Budeprion XL 300 and Wellbutrin XL 300: controversy over disparity in effects

Complaints surrounding a generic form of the extended-release drug Wellbutrin XL 300 bring the US determination of bioequivalence into question

Cynthia Challener/Vermont

THE US Food and Drug Administration (FDA) has lately weathered heavy criticism regarding its ability to ensure the safety of generic drugs. Most questions have focused on the supply chain, but last year, attention was drawn to an issue that goes right to the heart of the generics industry – the determination of bioequivalence.

The drug at the center of the controversy is Budeprion XL 300. Manufactured by Teva Pharmaceutical Industries, it is the generic form of long-acting antidepressant Wellbutrin XL 300, produced by UK pharmaceuticals giant GlaxoSmithKline (GSK). The active ingredient, bupropion HCl, is no longer under patent, but the membrane-based drug-delivery technology behind GSK’s once-a-day, extended-release product remains protected. Teva’s Budeprion XL 300 consequently relies on an unrelated erodable tablet technology.

Teva, based in Jerusalem, Israel, launched Budeprion XL 300 in December 2006. Within a short time following its introduction to the market, complaints about the generic began appearing on health-related websites. People who had taken Wellbutrin successfully for years reported unpleasant symptoms ranging from panic attacks, mood swings, anxiety, nausea and insomnia to severe depression and suicidal tendencies when switched to the generic form. Those who switched back to Wellbutrin reported that the symptoms disappeared.

Joe and Terry Graedon, founders of the website The People’s Pharmacy, noticed the peculiar number of complaints about Budeprion XL 300, and notified the FDA in March 2007.

As of mid-February, the agency had not completed its study. “We hope to be able to provide the results of our evaluation in the coming weeks,” said Crystal Rice, a media relations professional at the FDA’s Center for Drug Evaluation and Research (CDER).

However, the Graedons also suggested that ConsumerLab.com, an independent product analysis group that has ­published evaluations of more than 2,000 products, including herbal supplements, vitamins and functional foods, analyze Wellbutrin XL 300 and Budeprion XL 300 to determine if there were any notable differences between the two. According to ConsumerLab president Tod Cooperman, the results, published on its website last October, were telling.

Both drugs contained the same amount of active ingredient. However, when they were subjected to the dissolution testing methods described in the FDA’s approval letters for Wellbutrin XL 300 and Budeprion XL 300, ConsumerLab discovered that the release rates for the two products were quite different. Whereas GSK’s Wellbutrin XL 300 had released 8% of its bupropion HCl after two hours, Teva’s Budeprion XL 300 had released 34%.

After four hours, a similar disparity was observed: Well-butrin XL 300 had rel-eased 25% of the active ingredient, while Budeprion XL 300 had released 49%. It was only after eight hours that results for the two drugs became comparable, says Cooperman.

“The more rapid release means that more active drug was getting into the blood stream faster with the generic than the originator compound, and [it] could easily explain why hundreds of people have reported on our website side effects [such as nausea and anxiety] typical of too much bupropion when they took the generic,” says Joe Graedon.

However, a generic can be considered bioequivalent even when there is a significant difference in release rates, notes Cooperman. For example, a twice-a-day (SR) version of bupropion HCl is permitted to release anywhere from 60-85% of its ingredient after four hours into a dissolution test, and anywhere from 80-100% or more by the end of the eight-hour test.

SIGNIFICANT ABSENCES

So, what does “bioequivalent” mean?

Bioequivalence is defined in US drug law 21 CFR 320.1 as “the absence of a ­significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”

Additionally, for two orally administered drug products to be bioequivalent, the active drug ingredient or active moiety in the test product must exhibit the same rate and extent of absorption as the reference drug product.

Extended-release products from different manufacturers typically have different dissolution procedures, profiles and tolerances, even though each product contains the same active ingredients, notes Darrell Abernethy, chief science officer at the US Pharmacopeia (USP).

Based in Rockville, Maryland, the USP is the official standards-setting authority for prescription and over-the-counter medicines in the US. “To the extent that these different dissolution tests relate to in vivo bioequivalence, different products often have different dissolution acceptance criteria,” says Darrell.

