Medscape recently surveyed readers to examine their experiences with use of generic products. While the majority voiced support for use of generics in general, noting that they were typically safe and cost-effective, a number of drug classes were singled out for being of concern. Among others, readers voiced concern about generic antidepressants. Almost half of our survey participants indicated that they often resorted to writing "dispense as written" when ordering a branded product, though even this tactic was not always successful and many patients were dispensed generics despite dispense-as-written orders. One psychiatrist reported that, in his experience, diminished efficacy of generic antidepressants in comparison with their branded counterparts was particularly notable at higher doses. Another told a story of a previously stable patient who became suicidal following a generic substitution. Yet, a pharmacist reader noted that the change from brand to generic was often made at the request of the patient due to cost.
Medscape spoke with Gregory P. Geba, MD, MPH, Director of the Office of Generic Drugs at the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), and Lawrence X. Yu, PhD, Deputy Director for Science and Chemistry at the Office of Generic Drugs, specifically about generic antidepressants, bupropion in particular, and the most recent data, including that gleaned through post-marketing reports, on their use.
Medscape: Dr. Geba, can you please review the regulatory history of generic antidepressants including bupropion?
Dr. Geba: Bupropion hydrochloride was first approved in 1985 under the brand name of Wellbutrin® (GlaxoSmithKline; Philadelphia, Pennsylvania) as an antidepressant drug that was indicated for the treatment of major depressive disorders and prevention of seasonal affective disorder. Wellbutrin XL, an extended-release version of the drug, was approved in 2003.
The FDA has approved 5 generic versions of Wellbutrin XL 300 mg, including Budeprion XL® (manufactured by Impax Laboratories; Hayward, California, and marketed by Teva Pharmaceuticals; North Wales, Pennsylvania), which was approved in 2006. Approval was based on bioequivalence studies comparing the 150-mg strength of Budeprion XL to Wellbutrin XL 150 mg. Studies were not performed directly on the 300-mg strength of the product. The results of 150-mg strength were extrapolated to establish bioequivalence of the 300-mg Budeprion XL product. This methodology was based on the FDA's guidance at the time that the product was approved; however, the FDA has determined that this approach is no longer appropriate to establish bioequivalence of 300-mg bupropion hydrochloride extended-release tablets to Wellbutrin XL 300 mg.
Medscape: Can you speak to the case reports of varying efficacy between brand and generic antidepressants, including bupropion? Assuming bioequivalence between products, what are other potential mechanisms to explain these reports?
Dr. Geba: In the case of Budeprion XL 300 mg, this issue began to emerge in the first 6 months that the Impax-Teva product was on the market. From approximately January to June 2007, the FDA received 85 postmarketing reports, describing either adverse events or lack of effect after switching from the innovator, Wellbutrin XL 300 mg, to the generic, Budeprion XL 300 mg.
The reported adverse events were consistent with the adverse events noted in bupropion XL product labels. The reports relating to lack of efficacy involved lack of antidepressant effect and, in some instances, worsening of the depression symptoms following the switch from the brand name to a generic product. Nearly half of those patients who actually reported this phenomenon -- experiencing this lack of effect or adverse event upon switching to the generic -- reported some improvement in their condition when subsequently switched back to Wellbutrin XL 300 mg.
Medscape: Is it correct that the FDA initially called on the manufacturer to conduct a study and, when there was not enough participation in that investigation, commissioned one of their own?
Dr. Geba: That's correct. We discussed with both the manufacturer and marketer of the drug. Because these reports were occurring in a very small percentage of patients -- 85 reports sounds like a lot, but you have to understand that the denominator is very large -- that appeared to be particularly susceptible. The FDA suggested doing a double-blind exposure in those patients who had experienced these events to determine whether or not such differences were real. It took a little while to put a study together that could address the issue. The sponsor then attempted to conduct the trial but was unable to enroll a sufficient number of patients meeting the stated requirements.
Dr. Yu: By 2010, the FDA realized, given the difficulty in recruiting patients, that the study would be impossible to complete, and it was eventually terminated by the sponsor.
Medscape: To confirm, this study involved the 300-mg dose only, not the 150 mg?
Dr. Yu: Correct.