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Questions and Answers Regarding Market Withdrawal of Budeprion XL 300 mg Manufactured by Impax and Marketed by Teva

Q1: What is FDA announcing today?
Q2. What are bupropion hydrochloride and Budeprion? 
Q3:  What actions has FDA taken as a result of its findings?
Q4. What is FDA’s recommendation for patients currently taking a 300 mg extended-release bupropion product?
Q5. Is the 150 mg strength Impax/Teva bupropion product bioequivalent to Wellbutrin 150 mg?
Q6. Why doesn’t Budeprion XL 300 mg, or a generic extended-release bupropion product by Teva, appear in the Orange Book?
Q7. How does FDA determine bioequivalence?
Q8.  What are the Therapeutic Equivalence (TE) Codes used by FDA?  What do these codes mean?
Q9. Why did FDA approve Impax’s 300 mg strength Budeprion XL product based on bioequivalence data for the 150 mg strength of the drug?
Q10.  When did FDA learn about potential problems associated with Impax/Teva’s 300 mg Budeprion XL product?
Q11. What was FDA’s initial response to the postmarketing reports submitted in the first half of 2007?
Q12.  What further action did FDA take in response to these concerns?
Q13.  Why did FDA do the study in healthy adult volunteers after asking Impax/Teva to conduct the study in a targeted patient population? 
Q14. What are the key results of the FDA-sponsored bioequivalence study?
Q15. Why did it take FDA two years to complete the bioequivalence study?
Q16.  What is FDA doing to ensure that other generic substitutes for Wellbutrin XL 300 mg are therapeutically equivalent?  Are these other approved generic versions of extended-release bupropion 300 mg still regarded as safe and effective by FDA? 
Q17. In retrospect, were FDA’s decisions regarding the approval and ongoing monitoring of Budeprion XL 300 mg appropriate?
Q18. What other manufacturers are approved to market bupropion extended-release tablets in the 300 mg strength?
Q19. How can health care professionals and patients report a suspected drug side effect?
Q20. Who can patients contact for more information?

Q1: What is FDA announcing today?

A1.  FDA is announcing that the generic drug, Budeprion XL 300 mg, manufactured by Impax Laboratories, Inc. (Impax) and distributed by Teva Pharmaceuticals USA, Inc. (Teva), is not therapeutically equivalent to the reference listed drug (RLD), Wellbutrin XL 300 mg.  The Agency is also announcing that Impax is withdrawing Budeprion XL 300 mg from the market.  New FDA-sponsored research shows that the Impax/Teva product fails to demonstrate bioequivalence to the RLD and therefore may not produce the same therapeutic benefits for some patients. 

Q2. What are bupropion hydrochloride and Budeprion? 

A2.  Bupropion hydrochloride was first approved under the brand name Wellbutrin as an antidepressant drug indicated for the treatment of major depressive disorder (MDD) and for the prevention of seasonal affective disorder.  Budeprion is a generic drug manufactured by Impax and distributed by Teva that contains the same active ingredient as Wellbutrin (bupropion hydrochloride). Other companies also make generic versions of bupropion hydrochloride.

Q3:  What actions has FDA taken as a result of its findings?

A3.  FDA has asked Impax Laboratories, Inc. (Impax) to voluntarily withdraw its application for the 300 mg strength of Budeprion XL (bupropion hydrochloride extended-release tablets, USP), because the drug failed to meet FDA’s bioequivalence standards for a generic drug.   The company agreed to do so.

At FDA's request, Impax and Teva ceased product distribution as of 9/28/12, and is conducting a voluntary market withdrawal (an action to remove product currently in distribution) of Budeprion XL 300 mg.  Impax and Teva are notifying customers, down to the retail level.

FDA has also changed the therapeutic equivalence (TE) rating for this product in the Agency’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) from AB to BX, signifying that Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg. 

FDA recently asked each of the other manufacturers – Anchen, Actavis, Watson, and Mylan – to conduct their own studies to assess the bioequivalence of their 300 mg extended-release bupropion tablets to Wellbutrin XL 300 mg.  FDA has asked these companies to submit the data from those studies no later than March 2013.  FDA believes that the failure of the Impax/Teva product to meet bioequivalence standards may reflect the product’s formulation, which is unique to the Impax/Teva version of bupropion hydrochloride. FDA is also revising its guidance to industry for how to conduct premarket bioequivalence studies in generic bupropion products.