The USP does have drug product monographs for Budeprion XL 300 and Wellbutrin XL 300, and the organization has noted in a press release that these monographs allow different dissolution requirements: “This is appropriate on the assumption that the FDA has reviewed and found acceptable bioequivalence studies for formulations conforming to the monographs. USP does not verify drug products approved by the FDA,” adds Darrell.

Last December, the USP released its own ­dissolution test results ­showing that Budeprion XL 300 released its active ­ingredient at a different rate from Wellbutrin XL 300. Budeprion was found to release 25-50% of bupropion HCl in the first two hours, compared to less than 20% for Wellbutrin.

These USP dissolution standards are based upon performance characteristics that the FDA approved for the original and generic drugs, respectively, and were provided to the USP by the manufacturers.

“The publication of this information by USP corroborates the findings of ConsumerLab.com and should address any concerns that might have existed about the validity of our results,” asserts Cooperman.

The FDA was aware of the difference in behavior of Budeprion XL 300 and Wellbutrin XL 300 when it granted marketing approval to the generic product, but was untroubled. As Bob Temple, FDA Director of the Office of Medical Policy at the CDER remarked during an interview on Southern California Public Radio station KPCC in December, “having the blood levels come up a little bit sooner – two hours instead of four hours, say – should not interfere with the therapy. In fact, you might even think it would enhance it.”

METHODOLOGY QUESTIONED

Teva responded last October, noting that, in contrast to the amount of attention it had received, the number of complaints regarding Budeprion XL 300 was no greater than for other drugs.

“Since the launch of Budeprion XL 300mg after its FDA approval 12 months ago, there have been approximately 4.5m prescriptions filled and reports received at a rate of 0.002%, as of October 12, a percentage that we believe is consistent with the rate of such reports for all prescription pharmaceuticals,” said a Teva official.

Teva did not question the validity of ConsumerLabs.com’s results, but rather their relevance, noting that the FDA compares blood levels rather than dissolution rates to determine bioequivalence.

“The testing methodology employed in this report is not that which is currently approved y the FDA for comparisons of generic products and is, therefore, inappropriate,” said the company official. “The current FDA standard, by which Budeprion has been evaluated and determined to be interchangeable with the brand, remains a test measuring the blood levels of both products over time in patients.”

Jerome Skelly, now a consultant to the pharmaceutical industry, but formerly the director of the division of biopharmaceutics and associate director for science in the Office of Generic Drugs at the FDA, agrees.

Dissolution tests are not an acceptable method for determining bioequivalence of extended-release dosage forms, he says. “Pharmacokinetic evaluations are the only method employed by the FDA for ascertaining whether or not a generic version of an innovator drug is bioequivalent.”

For extended-release drugs, these studies are typically conducted in 36-75 human volunteers, and they are carefully designed to account for individual variations in response to the drugs under evaluation, he says.

The dissolution test, in the case of extended-release drugs, is specific for each delivery system and it is used only to assure batch-to-batch uniformity within each manufacturer’s product line.

PERFORMANCE ANALYSIS

Skelly believes that the current system used by the FDA for determining bioequivalence is effective.

“No verifiable data has been presented yet to support the idea that the system does not work,” he says. “Therefore, it is highly unlikely that it wouldn’t be appropriate for determining bioequivalence for extended-release products, even those with different drug delivery technologies. Of course, just because it has not been seen before, doesn’t mean it’s impossible.”

The FDA has not made any determination as to whether there is a scientific preference for one type of delivery system over another, Skelly adds.

For Graedon, however, the FDA’s actions are worrisome.

“Bob Temple [of CDER] has verified that the human bioequivalence tests, like the dissolution tests, also demonstrated a more rapid release of active drug,” he says. “Apparently the FDA does allow differences in bioequivalence curves when it comes to brand versus generic drugs. What the FDA has not told us is what kinds of differences it allows.”

Graedon believes the differences should be clearly stated. “If the agency allowed a different bioequivalence curve for Budeprion XL 300, then it is entirely possible that it has allowed similar differences with other extended-release generics,” he says.

“The bottom line is that I have lost a lot of confidence in the FDA’s ability to guarantee equivalence. Were the agency to actually start testing products and be more transparent about its approval standards, I would be much more comfortable.”

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