Regulatory Focus™ > News Articles > Now-Withdrawn Antidepressant's Bioequivalency Problems Raises Unanswered Issues, FDA Says

Now-Withdrawn Antidepressant's Bioequivalency Problems Raises Unanswered Issues, FDA Says

Posted 15 April 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) is looking to sponsor its own bioequivalency studies on more generic versions of a popular antidepressant in the wake of the agency's October 2012 finding that at least one generic version was not bioequivalent.


In September 2012, FDA announced that it had asked Israel-based manufacturer Teva Pharmaceuticals to stop distributing Budeprion (bupropion) XL 300 mg after it conducted testing and found that significant differences existed between Budeprion and Wellbutrin XL 300 mg, its reference listed drug (RLD) in FDA's 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," the agency 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The drug was officially withdrawn from the market on 15 March 2013, when FDA announced in the Federal Register that the ANDA (#77-415) was no longer able to be legally distributed.

Other Problems

But that isn't the end of bupropion's problems, or FDA's for that matter.

At the time of FDA's October 2012 announcement, the agency said it had asked four other manufacturers-Anchen (ANDA # 77-284), Actavis (ANDA # 77-285), Watson (ANDA # 77-715) and Mylan (ANDA #77-415)-to conduct similar bioequivalency testing on their drugs. As of 15 April 2013, none of those drugs had yet been recalled from the market.

Could those drugs have similar problems to those exhibited by Impax's 77-415 ANDA? FDA remained skeptical of the possibility. In a response to Valeant Pharmaceuticals on 1 April 2013, FDA explained that Impax's drug was materially different than the other four ANDA's.

"The Agency … believes that the bioequivalence issues with the Impax/Teva 300 mg product may have been the result of that product's particular formulation and thus limited to that product," it wrote. "Based on the information available to us, we do not believe it is necessary to withdraw approval of these products prior to completing our review of the results of the confirmatory BE studies. Once our review of the study data is complete, FDA will take any appropriate regulatory action."

It also said at the time that it has "asked these sponsors to conduct additional studies to confirm the BE of their 300 mg bupropion HCl ER tablets and to submit the results to FDA," and in the meantime released new bioequivalency guidelines aimed at enhancing requirements for the drug.

'Understanding Failure… Important for Future Guidance'

But the formulation response is more of a hypothesis than a response, and one FDA indicates it wants to respond to as quickly as possible. In a 12 April 2013 posting on the Federal Business Opportunities website-the location used for posting the agency's contract solicitations-FDA said it was looking for sources that would be able to conduct a "two-year pharmacokinetic study of bupropion HCl products with different release patterns."

"Understanding the scientific basis causing the failure of the 300 mg tablets is important for future guidance development and review processes," FDA explained. "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.

Continued FDA: "One of the hypotheses for the failure of bioequivalence study on the 300 mg tablets is that bupropion is eliminated differently in the GI tract due to the different in vivo release patterns. In addition, subjects with different metabolic genotypes may have different sensitivity ... Pharmacokinetic study of bupropion HCl products with different release patterns at different dose levels will help understand the [underlying] mechanisms."

Thus, the agency is looking to conduct a two-year study that is far more comprehensive than any yet undertaken by either the agency or industry. The project it envisions would be single dose in vivo crossover pharmacokinetic studies of bupropion HCl products of the immediate release (IR), sustained release (SR) and extended release (ER) variety and at multiple dose levels in healthy subjects.

What remains to be seen then is whether the study puts issues to rest or raises a host of new and troubling issues that might portend trouble for other generic versions of bupropion on the market.

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