The US Food and Drug Administration (FDA) has approved a supplemental Abbreviated New Drug Application (sNDA) sponsored by Par Pharmaceuticals for a 300 mg, extended-release version of the popular antidepressant Wellbutrin XL (bupropion). The approval appears to be the first since the agency formally withdrew a nearly identical drug from the market several months ago after the product was found to not be bioequivalent to the reference listed drug (RLD).
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 RLD. 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."
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 FDA has not called for any of those drugs to be withdrawn from the market, though it has re-issued bioequivalency standards for the drug at the 100, 200, 300, 450 and 522 mg dose levels.
The drug was formally withdrawn by FDA in a 15 March 2013 Federal Register notice, removing its new drug application (ANDA #77-415) from the list of approved generic drugs, but leaving a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.
Since then, FDA has continued to release hints about ongoing concerns related to bupropion-based generic drugs.
Several sponsors have been asked to conduct new bioequivalency testing on their products, though a report in August 2013 by The Pink Sheetfound that only Mylan and Par Pharmaceutical had completed those tests, 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?"
But with one product already recalled from the market, FDA has shown it is not willing to rely solely on the manufacturers to conduct testing. In April 2013 it 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.
Validation for Par Pharma
But in at least one case, FDA has shown that it is comfortable with new data showing appropriate levels of bioequivalence.
On 20 August 2013, Par Pharmaceutical-one of the companies whose products FDA had asked to be studied-announced it has received FDA's approval of its new sANDA for the 300 mg extended release formulation of the drug.
Par said that it had submitted an sANDA containing the study data requested by FDA in December 2012. The application reportedly showed the product to demonstrate in vivo bioequivalence to Par's bupropion tablets relative to the updated bioequivalence standards and GlaxoSmithKline's Wellbutrin XL 300 mg.
Approval for the sANDA came in April 2013. It is not immediately clear why Par waited four months to announce FDA's approval.