Hydroxybupropion were greater in patients with alcoholic liver disease.  Cmax [c_max] and AUC of bupropion and half-lives of bupropion and its metabolites were increased in patients were severe hepatic cirrhosis compared to healthy volunteers.

 

Genetic Polymorphisms – The role of genetic polymorphisms in the metabolism of bupropion has not been described.

 

Left Ventricular Dysfunction – No apparent effect on the pharmacokinetics of bupropion or its metabolites was identified in a chronic dosing study in patients with left ventricular dysfunction.

 

Pregnancy and Lactation – According to the label, there are no adequate and well-controlled studies in pregnant women and the effect on labor and delivery in humans in unknown.  Bupropion and its metabolites are secreted in human milk.

 

4.3.2        Based upon what is known about exposure-response relationships and their variability, and the groups studied, what dosage regimen adjustments, if any, are recommended for each of these groups?

 

Elderly – The labeling of WELLBUTRIN SR has a precaution stating that care should be taken in dose selection in the elderly due to a likelihood of decreased renal function.  It does not give specific guidelines for dosage adjustment other than suggesting a consideration of reduced frequency and/or dose in renal impairment.  This recommendation is extended to the proposed labeling of WELLBUTRIN XL.

 

Pediatrics – The proposed labeling states that safety and effectiveness of WELLBUTRIN XL in pediatric patients below 18 years old have not been established.  The Sponsor has submitted a formal request for a partial deferral to conduct a study to fulfill the requirements of the pediatric Rule in children and adolescents 7 to 17 years, with a proposal to conduct that study after the approval of the present NDA.  According to the Sponsor inclusion of children less than 7 years old is not supported by published literature.  Therefore, the Sponsor has requested a waiver with respect to studying pediatric age groups less than 7 years of age.

 

Renal Impairment – Specific guidelines are not given in the WELLBUTRIN SR label other than suggesting a consideration of reduced frequency and/or dose.  This recommendation is extended to WELLBUTRIN XL in the proposed label.

 

Hepatic Impairment – It is recommended that WELLBUTRIN SR be used with extreme caution in patients with severe hepatic cirrhosis.  Specific recommendations are that dose should not exceed 100 mg every day or 150 mg every other day in these patients.  In patients with hepatic impairment (including mild to moderate hepatic cirrhosis) caution and consideration of reduced frequency and/or dose is recommended.  These guidelines are extended to WELLBUTRIN XL with the dose not exceeding 150 mg every other day in patients with severe hepatic cirrhosis.

 

Pregnancy and Lactation – The proposed label of WELLBUTRIN XL reflects the labeling for WELLBUTRIN SR.  It is recommended that, although teratology studies in rats and rabbits reveal no evidence of harm to the fetus due to bupropion, this drug be used in pregnancy only if clearly needed.  GlaxoSmithKline maintains a Bupropion Pregnancy Registry and the number is

 

 

14

 

 

 

 

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