Back in the Headlines – FDA Updates Bioequivalence of Bupropion Extended-Release 300mg Tablets

On October 3, 2012, the FDA announced its finding that the Impax Bupropion Extended-Release Tablets, 300mg, distributed by Teva, was found to be bio-inequivalent to the reference listed drug (RLD)  Welbutrin XL 300 mg Tablets.  The firms withdrew their product from the market.

A little over a year later, on October 10, 2013, FDA announced the results of the bioequivalence studies required by four additional companies, Actavis, Mylan, Par Pharmaceuticals, and Watson conducted to confirm a finding of bioequivalence of their approved 300 mg Bupropion Extended-Release Tablets.  The studies submitted by Actavis, Mylan, and Par Pharmaceuticals confirmed that their products are bioequivalent to Welbutrin XL 300 mg Tablets.  However, the study performed by Watson failed to confirm bioequivalence to the RLD, and the firm has agreed to voluntarily withdraw its product from the distribution chain.

The FDA’s full Update on this issue can be found here.   No further details were released by the FDA.

The Agency’s original bioequivalence requirements, based on a potential safety issue (possible risk of seizure) with giving 300 mg of Bupropion to healthy volunteers permitted firms to perform their in vivo bioequivalence studies to support application approval of the 150 mg and 300 mg Tablets on the lower 150 mg dosage strength and waived the in vivo requirements for the 300 mg Tablet, relying on in vitro testing alone for the higher strength product.  Adverse events began surfacing shortly after the generic products for the 300 mg product were introduced into the marketplace.  Based on the adverse events reported and publicity surrounding these reports, the Agency ultimately decided to require all firms to conduct in vivo studies on their approved 300 mg strength products to confirm the bioequivalence to the RLD.  In this particular case, two of the five products involved in the newly required studies failed to confirm bioequivalence to the RLD.

While this is a significant issue and will likely cause the Office of Generic Drugs to rethink some of its procedures and bioequivalence evaluations, one must remember that you can count on one hand the number of occasions where there has been a documented bioequivalence problem with an approved generic product.  The FDA has approved well over 15,000 generic products since the passage of Hatch-Waxman in 1984.  While there are numerous reports of problems with certain generic (as well as brand name) products, the FDA is continually evaluating its bioequivalence testing requirements to assure that products approved are indeed therapeutically equivalent to the RLD upon which the generic product relies as a basis for approval.  As a former OGD official, I have complete confidence in the generic drugs approval process and findings in this country.  Not to say there will never be an issue for some people with a generic (or for that matter, a brand) product; however, two stories come to my mind that may indicate that observed physical differences may also impact on the number of adverse events reported when the products are actually the same.  In one instance, when the originator company that made Tegretol (carbamazepine), an anti-epileptic product, was facing potential generic competition, the firm decided to include a small amount of blue dye in its previously white tablet brand product to differentiate its product from the white generic products.  Patients reported an increased number of breakthrough seizures with the new blue tablet which was unchanged except for the color.  In the other example that comes to mind, the innovator of Tenormin (atenolol) (a drug to treat high blood pressure, among other ailments) obtained ANDA approval with the exact same formulation to complete against itself when other generics were approved.  Patients claimed the generic of the brand product Tenormin (which was actually ultimately distributed out of the approved ANDA) did not work as well as the Tenormin Tablets.   My guess is that such adverse events are reported for authorized generics-which are actually the brand name product distributed as a generic.

Of course, there does need to be diligence in post-approval adverse event monitoring and the Agency must continually assess what this monitoring shows.  This is a job that is not easy, but the American public should have the utmost confidence in the generic drug review and approval process.  Consumer and healthcare provider feedback is tantamount to assuring that all drug products approved for marketing in the United States are both safe and effective and in the case of generic products, are therapeutically equivalent to their brand name counterparts.