Pink Sheet Daily
August 13, 2013
Executive Summary
Could the nearly five-month delay in submitting FDA mandated bioequivalence tests signal something is wrong with its two 300 mg bupropion generics?
Actavis Inc. refuses to comment on what has caused a five-month-and-counting delay on FDA-required bioequivalence testing for its two 300 mg generic versions of GlaxoSmithKline PLC’s antidepressant WellbutrinXL (bupropion), opening the door to questions as to whether the company is simply late or whether there may be equivalence problems lurking for the drugs.
FDA requested the bioequivalence tests in 2012 after it determined that the 300 mg bupropion generic formally marketed by Teva Pharmaceutical Industries Ltd. and manufactured by Impax Laboratories Inc. as Budeprion XL was not equivalent to Wellbutrin, leading to the product’s withdrawal.
Actavis is responsible for the in-vivo testing of two generic versions, one initially marketed by the company and another product that was originally made by Watson Laboratories Inc., which is now a part of Actavis.
The other two 300 mg bupropion sponsors have submitted their results to FDA. The agency has already evaluated and given the OK to Mylan Inc.’s product and as of Aug. 5 said it was still reviewing Par Pharmaceutical Cos. Inc.’s study. Par’s study also was submitted to the agency after the March deadline.
FDA said it is in contact with Actavis and that the company is still in the process of completing its studies, but plans to submit as soon as possible. The agency has maintained all along that it does not anticipate problems with any other generic version besides Impax/Teva’s as it believes Impax/Teva’s troubles were due to the product’s unique formulation.
Bioequivalence studies for 300 mg bupropion extended release were not previously required by the agency. Due to concerns about seizures, the agency had allowed approval of the generics based on extrapolation from the lower 150 mg dose. But after complaints about the Impax/Teva product the agency revaluated existing data and determined that limited bioequivalence testing of the higher dose in healthy volunteers was appropriate.
In March, FDA updated its draft guidance on bioequivalence recommendations for 300 mg bupropion extended release. It says the most significant update was to call for the measuring of all four active metabolites as supportive evidence of bioequivalence.
FDA is currently seeking contractors who could conduct both in vitro and in vivo studies to determine why Impax/Teva’s generic failed and what that might mean for generic development and review as a whole. FDA hypothesizes that the in vivo release patterns may be related to the drug’s downfall because it releases earlier in the gastrointestinal track and is eliminated differently in the GI tract due to the different release pattern. The agency also wants more data on the metabolism of bupropion due to a lack of and also contrary results in the literature.
One concern that has been taken off the table regarding bupropion generics is Tmax, the time required to reach the peak drug concentration. FDA determined several hours of difference in Tmax is not considered meaningful to efficacy given that it can take weeks to reach the drug’s desired effect.