Q4. What is FDA’s recommendation for patients currently taking a 300 mg extended-release bupropion product?

A4.  Patients taking Impax/Teva Budeprion XL 300 mg as a substitute for Wellbutrin XL 300 mg who have questions or concerns should discuss their medication with their health care professional.  FDA has not identified any new safety information associated with Budeprion XL 300 mg; however, in some patients, the drug may not provide the desired efficacy (beneficial effect). 

The other four generic versions of 300 mg extended-release bupropion tablets (manufactured by Anchen, Actavis, Watson, and Mylan) are not affected by today’s announcement.  FDA does not currently have data indicating that these products are not bioequivalent to Wellbutrin XL 300 mg.  Patients taking these other products should contact their health care professionals if they have questions or concerns.

Budeprion XL 300 mg is supplied as a yellow, oval, film-coated tablet, with "682" showing on one side and plain on the other side (Figure 1). Patients should ask their doctor or pharmacist to check what brand of bupropion XL 300 mg they are taking if they are unsure.

Budeprion

Q5. Is the 150 mg strength Impax/Teva bupropion product bioequivalent to Wellbutrin 150 mg?

A5. Yes, the 150 mg strength Impax/Teva bupropion product was shown to be bioequivalent to Wellbutrin 150 mg.  It was approved by FDA and is currently marketed.

Q6. Why doesn’t Budeprion XL 300 mg, or a generic extended-release bupropion product by Teva, appear in the Orange Book?

A6. The product that Teva markets as Budeprion XL 300 mg (extended-release bupropion hydrochloride 300 mg) is manufactured by Impax Laboratories, Inc.  The approved abbreviated new drug application (ANDA) number for this product is 077415 and the application is held by Impax. Therefore, this product is listed in the FDA publication Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) under the company who holds the ANDA, Impax Laboratories, Inc.

Q7. How does FDA determine bioequivalence?

A7. To market a generic drug, a manufacturer needs to demonstrate, among other things, that its product is bioequivalent to an FDA-approved reference listed drug.  Bioequivalent products are those that demonstrate a similar rate and extent of absorption of the therapeutic ingredient (the drug and/or active metabolite).  Methods to establish bioequivalence vary by the type and nature of the drug.  Because all drugs taken by mouth have some variation in absorption from one individual to another, or from batch to batch, FDA sets appropriate ranges to account for such variation.  FDA publishes bioequivalence recommendations for many drugs on the FDA website.

Generic drugs that are pharmaceutically equivalent and bioequivalent to the reference listed drug generally are given a therapeutic equivalence (TE) code of therapeutically equivalent (or “AB”) (see question below for an explanation of TE Codes).

Q8.  What are the Therapeutic Equivalence (TE) Codes used by FDA?  What do these codes mean?

A8. Therapeutic equivalence (TE) codes are a standard format for representing known information about a specific generic drug.  TE codes provide guidance to health care professionals regarding whether different prescription drug products are therapeutically equivalent to one another.  More complete information about the coding system.

Q9. Why did FDA approve Impax’s 300 mg strength Budeprion XL product based on bioequivalence data for the 150 mg strength of the drug?

A9.  At the time of the approval of Budeprion XL 300 mg, FDA permitted Impax and other sponsors to conduct bioequivalence studies on the 150 mg strength of the drug and to extrapolate the results to establish bioequivalence of the 300 mg product.  Typically, FDA’s Center for Drug Evaluation and Research recommends that the highest strength of a drug be used to establish bioequivalence to support a generic drug approval.  In the case of extended-release bupropion, the 300 mg strength of the drug was not used in bioequivalence studies due to concerns that this higher strength of the drug could cause seizures in healthy adult volunteers.  Therefore, FDA granted Impax a waiver, pursuant to which the company was not required to perform a bioequivalence study at the 300 mg strength but, instead, performed its bioequivalence studies on the next lower strength, 150 mg.  This practice is known as “waiving up.”  When it is thought that a bioequivalence study using the higher strength of a drug product line may cause unacceptable adverse events in healthy adult volunteers, FDA may recommend or consent to “waiving up.”

