Posted 15 October 2013
By Alexander Gaffney, RF News Editor
The US Food and Drug Administration (FDA) on Friday quietly announced that a second generic version of Wellbutrin XL 300 mg, a popular antidepressant manufactured by GlaxoSmithKline, has been found to not be bioequivalent to the drug and will be pulled off the market.
In September 2012, FDA announced that it had asked Israel-based manufacturer Teva Pharmaceuticals to stop distributing Budeprion XL (bupropion) 300 mg after it conducted testing and found that significant differences existed between Budeprion and Welbutrin XL 300 mg, its Reference-Listed Drug (RLD) in the Orange Book. Teva marketed Budeprion on behalf of Impax, which owned its application and manufactured the drug.
Though a similar review in 2007 had found the drugs existed within acceptable tolerances of one another, a 2012 review by FDA found the opposite. "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg," FDA wrote in its findings.
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/Impax a waiver for the studies-a process it refers to as "waiving up."
The drug was formally withdrawn by FDA in a 15 March 2013 Federal Register notice, removing its new drug application (ANDA #77-415) from the list of approved generic drugs, but leaving a related 150 mg formulation on the market.
At the time of FDA's October 2012 announcement, the agency said it had asked four other manufacturers-Anchen, Actavis, Watson and Mylan-to conduct similar bioequivalency testing on their drugs. FDA has not called for any of those drugs to be withdrawn from the market, though it has re-issued bioequivalency standards for the drug at the 100, 200, 300, 450 and 522 mg dose levels.
Since then, FDA has continued to release hints about ongoing concerns related to bupropion-based generic drugs.
Several sponsors had been asked to conduct new bioequivalency testing on their products, though a report in August 2013 by The Pink Sheet found that only Mylan and Par Pharmaceutical had completed those tests at the time, leaving Actavis running months behind schedule.
Asked The Pink Sheet's Sarah Karlin: "Could the nearly five-month delay in submitting FDA-mandated bioequivalence tests signal something is wrong with its two 300 mg bupropion generics?"
The answer, it seems, was yes-there was something very wrong.
FDA: Watson's Generic Isn't
In a 10 October 2013 update quietly posted to its website, FDA announced that Actavis-now owned by Watson Pharmaceuticals-had submitted data that "determined that [the] company's generic bupropion HCl ER 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL 300 mg."
"Watson has agreed to voluntarily withdraw this product from the distribution chain," FDA wrote.
The agency said it had already moved to change the product's bioequivalency codes from A-rated (therapeutically equivalent) to B-rated (not bioequivalent). "We recommend that patients taking the Watson product continue taking their medication and contact their health care professional or pharmacist to address any concerns," it added.
The other three manufacturers' data, however, confirmed that their generic products were therapeutically equivalent to GSK's Wellbutrin, FDA said.
The withdrawal, however, marks a second and potentially embarrassing-and not to mention concerning-lapse for the agency. The incident has already caused the agency to re-evaluate how it conducts bioequivalency testing, and in April 2013 initiated a contracting process with the stated intent of "understanding the scientific basis causing the failure of the 300 mg tablets," calling it "important for future guidance development and review processes."
"It is noted that the generic version had different formulation design as the reference product so that the generic product releases earlier in the gastrointestinal (GI) tract," FDA wrote, adding that the cause of the problems could be attributable to different in vivo release patterns relative to the RLD.
That study has not yet been completed, but as Focus found earlier, the study is already running into a notable problem: Unless it can obtain supplies of Teva and Watson's generic drugs, researchers won't be able to study them since they will have been pulled off the market and their manufacturing operations ceased. That would get in the way of FDA's attempts to understand what went wrong.
FDA Update on Generic Wellbutrin XL 300 mg