FDA Formally Withdraws Approval for Second Generic Version of Popular Antidepressant

| 11 April 2014 |  By 

This week the US Food and Drug Administration (FDA) formally-and quietly-withdrew a generic version of GlaxoSmithKline's Wellbutrin XL (bupropion) 300 mg following a determination that the drug was not bioequivalent to its originator.


The withdrawal of the generic buproprion, an antidepressant marketed by Watson Pharmaceuticals, follows similar concerns raised about other generic versions of bupropion.

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."

FDA would ultimately reissue bioequivalency standards for the drug at the 100, 200, 300, 450 and 522 mg dose levels.

Teva's drug was formally withdrawn by FDA in a 15 March 2013 Federal Register notice, removing its new drug application (ANDA #77-415) from the list of approved generic drugs, but leaving a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.

FDA: Watson's Generic Isn't

More than a year after raising concerns about Teva's Budeprion XL, FDA posted an update to its website announcing 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."

The agency immediately changed 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.

While FDA explained that Watson had agreed to "voluntarily withdraw this product from the distribution chain," it took until 9 April 2014 to withdraw approval of its ANDA (#77-715)-more than a year after Teva withdrew its own version of the drug.

FDA said it had asked Watson to withdraw the drug on 24 September 2013, and that Watson had agreed to do so in a 30 September 2013 response to the agency.

"Therefore, under section 505(e) of the FD Act (21 U.S.C. 355(e)) and § 314.150(d), and under authority delegated by the Commissioner to the Director, Center for Drug Evaluation and Research, approval of the 300-mg strength of Bupropion HCl Extended-Release Tablets under ANDA 77-715 is withdrawn," FDA said in its Federal Register notice.

No notice of the withdrawal was posted on FDA's website at www.fda.gov.

Four other versions of bupropion 300 mg, manufactured by Anchen, Watson, Mylan and Zydus remain on the market after they did not exhibit bioequivalence concerns.

Could it Hurt Research?

Ironically, the withdrawal of the drug could hurt researchers' attempts to understand the failures of bupropion generics and to help ensure the safety and efficacy of future generic drug products.

In April 2013, FDA 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.

Federal Register Notice


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