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The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

We investigated impacts of increased generic drug use on spontaneous adverse event reports (SAERs), because SAERs have been a major source of data for drug safety assessment at the postmarket stage. Reporting proportion of SAERs for the generic drugs was consistently and significantly lower than that for the original branded drugs. The reporting proportion targeting for 55 active product ingredients, which had the longest follow-up period after generic drug marketed, gradually decreased for the original branded drugs and increased for the generic drugs. However, these transitions did not parallel the changes in market share over the same period. These results suggest that the reporting proportion of SAERs for generic drugs may not keep pace with growth in market share. When generic drugs account for the majority of market share, utilization of multiple sources of information and data, in addition to SAERs, may be a key to assuring drug safety at the postmarket stage., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Controversy persists about bupropion XL 300 mg generic equivalence to brand product. A prospective, randomized, double-blinded crossover in 70 adults with major depression in stable remission taking any bupropion XL 300 mg tested bioequivalence and therapeutic equivalence of available XL 300 mg products. After a 4-week lead-in on patients' existing bupropion, four 6-week phases evaluated brand and three generics. Patients were uninformed of switching. Drug overencapsulation ensured blinding. There were no differences between any generic and brand, or between generics, in peak plasma concentration (C max ) and area under the plasma concentration-time curve over the 24-hour dosing interval (AUC 0-24 ) for racemic bupropion or major metabolites. All generics met formal bioequivalence criteria for bupropion and metabolites. There were no differences between generics and brand, or between generics, in depression symptoms or side effects, assessed by every 3-week in-person interview and daily smartphone-based self-report. There were no differences in patients' perceptions of bupropion products. Results show three bupropion XL 300 mg generic products are both bioequivalent and not therapeutically different from brand drug and each other., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

The European Medicines Agency's (EMA) product-specific bioequivalence guidelines outline harmonized regulatory requirements for studies to demonstrate bioequivalence for products that may have particular needs due to their pharmacokinetics, in addition to those outlined in general guidance. As such they are potentially very useful to the pharmaceutical industry in the development of generic medicinal products and to regulatory authorities for harmonized decision-making. Since their introduction in 2013, EMA product-specific bioequivalence guidelines continue to increase in number, and as of June 2017, encompass a number of different pharmacotherapeutic groups and pharmaceutical forms. This article further elucidates the processes involved for stakeholders and reviews the Agency's experience with the development of these guidelines, including the scientific issues witnessed with their advancement. A comparison with the United States Food and Drug Administration approach to similar guidelines is also provided., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Small changes in bioavailability of narrow therapeutic index (NTI) drugs can alter clinical outcomes, raising concern over generic NTI substitution. We surveyed pharmacists to identify their perceptions of generic NTI drugs, their frequency of performing generic NTI substitution, and predictors of this behavior. Of 710 respondents (33% response rate), 87% perceived generic NTI drugs as effective as their brand-name versions and 94% as safe. Whereas 82% almost always performed generic NTI substitution for initial prescriptions, only 60% did for refills. Pharmacists in non-chain settings (odds ratio (OR) = 2.37; 95% confidence interval (CI) = 1.40-4.02), in practice longer (per year OR = 1.04; 95% CI = 1.02-1.06), in states with affirmative patient consent laws (OR = 1.88; 95% CI = 1.06-3.32), and in states with NTI-specific substitution requirements (OR = 1.95; 95% CI = 1.16-3.26) were more likely not to substitute initial prescriptions. Education of non-chain and veteran pharmacists and elimination of affirmative patient consent and NTI-specific substitution requirements could increase generic NTI substitution., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. This retrospective cohort study compared outcomes for generics and authorized generics, which serves as a generic vs. brand proxy that minimizes bias against generics. For the seven drugs studied between 1999 and 2014, 5,234 unique patients were on brand drugs prior to generic entry and 4,900 (93.6%) switched to a generic. During the 12 months following the brand-to-generic switch, patients using generics vs. authorized generics were similar in terms of outpatient visits, urgent care visits, hospitalizations, and medication discontinuation. The likelihood of emergency department (ED) visits was slightly higher for authorized generics compared with generics. These data suggest that generics were clinically no worse than their proxy brand comparators., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Spontaneous adverse event reports constitute an important source of information on previously unknown adverse reactions to marketed medicines. However, the dynamics of such reporting following generic introduction are poorly understood. Using adverse event reports on five antiepileptic drugs from the US Food and Drug Administration's Adverse Event Reporting System, we describe temporal trends in adverse event reporting before and after generic introduction, and survey the quality of product-identifying information contained therein. The majority of reports were sent by innovator drug manufacturers while few were sent by generic manufacturers, even when generics accounted for >90% of dispensed prescriptions. We manually reviewed narratives from 2,500 reports and found that the suspect product type (brand or generic) could not be determined in 84% of reports, while generic products (16%) were identified more often than brand-name products (<1%). These results suggest that pharmacovigilance stakeholders should act to promote more detailed reporting practices., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

