Generic Drugs: Dangerous Differences?

Oct. 15, 2007— -- The accounts are disturbing. Patients taking a popular antidepressant who switched to its generic equivalent expected the same effects.

"I got switched to a different generic of Wellbutrin XL, and my life was destroyed," reads one account submitted to the Web site of the syndicated newspaper column The People's Pharmacy. "I became suicidal. I had not been this depressed in years. ... My experience with the generic destroyed everything in my life that was important to me."

"For the first few months, I got the Wellbutrin, then my insurance company said I had to get the generic," reads a recent post on the ConsumerLab.com Web site. "I didn't think it was a problem; I'd used generics before.

"Within weeks my depression reoccurred. ... By April I was suicidal. Following a suicide attempt, I spent one week in a mental hospital. I will never take the generic [for] Wellbutrin again."

Until last week, such reports from consumers were by and large the only hints that the generic version of the antidepressant drug known as bupropion might not function in the same way as the brand-name product it was formulated to represent.

However, a report released last week by the independent testing organization ConsumerLab.com has doctors divided in the debate over whether the cheaper generic versions of the drug -- as well as of many other prescription drugs -- are as safe and effective as their brand-name counterparts.

The findings could raise concerns for patients who, in trying to save money, switch to cheaper generic versions of the drugs they need.

"I think there is little doubt that our results, along with the dramatic and mounting consumer complaints, justify cautioning consumers of a potential difference," said Dr. Tod Cooperman, president of ConsumerLab.com, based in Westchester, N.Y.

The research ConsumerLab.com conducted -- which measured how much of the active ingredient was released from pills as they dissolved over the course of several hours -- suggested that while the active ingredient in the generic Budeprion XL 300 mg and brand-name Wellbutrin XL 300 mg products were the same, the rate at which it was released was differed.

Dr. Harold Koenig, associate professor of psychiatry and medicine at Duke University, said the discovery of any type of difference in a generic version of an antidepressant is "very worrisome."

"I have had many patients complain that generic versions of drugs were not effective or had different side effects than brand-name drugs," Koenig said. "I've repeatedly reassured them that the generic and brand forms of the drug were identical in every way.

"If this turns out not to be the case, then many patients may be vindicated in their experiences and us psychiatrists proved wrong."

But not all doctors and pharmacy experts agree that the findings are a cause for alarm -- particularly since the tests conducted by ConsumerLab.com were not conducted on human subjects.

"The FDA already looked into this and concluded that the generic version of the drug was equivalent to the brand name," said Dr. Sidney Wolfe, director of the Washington-D.C.-based Public Citizen's Health Research Group. "The FDA requirements include measuring blood levels in patients using the drug, the only reliable way to examine bioequivalence. ConsumerLab.com looked, I believe, only at test tube dissolution, which is not sufficient."

"I would say that while differences in in vitro dissolution tests raise some concern. The real gold standard is how the products release and blood levels achieved in humans," agreed James Stevenson, director of pharmacy services at the University of Michigan Health System College of Pharmacy in Ann Arbor.

"Unless there are data showing clinical differences in drug release and blood levels I would be cautious in drawing any conclusions," he said. "It sounds like some more clinical testing might be in order to fully answer this concern."

In response, Cooperman admits blood-level tests could provide useful data. "But," he noted, "as the active ingredient is known to be rapidly and well absorbed, it's likely that you would again see that much of the drug from the [generic] product enters the blood sooner than Wellbutrin."

Cooperman said that even if blood level studies were performed, the Food and Drug Administration allows a certain level of variation in these tests between brand-name products and their generic versions.

"Even if within those bounds those limits may not have been appropriate in the first place to say that the drug is truly equivalent," he said. "In short, even a blood-level study may not be definitive.

Time Release Concerns

Throughout the course of ConsumerLab.com's investigation, there was never a doubt that the generic bupropion studied had the same amount of the same active ingredient contained in Wellbutrin. It was only the rate of release that researchers said differed. But for some patients, doctors said, these differences can be important ones.

"For most drugs, there's very little concern about the equivalence of brand and generic drugs or about equivalence of different generic drugs; the active ingredients are absolutely identical," said Dr. Gregory Simon, psychiatrist and researcher at the Group Health Cooperative in Seattle. "But there is more concern about equivalence for slow-release or sustained-release formulations. These can vary between manufacturers -- either in how rapidly the drug is released or how completely it is released.

"If a drug is released more rapidly, there can be more side effects. If it's not released completely, it can be less effective."

In the case of bupropion, the time-release mechanism of the name-brand Wellbutrin was still patent-protected, meaning that generic purveyors were forced to develop slightly different means of delivering the same active ingredient.

"Sustained release mechanisms are not that easy to develop, and they tend to be proprietary in nature," said Michael Katz, clinical associate professor of pharmacy practice and science at the University of Arizona College of Pharmacy in Tucson.

"It would be difficult for a generic manufacturer to reproduce the same release characteristics as the brand-name product," he continued. "Such differences clearly could have an impact on patients who may switch from one product to another, and my view is that sustained-release products are among the relatively short list of products that should not be switched."

Time-release issues may not be exclusive to psychiatric drugs.

"In our field -- ophthalmology -- generic suspensions where drug release can be very variable is often a concern," said Dr. Randall Olson, director of the University of Utah's John A. Moran Eye Center in Salt Lake City. "Clearly, generics may not measure up at times, so buyer beware."

Still, physicians continue to debate whether the findings of ConsumerLab.com can be tied to the reports of adverse effects from generics. Indeed, Simon said that the slight differences in generic formulations are not always detrimental to patients.

"I think it crucial to emphasize, however, that the differences can go in either direction," he said. "I've certainly seen patients who had better results -- fewer side effects or better benefit -- from a generic-sustained release product than the brand product. So I'd strongly discourage any generic warnings about generic drugs."

How Patients Can Protect Themselves

If there is one point on which all the doctors agree, it is that patients can do much to protect their health by sharing any concerns they have about a recent switch to generics with their doctors.

"If a patient is experiencing symptoms, they should talk to their doctor or pharmacist regardless of what treatment they are getting," said Kevin Moores, director of the Division of Drug Information Service at the University of Iowa.

Cooperman added that homing in on which generics are exactly the same as their brand-name counterparts may be key.

"We have a number of tips for consumers in the report," he said. "For example, some generics are actually identical to the original products. So if you know which ones are identical, you will at least know they will act like the original product. Consumers should try to find authorized generics.

"If you find one that's working for you, when you get your prescription filled again, insist that you get that brand."