recommendation.

 

Dosage modification based on smoking status is not required.

 

4.4.3        Drug-Drug Interactions

 

4.4.3.1    Is there an in vitro basis to suspect in vivo drug-drug-interactions with bupropion that are mediated by CYP450?

 

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.  In addition bupropion and hydroxybupropion are inhibitors of CYP2D6 in vitro.

 

The reviewer has identified two publications in the literature evaluating in vitro the potential for P450-mediated drug interactions with bupropion.  Hesse et al (Drug Metab Disposition 200; 28:1176-1183) evaluated potential drug interactions with other antidepressants in human liver microsomes and reported a mean IC₅₀ value for paroxetine of approximately 1.6µM.  Sertraline, norfluoxetine, and fluvoxamine also inhibited bupropion metabolism with mean IC₅₀ values of 3.2, 4.2, and 6.1 µM, respectively.  Hesse et al (Drug Metab Disposition 2001; 29:100-2) have also reported inhibition of bupropion hydroxylation in human liver microsomes by nelfinavir, ritonavir, and efavirenz with mean IC₅₀ values 2.5, 2.2, and 5.5 µM respectively.

 

 

15

 

 

 

Back a Page
Next Page
Back to Wellbutrin XL NDA Index Page
Back to Main Index Page