The summary of product characteristics (SPC) should provide information for the safe prescription and use of a drug. We evaluated the consistency of critical interaction warnings, the quality of presentation of undesirable effects as well as concordance of critical information of representative drugs marketed in the United States, the UK, and Germany. Reciprocal warnings regarding drug-drug interactions that constitute contraindications were frequently missing in the SPCs of the drugs concerned (all countries >40%). Most SPCs did not explicitly exclude adverse reactions considered not reasonably attributable to the use of the drug. Comparing SPCs of different generic brands of the same drug, only 60, 10, and 20% of the US, UK, and German SPCs, respectively, provided identical contraindications. Current SPCs contain inconsistencies and misleading data that are not compatible with the purpose of SPCs, which is to provide a basis for the safe prescription and use of drugs.

We sought to estimate the risk of seizure-related events associated with refilling prescriptions for antiepileptic drugs (AEDs) and to estimate the effect of switching between brand-name and generic drugs or between two generic versions of the same drug. We conducted a case-crossover study using health-care databases from British Columbia, Canada, among AED users who had an emergency room visit or hospitalization for seizure (index seizure-related event), defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes 345.xx (epilepsy and recurrent seizures) and 780.3x (convulsions), between 1997 and 2005. AED prescription refilling itself was associated with 2.3-fold elevated odds of seizure-related events when the refill occurred within 21 days before the index event (odds ratio (OR) 2.31; 95% confidence interval (CI) 1.56-3.44). The OR was 2.75 (95% CI 0.88-8.64) for refills that involved switching, yielding a refill-adjusted OR for switching of 1.19 (95% CI 0.35-3.99). Refilling the same AED prescription was associated with an elevated risk of seizure-related events whether or not the refill involved switching from a brand-name to a generic product.

In this issue Gagne et al. report an elegant case-crossover study of seizures in patients on antiepileptic drugs. They found that a dispensation episode approximately triples the risk of having a seizure within 21 days, but the risk is not statistically different whether the dispensation was of the same brand-name or generic drug as previously used or a switch from brand-name to a generic or from a generic to a brand name. The cause of the seizure might be a delay in taking medication or late redispensation, among others, but apparently the nature of the product dispensed is not relevant in this study; this may alleviate some of the concerns about generic drugs and epilepsy.

As Congress begins drafting legislation concerning the US Food and Drug Administration (FDA) regulation of biosimilars, it is critical to keep in mind that these agents may differ from their innovator compounds. Therefore, it is of the utmost importance to be able to differentiate among innovators and biosimilars in administrative data in order to facilitate the conduct of population-based safety and comparative effectiveness studies. This Commentary proposes methods that would allow these agents to be distinguished in such data.

Objective: Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998., Methods: In the computerized records of a health maintenance organization database, we identified 975 patients who took warfarin continuously over two 6-month periods, before (period 1) and after (period 2) the generic switch. In this sample we performed a retrospective, between-period paired comparison of warfarin doses dispensed and international normalized ratio (INR) levels maintained, as well as of the apparent warfarin sensitivity index (calculated as INR/Warfarin dose [in milligrams per day])., Results: Overall, for period 2, doses were 26.5% higher and INR 4.2% lower, with a 14.7% reduction in warfarin sensitivity index (P <.001). The findings were strongest in the 61 of 975 patients (6.3%) dispensed the lowest maintenance doses (<1.0 mg/d), with minimal change at greater than 3 mg/d. In 94 other patients (9.6%) in whom doses were unchanged, INR (median with 5th and 95th percentiles) dropped to subtherapeutic levels, from 2.2 (1.8, 3.0) to 1.7 (1.3, 1.8) (P <.001). There were no adverse events, expressed as no change in hospital admissions. Apparent warfarin sensitivity was reduced in period 2 by 15% to 20% (P <.001) across all period 1 INR levels., Conclusion: Because a general unidirectional change in INR response per unit warfarin dose cannot be explained by biologic mechanisms or confounding, we conclude that slightly reduced bioavailability (within the acceptable bioequivalence range) of the new formulation led to overestimated period 2 doses and reduced apparent warfarin sensitivity in all patient subgroups (by period 1 dose or INR), which was most prominent in those individuals with the lowest maintenance dose requirements.