Bioequivalence and Bioavailability Forum

Dear all,

interesting story. FDA approved generics to Wellbutrin XL 300 mg based on BE of the 150 mg strength (safety concerns of the higher dose in healthy subjects). Soon after approval (in 2006) post marketing reports showed efficacy/safety issues. 2007 FDA requested a BE study of the 300 mg strenght in patients who experienced problems after switching to the generic. Teva began the study but terminated it in 2011 due to recruitment difficulties. FDA sponsored at BE study in healthy subjects (ethical?), which showed lacking BE in August 2012. Quote:

The Agency determined that it was important to conduct direct bioequivalence studies comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg, in light of the reports that patients and health care professionals had submitted to FDA. FDA believed that the optimal patient population for those studies would be patients who had reported a lack of efficacy or unwanted side effects after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. The rationale for this was two-fold. First, the Agency believed that such a study would better target the reported problems and thereby provide the best information as to why the drug did not appear to be effective. Second, because that patient population was taking the 300 mg strength of the drug already, this study design would not unnecessarily expose healthy adult volunteers to the higher strength of the drug, particularly given concerns that this strength might be associated with risk of seizures.

Impax/Teva, however, was unsuccessful in recruiting a sufficient number of patients who had reported a lack of efficacy or unwanted side effects after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg. Due to the continuing questions about the efficacy of the Impax/Teva 300 mg bupropion product, the risks associated with reduced efficacy in patients with major depressive disorder, and increased experience with the safety profile of the drug, FDA concluded that a small bioequivalence study in healthy adult volunteers should be conducted.

In 2010, FDA decided to sponsor a study to be performed in healthy adult volunteers who were not being treated with the drug. FDA developed the study protocol and a test method that could identify bupropion and very closely related metabolites of bupropion, providing more accurate information about how bupropion is absorbed and subsequently metabolized by the body. The results of the FDA-sponsored bioequivalence study became available in August 2012, and they showed that Budeprion XL 300 mg fails to demonstrate bioequivalence to Wellbutrin XL 300 mg.

As a consequence the rating was changed from AB to BX, patients taking Budeprion XL 300 mg as a substitute for Wellbutrin XL 300 mg should talk with their health care professionals if they have questions about taking this medication. Impax/Teva is withdrawing Budeprion XL 300 mg from the market. The API-specific guidance was removed form FDA’s website.

Lessons learned: “Waiving up” is a risky business and should be avoided.

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References:

• FDA Update: Budeprion XL 300 mg Not Therapeutically Equivalent to Wellbutrin XL 300 mg (October 3, 2012)
  
• Questions and Answers Regarding Market Withdrawal of Budeprion XL 300 mg Manufactured by Impax and Marketed by Teva

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P.S.: Amazing how the FDA plots a plasma profile (equidistant x-axis instead of a time scale): http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm.