FDA Admits Contradictions in Generic Drug Labeling

Generic medications provide many Americans with a money-saving alternative to name brand drugs. It is estimated that generic drugs save consumers $8 to $10 billion a year at retail pharmacies. The law requires that in order to gain FDA approval, a generic drug must meet the same standards as the innovator drug. It must: contain the same active ingredients; be identical in strength, dosage form, and route of administration; have the same use indications; be bioequivalent (meaning the generic drug’s rate and extent of absorption do not show a significant difference between that of the branded drug); meet the same batch requirements for identity, strength, purity, and quality; and be labeled the same as the branded product. That said consumers can expect that a generic drug will produce the same clinical effect and safety profile as the name brand, right? Not always!

Consider the case of Budeprion XL 300 mg, a generic version of the popular antidepressant Wellbutrin XL 300 mg. Between January 1 and June 30, 2007, the FDA received 85 post-marketing reports in which patients who switched from Wellbutrin XL 300 mg to Budeprion XL 300 mg experienced an undesirable effect. Specifically, in 78 of these cases, there was a reported loss of antidepressant effect following the switch. In addition, a number of cases reported the new onset or worsening of side effects. Personal accounts indicated that while taking the name brand Wellbutrin XL 300 for months or even years, people felt well and their psychological symptoms of depression were successfully controlled. But after switching to the generic formulation (Budeprion XL 300), many reported symptoms such as headaches, irritability, nausea and insomnia. Others shared stories of becoming easily upset or aggressive, crying, gaining weight or experiencing a return of depressive symptoms. Some reported thoughts of suicide while taking the generic form. More than half of the patients who switched back to Wellbutrin XL 300 reported improvement of depression and/or abatement of side effects.

These reports prompted ConsumerLab.com, a leading provider of consumer information and independent evaluations of products that affect health and nutrition, to investigate whether extended-release (XL) and sustained-released (SR) bupropion generics were truly equivalent to original Wellbutrin and to each other. Their analysis revealed that, while each product contained its claimed amount of active ingredient—bupropion hydrochloride—the rates at which the products released their ingredient were quite different, raising concerns about their equivalency. Results from a second lab confirmed these differences.

ConsumerLab.com also noted that statements in the package insert of the generic contradict information published by the FDA about the product. The insert claims that the product has been clinically tested, while the FDA has acknowledged that it has not. The insert states that food does not affect the absorption of drug, but the FDA has acknowledged that tests have not been done to support this. The insert states that the time to peak plasma concentration of the drug is about 5 hours, while the FDA has reported it to be 2 to 3 hours. ConsumerLab.com’s President, Tod Cooperman, brought the inconsistencies to the FDA’s attention, hoping for corrections to be made.

Surprisingly, despite these inconsistencies, the FDA issued a statement in April of this year saying that the agency considers the generic form of bupropion XL 300 mg “bioequivalent and therapeutically equivalent (interchangeable) with Wellbutrin XL 300 mg. And though they admitted “small differences in the pharmacokinetic profiles” of the two formulations, they said they “are not outside the established boundaries for equivalence nor are they different from other bupropion products known to be effective.” According to the FDA statement, the recurrent nature of depression provides a “scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product.”

On October 2nd, an FDA spokeswoman told Dow Jones that the FDA considers the product to be “labeled appropriately.” Apparently, the unsupported statements are copied from the package insert for the original Wellbutrin XL but, as explained by the spokeswoman, the labeling of a generic drug must match that of the drug it copies and this is “the standard” for all generics. After a review of the FDA’s test requirements, ConsumerLab.com found that generic products are allowed to vary from one another by a fairly wide range. For example, a twice-a-day (SR) version of bupropion is permitted to release anywhere from 60 to 85 percent of its ingredient after four hours into a dissolution test. At the completion of such a test (which only runs eight hours), a product could be as little as 80 percent dissolved or over 100 percent dissolved and still be considered bioequivalent. ConsumerLab also discovered that the acceptable limits for once-a-day (XL) versions have been blacked-out or deleted in documents on the FDA website. Dr. Cooperman says the FDA rules “clearly need to be changed to protect consumers.”

The Dow Jones also reported that the FDA is considering a highly unusual step—new tests of Budeprion XL 300 to help them understand complaints about the product.

ConsumerLab.com suggests that if you find a generic version of Wellbutrin is not working for you, either have your doctor prescribe the brand-name version and indicate “Dispense as Written” or “Do Not Substitute.” You might also try a different generic or consider a different version of the drug. For example, if a once-a-day generic is not working, consider a twice-a-day (SR) or three-times-a-day version that will yield the same total daily dose. However, you will have to remember to take the medication on schedule.