(See FDA Guidance for Industry, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products, General Considerations.)

Q10.  When did FDA learn about potential problems associated with Impax/Teva’s 300 mg Budeprion XL product?

A10.  FDA began to receive reports regarding generic extended-release bupropion products shortly after the Impax/Teva product was approved in December 2006.  Between January 1 and June 30, 2007, FDA received 85 post-marketing reports describing either adverse events or lack of an effect after switching from Wellbutrin XL 300 mg to Impax/Teva’s Budeprion XL 300 mg.  The reported adverse events were consistent with the adverse effects noted in bupropion XL product labels.  The reports relating to efficacy involved lack of antidepressant effect, and in some instances, worsening of depression symptoms, following a switch from the brand name to a generic product.  Nearly half of the patients who reported experiencing a lack of effect or adverse events upon switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg subsequently reported experiencing an improvement in conditions when they resumed their Wellbutrin XL 300 mg regimen.  Reports of lack of effect were difficult to interpret given the natural course of depression in the treated population.  FDA’s decision to require additional bioequivalence testing was intended to provide further data to facilitate interpretation of the post-marketing reports submitted to the Agency.

Q11. What was FDA’s initial response to the postmarketing reports submitted in the first half of 2007?

A11.  FDA re-examined the data comparing the bioavailability of the two bupropion XL 150 mg products (Wellbutrin XL and Impax’s Budeprion XL).  Based on that data, FDA concluded that Impax’s Budeprion XL 150 mg was bioequivalent and therapeutically equivalent to Wellbutrin XL 150 mg.  Although FDA observed differences in the pharmacokinetic profiles of these two products at that time, they were not outside of the established boundaries for bioequivalence and they were consistent with bioequivalence data for other bupropion products known to be effective.  Based on the data available at the time, FDA determined that these findings could be extrapolated to the 300 mg strengths of extended-release bupropion.

Q12.  What further action did FDA take in response to these concerns?

A12.  FDA continued to review postmarketing reports throughout 2007.  In November 2007, taking into consideration reports of lack of efficacy, FDA requested that Impax/Teva conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg.  The study protocol stipulated the enrollment of patients who reported problems after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg.  Impax/Teva began the study, but terminated it in late 2011, reporting that despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients.

In 2010, because of the public health interest in obtaining bioequivalence data, FDA decided to sponsor a bioequivalence study comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg.  The FDA-sponsored study enrolled 24 healthy adult volunteers and examined the rate and extent of absorption of the two drug products under fasting conditions.  In that study, the results of which became available in August 2012, Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

Q13.  Why did FDA do the study in healthy adult volunteers after asking Impax/Teva to conduct the study in a targeted patient population? 

A13.  The Agency determined that it was important to conduct direct bioequivalence studies comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg, in light of the reports that patients and health care professionals had submitted to FDA.  FDA believed that the optimal patient population for those studies would be patients who had reported a lack of efficacy or unwanted side effects after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg.  The rationale for this was two-fold.  First, the Agency believed that such a study would better target the reported problems and thereby provide the best information as to why the drug did not appear to be effective.  Second, because that patient population was taking the 300 mg strength of the drug already, this study design would not unnecessarily expose healthy adult volunteers to the higher strength of the drug, particularly given concerns that this strength might be associated with risk of seizures.

Impax/Teva, however, was unsuccessful in recruiting a sufficient number of patients who had reported a lack of efficacy or unwanted side effects after switching from Wellbutrin XL 300 mg to Budeprion XL 300 mg.  Due to the continuing questions about the efficacy of the Impax/Teva 300 mg bupropion product, the risks associated with reduced efficacy in patients with major depressive disorder, and increased experience with the safety profile of the drug, FDA concluded that a small bioequivalence study in healthy adult volunteers should be conducted. 

In 2010, FDA decided to sponsor a study to be performed in healthy adult volunteers who were not being treated with the drug. FDA developed the study protocol and a test method that could identify bupropion and very closely related metabolites of bupropion, providing more accurate information about how bupropion is absorbed and subsequently metabolized by the body.  The results of the FDA-sponsored bioequivalence study became available in August 2012, and they showed that Budeprion XL 300 mg fails to demonstrate bioequivalence to Wellbutrin XL 300 mg.

