Withdrawal of Generic Budeprion for Nonbioequivalence
ABSTRACT The Food and Drug Administration (FDA) has completed a head-to-head bioequivalence study of single doses of the generic drug Budeprion XL 300 mg (extended-release bupropion hydrochloride, manufactured by Impax Laboratories and distributed by Teva Pharmaceuticals) and the brand-name drug Wellbutrin XL 300 mg (Biovail). The agency has concluded that Budeprion XL 300 mg cannot be considered therapeutically equivalent to the brand-name product. We at the FDA are therefore changing our bioequivalence recommendations for extended-release bupropion products and have asked other manufacturers of 300-mg extended-release bupropion products to conduct additional bioequivalence studies. Within a year after gaining approval at the end . . .
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ABSTRACT: Tacrolimus (FK506) is a potent, narrow therapeutic index, immunosuppressive drug used to avoid organ rejection in patients that have undergone organ transplantation. Recent clinical reports suggested a significant reduction in the tacrolimus concentration/dose ratio in the plasma of liver and kidney recipients when the reference listed drug was substituted with a generic drug. In response to these concerns about switching between tacrolimus from different approved manufacturers during treatment, the FDA initiated purity, potency and quality studies of the innovator and generic tacrolimus products available in the US marketplace. A combination of analytical methods, including mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) and bioactivity assay were developed and validated to assess the quality of tacrolimus. These tests measured the identity, impurities and activity of tacrolimus from active pharmaceutical ingredient (API) sources and with formulated drug product from five different approved manufactures. In addition, some testing was performed on tacrolimus capsules obtained from a non US approved Indian source. The data obtained showed no discernible difference in the impurity profiles and potency between the generic and innovator tacrolimus products.Journal of pharmaceutical and biomedical analysis 07/2013; 85C:108-117. DOI:10.1016/j.jpba.2013.07.001 · 2.83 Impact Factor
- The Journal of Clinical Endocrinology and Metabolism 02/2013; 98(2):511-4. DOI:10.1210/jc.2012-4310 · 6.31 Impact Factor
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ABSTRACT: For economic reasons, the generic substitution of branded medications is common and welcome. These replacements are based on the concept of bioequivalence, which is considered equal to therapeutic equivalence. Regulatory standards for bioequivalence require the 90 % confidence intervals of group averages of pharmacokinetic measures of a generic and the original drug to overlap within ±20 %. However, therapeutic equivalence has been challenged for several psychotropic agents by retrospective studies and case reports. To evaluate the degree of bioequivalence and therapeutic equivalence of branded and generic psychotropic drugs, we performed an electronic search (from database inception until 24 May 2012 and without language restrictions) in PubMed/MEDLINE, Cochrane Library, and Web of Science. Search terms were "(generic) AND (psychotropic OR psychoactive OR antipsychotic OR antiepileptic OR antidepressant OR stimulant OR benzodiazepine)" or the respective individual substances. We included clinical studies, regardless of design, comparing branded with generic psychotropic drug formulations, identifying 35 such studies. We also included case reports/series reporting on outcomes after a switch between brand and generic psychotropics, identifying 145 clinical cases. Bioequivalence studies in healthy controls or animals, in-vitro studies, and health economics studies without medical information were excluded. An overview of the few randomized controlled studies supports that US FDA regulations assure clinically adequate drug delivery in the majority of patients switched from brand to generic. However, with a growing number of competing generic products for one substance, and growing economic pressure to substitute with the currently cheapest generic, frequent generic-generic switches, often unbeknownst to prescribing clinicians, raise concerns, particularly for antiepileptics/mood stabilizers. Generic-generic switches may vary by more than ±20 % from each other in individual patients since the pharmacokinetic properties of each generic may differ from the innovator drug in opposing directions. Ideally, therapeutic equivalence studies in addition to pharmacokinetic equivalence studies would be performed for each generic, reflecting the full variability of clinical responses due to changes of pharmacokinetic properties related to age, sex, ethnicity, genetic factors, and body mass index. This is particularly relevant, as bioequivalence studies are based on single-dose studies in healthy controls who are likely not representative of the patients who are prescribed the psychotropic medications. Additionally, individual case reports suggest potential clinical effects during brand-generic switches. Knowledge and consideration of intra-individual variations can help guide the clinical management during brand-generic or generic-generic switch periods. To optimize outcomes, clinicians need to consider that when using generic psychotropic medications, a change in the patient's clinical status can be related to psychological, interactional, physiological, and pharmacological factors that may or may not be related to the change to a generic drug. In addition, throughout all treatment periods, clinicians need to be aware of the currently dispensed product (i.e., branded or exact generic formulation), particularly when evaluating clinical changes in efficacy, tolerability, and adherence. If clinical problems occur, the first response should be an assessment of adherence and a careful dose adjustments of the generic drug rather than an immediate switch back to the originator.CNS Drugs 04/2013; 27(5). DOI:10.1007/s40263-013-0045-2 · 4.38 Impact Factor