The US Food and Drug Administration (FDA) has asked Israeli generic drug manufacturer Teva Pharmaceuticals to stop distribution of Budeprion XL 300, a generic version of the antidepressant Wellbutrin XL 300, after becoming aware of significant differences between the two drugs.
The request-agreed to by Teva-comes five years after a similar review conducted by FDA came to the opposite conclusion. In 2007, FDA conducted a review of the therapeutic equivalence between the two drugs after receiving dozens of postmarketing reports indicating consumers who switched from Welbutrin to Budeprion exhibited a significant loss of efficacy.
Despite an extensive review, FDA said it still, "Considers the generic form of bupropion (Buprion)… bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300 mg."
"Although there are small differences in the pharmacokinetic profiles of these two formulations, they are not outside the established boundaries for equivalence nor are they difference from other bupropion products known to be effective," continued FDA.
New Data Reverses Old Findings
But new data has caused FDA to revisit and ultimately reverse its thinking on the subject, it announced on 3 October. The agency said it had received and reviewed additional data, "Signifying that Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg."
One of the most basic problems may have come from how the drug underwent bioequivalence testing. FDA said the product was approved at the 300 mg dose based on studies conducted using the 150 mg dose. "This methodology was based on FDA's guidance at the time the products were approved," explained FDA. The agency also noted the lower dose was used as the basis of approval due to concerns that the higher dosage could cause seizures in otherwise healthy adults, and this concern caused FDA to grant Teva a waiver for the studies-a process it refers to as "waiving up."
Budeprion was approved by FDA in 2006.
By 2010, FDA's concerns regarding differences in the bioequivalence of the two drugs led it to sponsor a head-to-head comparison between the drugs, which led to findings-made available to the agency in August-that Budeprion did not release the drug at the same rate as Wellbutrin. The agency also defended the two years it took to complete the 24-person study, saying it took time to secure funding, design the study, enroll volunteers, conduct the study and analyze data.
FDA also noted that it had asked Teva to conduct the same study shortly after its release, but that Teva claimed-according to FDA-that it was unable to recruit a sufficient number of volunteers to generate adequate data for the study.
Other Manufacturers in the Firing Line
FDA said it has asked four other manufacturers, all of which manufacture similar 300 mg generic versions of Wellbutrin XL, to conduct similar studies in light of the findings raised by the agency's study. Those manufacturers are Anchen, Actavis, Watson and Mylan, according to FDA.
FDA approved at least one company's generic bupropion as recently as July 2010, after it had been made aware of concerns and had initiated procedures to begin its study on Budeprion.
Under FDA regulations, generic products must show themselves to be therapeutically equivalent to a reference drug by falling within certain parameters for both bioavailability and bioequivalence. These standards differ for different products, and FDA already appears to have pulled its bioequivalence guidance for bupropion at the 150 mg extended release formulation used as the basis for Budeprion's approval. Two similar guidelines (1, 2) released by FDA indicate the agency recommends two single-dose, two-way crossover in vivo studies in patients and bioequivalence based on a 90% confidence interval.