Q14. What are the key results of the FDA-sponsored bioequivalence study?

A14. Key results of the FDA-sponsored bioequivalence study are as follows:

  • Budeprion XL 300 mg is not absorbed into the bloodstream at the same rate and to the same extent as Wellbutrin XL 300 mg.
  • The 90% confidence interval of the geometric mean area-under-the-curve (AUC) and Cmax test/reference ratios must fall within the limits of 80-125% to demonstrate bioequivalence.
  • The mean AUC for the 24 healthy adult volunteers after administration of Budeprion XL 300 mg was 86% (90% CI, 76.7-95.8%) of the value determined after administration of Wellbutrin XL 300 mg.
  • The corresponding Cmax value for Budeprion XL 300 mg was 75% of the value for Wellbutrin XL 300 mg (90% CI, 65.2-86.8%).
  • Pharmacokinetic measurements determined for hydroxybupropion, the major active metabolite of bupropion, also failed to meet the regulatory standards necessary to establish bioequivalence.
  • Therefore, the FDA-sponsored bioequivalence study showed that Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

Q15. Why did it take FDA two years to complete the bioequivalence study?

A15.   FDA made the decision in 2010 to sponsor a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg in 2010.  In that time, FDA worked to get funding for the study, designed the study, obtained approval from the Institutional Review Board for Protection of Human Subjects, recruited and enrolled healthy volunteers, conducted the study, developed an analytical method of analyzing the data, and completed its analysis of the study data.

Q16.  What is FDA doing to ensure that other generic substitutes for Wellbutrin XL 300 mg are therapeutically equivalent?  Are these other approved generic versions of extended-release bupropion 300 mg still regarded as safe and effective by FDA? 

A16.  FDA does not have data showing that the other four generic products are not bioequivalent to Wellbutrin XL 300 mg.  FDA believes the study results may be unique to the Impax/Teva version of 300 mg bupropion hydrochloride.   FDA did, however, recently ask each of the other manufacturers – Anchen, Actavis, Watson, and Mylan – to conduct their own studies to assess the bioequivalence of their 300 mg extended-release bupropion tablets to Wellbutrin XL 300 mg.  FDA has asked these companies to submit the data from those studies no later than March 2013.  FDA is also revising its guidance to industry for how to conduct premarket bioequivalence studies in generic bupropion products.

Q17. In retrospect, were FDA’s decisions regarding the approval and ongoing monitoring of Budeprion XL 300 mg appropriate?

A17. A less cautious approach in studying the bioequivalence of Budeprion XL 300 mg could have brought the data to light earlier. The FDA-sponsored study was completed only weeks ago, which is a very short time for data from a clinical experiment to be announced to the public. 

Bupropion is associated with a risk for seizures, which was the basis of the Agency's cautious approach with regard to the early Budeprion XL bioequivalence studies, in which data were extrapolated from Budeprion XL 150 mg in patients to the projected consequences of exposure to Budeprion 300 mg. In retrospect, it is clear that this extrapolation did not provide the right conclusion regarding bioequivalence of Budeprion XL 300 mg. FDA also has much more knowledge today of the seizure-associated risk of bupropion-containing drugs. The trial design of the sponsor-initiated study of 2007 could have been successful, had it been replaced by the trial design employed in the recent FDA-sponsored study.

Q18. What other manufacturers are approved to market bupropion extended-release tablets in the 300 mg strength?

A18.  Bupropion extended-release 300 mg tablets are available as generic products from four other manufacturers, in addition to the branded Wellbutrin XL 300 mg product (Table 1).

Table 1.  FDA-Approved Generic Bupropion Extended-Release 300 mg Tablets

Manufacturer

ANDA Number

Approval Date

AnchenA077284December 14, 2006
WatsonA077715June 13, 2007
ActavisA077285August 15, 2008
MylanA090942July 14, 2010

Q19. How can health care professionals and patients report a suspected drug side effect?
A19. Health care professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

  • Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
  • Download form or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

Q20. Who can patients contact for more information?

A20. Patients who have further questions should contact FDA’s Division of Drug Information: Toll Free (855) 543-3784, or (301) 796-3400 or by email druginfo@fda.hhs.gov.