Question from a Member:
Is brand name Wellbutrin (bupropion) more effective than generic? Many years ago, I read that this was the case.
For a broader explanation of generic versus brand-name medications, please see the following article:
A brief history of generic bupropion
When we hear that a particular generic was withdrawn, this understandably makes us doubt the quality of all generic versions for that medication and maybe even all generics, period. But, going over the history of the withdrawal of generic bupropion extended-release tablets will give us a more accurate understanding of why such problems occur and why we cannot generalize from a particular problem that occurred that all generics are problematic.
In late 2006, the US Food and Drug Administration (FDA) approved the first generic version of Wellbutrin XL (bupropion hydrochloride) extended-release 150 mg and 300 mg tablets (Food and Drug Administration, 2007). At that time, the FDA received a citizen petition asking it to review issues related to the generic bupropion extended-release. It did so and concluded that:
“Consumers and health professionals can be assured that an approved generic drug is bioequivalent to a brand-name drug and is its equal in dosage form, strength, and route of administration, quality, performance characteristics, and intended use.”
This turned out to not be true in this case.
In retrospect, the problem was that the FDA had conducted pharmacokinetic tests only on the 150 mg tablets of the generic bupropion extended-release manufactured by Impact Laboratories and marketed by Teva Pharmaceuticals and extrapolated the results to the 300-mg tablet (Woodcock et al., 2012). Why? This was because the FDA was concerned about giving a higher dose of bupropion to healthy volunteers, in whom pharmacokinetic studies for generics are done, due to a perceived risk of seizures with higher doses of bupropion. As you will see below, this turned out to be a mistake. Also, even the 150 mg tablets released bupropion earlier than the brand name tablets, but the difference fell within the range that the FDA considers to be acceptable (Woodcock et al., 2012).
Soon after the introduction of the generic bupropion extended-release, many complaints about it started to come in. Most of these were about patients who had been switched from brand name Wellbutrin XL 300 mg to the corresponding generic that was marketed by the pharmaceutical company Teva under the name Budeprion XL (Medical Letter on Drugs and Therapeutics, 2008). These complaints about lower efficacy and more side effects with generic bupropion continued for several years.
Also, in 2007, an independent laboratory conducted testing of the dissolution of the brand name (Wellbutrin XL) and generic (Budeprion XL) bupropion extended-release tablets. It found that the generic formulation released more bupropion in the first 4 hours than the brand name bupropion (Medical Letter on Drugs and Therapeutics, 2012).
The FDA conducted its own testing of Budeprion XL 300 mg tablets and the findings were the same.
It wasn’t until 2012 that the FDA asked Impax/ Teva to “voluntarily” withdraw Budeprion XL 300 mg tablets (Woodcock et al., 2012; Medical Letter on Drugs and Therapeutics, 2012). It asked other manufacturers of bupropion extended-release to conducted additional bioequivalence studies (Woodcock et al., 2012). The results of these studies came back in 2013 (see below).
The complaints and problems on testing were only about that one specific generic version of bupropion extended-release, Budeprion XL 300 mg. The 150 mg tablets and generic 300 mg tablets made by other manufacturers were not withdrawn.
Can a generic bupropion extended-release be made that did not have this problem? The answer depends on understanding what the reason was for the difference between Wellbutrin XL and Budeprion XL. The method by which the tablets released the drugs gradually was different. Wellbutrin XL used a membrane while Budeprion XL used a matrix method (Medical Letter on Drugs and Therapeutics, 2012). The other manufacturers of bupropion extended-release 300 mg tablets do not use the same technology as was used in Budeprion XL 300 mg tablets (Woodcock et al., 2012).
Authors who were from the FDA gave the opinion what happened with Budeprion XL should not “cause concern regarding the overall reliability of the agency’s approval process for generic drugs, including the use of extrapolation, when scientifically appropriate” (Woodcock et al., 2012).
The rest of the story
More data came from two sources: an FDA-funded clinical trial and FDA-mandated bioequivalence studies done by the generic manufacturers.
The FDA-funded clinical trial
A randomized, double-blind clinical trial comparing generic and brand name bupropion extended-release 300 mg tablets was done, funded mainly by a grant from the FDA (Kharasch et al., 2019).
Subjects: 70 adults with major depression in stable remission while taking any preparation of bupropion XL 300 mg
Methods: Without telling the patients and with the pills made to look identical, patients were switched one by one to three different generics manufactured by Mylan, PAR (formerly Anchen), Valeant, and Watson, and the brand name Wellbutrin XL (GlaxoSmithKline) 300 mg. Each preparation was taken for 6 weeks.
