Based on data submitted by Watson Pharmaceuticals Inc. ("Watson") (recently merged with Actavis Inc. ("Actavis")), FDA announced last week that Watson's generic bupropion hydrochloride ("HCl") extended-release ("ER") 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL® 300 mg, the reference listed drug ("RLD"). Therapeutically equivalent drugs generally may be substituted for each other with the expectation that the substituted product will produce the same clinical effect and safety profile when used according to the labeling. Watson has agreed voluntarily to withdraw this product from the distribution chain.
Last year, FDA also reviewed data indicating that Budeprion XL 300 mg (bupropion hydrochloride extended-release tablets), manufactured by Impax Laboratories, Inc. ("Impax"), and marketed by Teva Pharmaceuticals USA, Inc. ("Teva"), is not therapeutically equivalent to Wellbutrin XL® 300 mg. Impax requested that the Agency withdraw approval of Budeprion XL 300 mg extended-release tablets. Impax and Teva stopped shipping the product and issued detailed information to their customers.
FDA has changed the Therapeutic Equivalence Code in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) for the Impax and Watson products from AB (therapeutically equivalent) to BX (data are insufficient to determine therapeutic equivalence). FDA does not anticipate a drug shortage.
FDA also announced last week their analysis of studies to assess the bioequivalence of marketed bupropion HCl ER 300 mg tablets provided by the three other manufacturers currently on the market: Actavis, Mylan Inc. ("Mylan"), and Par Pharmaceutical ("Par") (formerly Anchen Pharmaceuticals). Bioequivalence means the generic drug's rate and extent of absorption do not show a significant difference from the branded drug's rate and extent of absorption. Data submitted by Actavis, Mylan, and Par confirmed that their generic bupropion HCl ER 300 mg tablet products are therapeutically equivalent to the reference-listed drug, Wellbutrin XL® 300 mg. Wellbutrin XL® is a once-daily prescription medication for the treatment of major depressive disorder ("MDD") and for the prevention of seasonal affective disorder. It was approved as a new formulation in August 2003. Wellbutrin XL® is owned by Smith Kline Beecham, a division of GlaxoSmithKline, and is manufactured by Biovail.
Each of the five generic versions of Wellbutrin XL® 300 mg was approved based on bioequivalence studies comparing the 150 mg strength of the products to Wellbutrin XL 150 mg. Studies were not performed directly on the 300 mg strength of the products, because FDA was concerned that studies may cause seizures in some subjects. The bioequivalence study results from the 150 mg strength were extrapolated to establish bioequivalence of the 300 mg product. This methodology was based on FDA's guidance at the time the products were approved.
Soon after approval of the Impax/Teva product, Budeprion XL 300 mg, in December 2006, FDA began to receive reports that patients who were switched from Wellbutrin XL® 300 mg to its generic counterparts experienced reduced efficacy. The complaints appeared to be linked to the Impax/Teva product. FDA then asked Impax/Teva to conduct a study directly on its 300 mg extended-release product to compare its bioequivalence to Wellbutrin XL® 300 mg. FDA asked that the study include patients who had reported lack of efficacy after switching from Wellbutrin XL® 300 mg to Budeprion XL 300 mg. Impax/Teva began the study, but terminated it in late 2011 because they were unable to recruit a significant number of affected patients to generate the necessary data.
In 2010, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL® 300 mg. This study was conducted in 24 healthy adult volunteers and was designed to measure both the rate and the extent of release of bupropion into the blood. The results of this study showed that Budeprion XL 300 mg tablets fail to release bupropion into the blood at the same rate and to the same extent as Wellbutrin XL® 300 mg.
Bupropion hydrochloride was first approved in 1985 as an immediate release ("IR") tablet (Wellbutrin-IR®) taken three times a day. In 1996, FDA approved a sustained-release tablet of bupropion (Wellbutrin SR®), allowing twice a day dosing.
