Wellbutrin

link
Review of Therapeutic Equivalence
Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg

Between January 1 and June 30, 2007, FDA received 85 post-marketing reports in which patients who switched from Wellbutrin XL 300 mg to Teva’s bupropion formulation (Budeprion XL 300 mg) experienced an undesirable effect. Specifically, in 78 of these cases, there was a reported loss of antidepressant effect following a switch from the branded to generic product. In addition to the loss of effect, a number of cases also reported the new onset or worsening of side effects. The reported side effects were consistent with the adverse effects in labeling for bupropion products. More than half of the patients who switched back to Wellbutrin XL 300 mg reported improvement of depression and/or abatement of side effects.

Given the temporal relationship between the switch to the generic product and the recurrence of depression and/or onset of side effects, these patients and physicians attributed these effects to poor performance of the generic product. These reported cases occurred at a time when sales data suggest that hundreds of thousands of patients using Wellbutrin XL were switched to the newly available Teva bupropion XL. The question is whether the reported lack of efficacy and/or new onset side effects in these patients who switched suggest a problem with the generic product, i.e., lack of bioequivalence to the branded product, or have some other explanation.

In order to evaluate this series of post-marketing reports, we have re-examined both the data on the bioequivalence of the two products (Wellbutrin XL and Teva's bupropion XL) and what is known about the natural history of treated depression.
What is the regulatory history of Wellbutrin and generic buproprion?

Bupropion hydrochloride is a drug used to treat Major Depressive Disorder (MDD). For many years bupropion was available only under the brand name Wellbutrin. It 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. In 2003, FDA approved an extended-release tablet of bupropion (Wellbutrin XL), allowing once a day dosing. Wellbutrin SR and Wellbutrin XL were approved based on the similarity of plasma levels of bupropion produced by these longer-acting products taken once or twice a day to the immediate-release product taken three times a day. The antidepressant effect of this drug does not appear for several weeks after initiation of treatment, and the effect is, in large part, related to long-acting metabolites. Therefore, no clinical effectiveness studies were considered necessary or required for the approval of Wellbutrin SR or Wellbutrin XL. Wellbutrin is owned by Smith Kline Beecham, a division of GlaxoSmithKline, and is manufactured by Biovail.

The law requires that generic drugs approved by FDA have the same active ingredient, dosage form, route of administration, and labeling as the branded product, and that the generic and branded drug be bioequivalent. The law also requires that generic drug applicants ensure the identity, quality, strength, and purity of their drug products. 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. Statistics are used to analyze whether differences are considered significant. Generic drug products approved by FDA are therapeutically equivalent to the branded product. 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.

In 2006, a generic XL version of bupropion, marketed as Budeprion XL, was approved by FDA. This generic formulation is manufactured by Impax Laboratories and distributed by Teva Pharmaceuticals. FDA approved this generic . . .
more