Results: No differences were found between the brand name and any of the three generic preparations in terms of peak plasma concentration and exposure to bupropion or its major metabolites over 24 hours. Also, were no differences between the brand name and the three generics in terms of depression symptoms and side effects that were systematically assessed. When asked, many patients reported feeling some differences between the different products but their reports were not statistically significantly different between the brand name product any of the three generics. Please note this: just because a patient says that a particular generic is less effective or has more side effects does NOT necessarily mean that that genetic is problematic because, when blinded, patients also said things like that for the brand name Wellbutrin XL. The three generics tested were also not different from each other on any of the variables.
Bioequivalence studies for the other bupropion extended-release generics
In 2013, the results of the bioequivalence studies that the FDA had asked for came back (Food and Drug Administration, 2013). The Watson generic was also “voluntarily” withdrawn.
But, here’s the good news: The other three generic bupropion extended-release 300 mg products, manufactured by Actavis, Mylan, and PAR (formerly Anchen) were found to be bioequivalent to brand name Wellbutrin XL (Food and Drug Administration, 2013).
There was definitely a problem with generic bupropion extended-release in the first few years after the medication went generic. That incident understandably shook the faith of prescribing clinicians in generic bupropion extended-release, and maybe even in the FDA’s regulation of generics in general.
But, I found it helpful to know that the FDA had made a specific mistake—not testing the 300 mg tablets of the generic due to concern about seizures in healthy volunteers. I assume that they have learned their lesson.
By the way, we should not think that it is common for the FDA to find later on that a generic version of some medication is not bioequivalent to the brand name preparation after all. It is very rare for the FDA to reverse its approval of a generic like it did for Budeprion XL.
There are many different generic preparations of bupropion extended-release available (Food and Drug Administration, 2020). Of these:
– Budeprion XL is no longer available as of March 2020 (source: goodrx.com).
– But, several other generic equivalents for bupropion extended-release (and for bupropion sustained-release) have also been rated by the FDA as being “therapeutically equivalent” to the brand name product (called the “Reference Listed Drug” by the FDA) based on specific bioequivalence testing.
– Optional to read: Just FYI, both the “Reference Listed Drugs” and the “therapeutically equivalent” generics for bupropion (and other medications) are listed by the FDA in its “Approved Drug Products with Therapeutic Equivalence Evaluations“, commonly known as the “Orange Book”, which can be searched at this link if needed. thought clinicians don’t really need to do this.
I think that as of April 2020, it seems that the problem with generic bupropion extended-release has been resolved.
Food and Drug Administration (FDA). Approved drug products with therapeutic equivalence evaluations. 40th edition. Available at: https://www.fda.gov/media/71474/download. Accessed March 26, 2020.
Food and Drug Administration (FDA). Generic version of Wellbutrin XL. FDA Consum. 2007 Mar-Apr;41(2):4. PubMed PMID: 17590892. Available at: https://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/departs/2007/207_upd.html#wellbutrin Accessed March 26, 2020. Announcement of the availability of generic bupropion extended-release.
Food and Drug Administration (FDA). Questions and Answers Regarding Market Withdrawal of Budeprion XL 300 mg Manufactured by Impax and Marketed by Teva. Available at: https://wayback.archive-it.org/org-1137/20170406044709/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm322160.htm. Accessed March 26, 2020.
Food and Drug Administration (FDA). Bioequivalence evaluation of innovator and generic bupropion XL products. 2012. Available at: https://wayback.archive-it.org/org-1137/20170406044720/https://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM323471.pdf.Accessed March 26, 2020.
Food and Drug Administration (FDA). Update: Bupropion Hydrochloride Extended-Release 300 mg Bioequivalence Studies. 2013. Available at https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/update-bupropion-hydrochloride-extended-release-300-mg-bioequivalence-studies. Accessed March 26, 2020.
Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Schweiger J, Miller JP, Lenze EJ. Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial. Clin Pharmacol Ther. 2019 May;105(5):1164-1174. doi: 10.1002/cpt.1309. Epub 2019 Jan 18. PubMed PMID: 30460996; PubMed Central PMCID: PMC6465131.
Medical Letter on Drugs and Therapeutics. Wellbutrin versus generic bupropion. Med Lett Drugs Ther. 2008 Jul 14;50(1290):54-5. PubMed PMID: 18617874.
Medical Letter on Drugs and Therapeutics. In Brief: Budeprion XL 300 Has Been Withdrawn. Med Lett Drugs Ther. 2012. Available at: https://secure.medicalletter.org/w1402c. Accessed March 26, 2020.
Woodcock J, Khan M, Yu LX. Withdrawal of generic budeprion for nonbioequivalence. N Engl J Med. 2012 Dec 27;367(26):2463-5. doi: 10.1056/NEJMp1212969. Epub 2012 Dec 5. PubMed PMID: 23216549.
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