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Latuda ®  is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda ® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40 mg of generic lurasidone or Latuda ® . After a 7-day washout period, subjects entered the second period with a crossover administration of 40 mg of generic lurasidone or Latuda ® . The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda ® were as follows: the C max was 28.84 ± 19.34 ng/ml and 28.22 ± 21.19 ng/ml, respectively; the AUC 0-t was 121.39 ± 58.47 h*ng/ml and 118.35 ± 52.24 h*ng/ml, respectively; and the AUC 0-∞ was 129.63 ± 63.26 h*ng/ml and 126.59 ± 57.99 h*ng/ml, respectively. The primary pharmacokinetic parameter, C max , was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC 0-t , AUC 0-∞ ) were evaluated using average bioequivalence (ABE). The results indicate that both C max and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda ® were as follows: the C max was 74.89 ± 32.06 ng/ml and 83.51 ± 33.52 ng/ml, respectively; the AUC 0-t was 274.77 ± 103.05 h*ng/ml and 289.26 ± 95.25 h*ng/ml, respectively; and the AUC 0-∞ was 302.44 ± 121.60 h*ng/ml and 316.32 ± 109.04 h*ng/ml, respectively. The primary pharmacokinetic parameters (C max , AUC 0-t , AUC 0-∞ ) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda ® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda ® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice., (© 2024 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The use of generic specialty medications amongst individuals with multiple sclerosis (MS) has expanded due to an increase in the number of available agents. We describe a woman who was denied continued use of brand name teriflunomide (Aubagio Ⓡ ), despite being clinically stable for 2.5 years, and switched to generic teriflunomide. She experienced a significant spinal cord exacerbation within a few months of starting treatment. We analyzed 3 generic teriflunomide agents, including the one used for treatment, in addition to Aubagio Ⓡ . The generic teriflunomide used by our patient contained 55.5 % content of the labeled amount, well below U.S. FDA specifications., Competing Interests: Declaration of competing interest D.T.O. received personal compensation for consulting and advisory services from Biogen, Eisai, EMD Serono, Genentech, Genzyme/Sanofi, Moderna, RVL Pharmaceuticals, Inc., Zenas Biopharma, and research support from EMD Serono/Merck, and Novartis. Dr. Okuda has issued national and international patents along with pending patents related to other developed technologies. Dr. Okuda received royalties for intellectual property licensed by The Board of Regents of The University of Texas System. Dr. Okuda is the Founder of Revert Health Inc. K.W.B., T.M.M., and M.A.P. report no disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Estradiol valerate (Progynova ® ) is used as hormone therapy to supplement estrogen deficiency. This study aimed to assess the bioequivalence of an estradiol valerate tablet and its generic form, under fasting and fed conditions., Methods: A randomized, open-label, single-dose, 2-period crossover study was conducted on healthy postmenopausal Chinese female volunteers under fasting and fed conditions. For each period, the subjects received either a 1 mg tablet of estradiol valerate or its generic. Blood samples were collected before dosing and up to 72 hours after administration. Plasma levels of total estrone, estradiol, and unconjugated estrone were quantified using a validated liquid chromatography-tandem mass spectrometry method., Results: A total of 54 volunteers were enrolled in this study. The primary pharmacokinetic parameters, including C max , AUC 0-t , and AUC 0-∞ , were similar for the two drugs under both fasting and fed conditions, with 90% confidence intervals for the geometric mean ratios of these parameters, all meeting the bioequivalence criterion of 80-125%. A total of 48 adverse events (AEs) were reported in the fed study compared with 24 AEs in the fasting study., Conclusion: Estradiol valerate and its generic form were bioequivalent and well tolerated under both fasting and fed conditions., Competing Interests: The trial staff interpreted all data for this study independently from the sponsor. Li Zhang, Mupeng Li, Lianlian Fan, Fangfang Liu, Peiwen Zhang, Qian Huang, and Gang Mai are employees of the Deyang People’s Hospital, and Jianzhong Shentu is an employee of the First Affiliated Hospital, Zhejiang University School of Medicine. The authors have no other relevant affiliations, financial involvement, or interests in any organization or entity related to the subject matter or materials discussed in this manuscript., (© 2024 Zhang et al.)

At Oita University Hospital, we switched our usage of pemetrexed(PEM)from brand-name to generic drugs. We conducted a comparative study of the preparation efficiency and therapeutic safety with the brand-name product and examined the economic effect thereof. The incidence of adverse drug reactions was investigated retrospectively using electronic medical records for patients who received PEM brand-name and generic drugs at our hospital between April 2021 and December 2022. The preparation time per mg was significantly shorter in the generic group at 0.17(0.08-0.38)seconds compared to 0.34(0.15-0.94)seconds for the brand-name group(p<0.01). Regarding the safety comparison, none of the 13 eligible patients developed new hematologic or non-hematologic toxicities of Grade 2 or higher after switching to the generic product. The switch to generics had an economic impact of 7,369,278 yen during the study period. The results suggest that switching from brand-name to generic products is reasonable from the perspectives of therapeutic safety and economic benefits, as well as the expected improvement in preparation efficiency.

Objective: Atrial fibrillation (AF) is the most common abnormal heart rhythm in elderly patients. Rivaroxaban has been widely used for stroke prevention. The anticoagulant response to rivaroxaban increases with age, which may make elderly patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products., Methods: We designed a cohort study of ≥65-year-old inpatients with AF. Sociodemographic and laboratory measures of qualified patients who received brand or generic rivaroxaban for at least 72 hours at the study hospital from January 2021 to June 2023 were collected retrospectively. The primary outcome was the incidence of bleeding., Results: A total of 1008 qualifying patients were included for analysis, with 626 (62.1%) receiving brand rivaroxaban and 382 (37.9%) receiving generic rivaroxaban. After propensity score matching and weighting to account for confounders, the odds ratios comparing brand vs generic rivaroxaban (95% confidence intervals) for the bleeding was 1.15 (0.72-1.82). Results from subgroup analyses of patients with age ≥85, HAS-BLED score ≥ 3, containment of antiplatelet drugs, and female patients were consistent with the primary analysis., Conclusion: It provides evidence regarding the clinical safety outcome of generic rivaroxaban in the elderly AF population that may be particularly susceptible to adverse outcomes resulting from small allowable differences in pharmacokinetics., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 Chen et al.)

Background: South Africa is home to a multi-ethnic society with a large range of cultures and lifestyles. Cardiovascular disease is a major cause of morbidity and mortality. South Africa is known to have one of the highest incidence rates of hypercholesterolaemia in the world, especially among the Caucasian population., Aim: The aim of this retrospective chart review was to establish whether a multisource simvastatin (Simvotin ® , Ranbaxy, a Sun Pharma company) maintained the cholesterol-lowering effect after switching from the innovator brand Zocor ® (MSD South Africa) in the public-sector hospitals. Since prescribers often doubt the registration requirements of multisource products based on bioequivalence alone, this research was done to confirm similar clinical outcomes in a real-world setting., Methods: More than 200 charts were identified from patients treated for hyperlipidaemia. Patients were treated for at least six months prior to and again six months after the switching of brands in order to meet criteria to be eligible for inclusion. The lipid values at initiation of therapy as well as before switching (visit 1 and 2) had to be available and again six months after treatment on the multisource product (visit 3)., Results: No significant change was observed in the lipid control after switching, confirming similarity., Conclusion: This real-world evidence should allay any fears of generic inferiority of this important medicine in the treatment and prevention of high cardiovascular risk in patients requiring lipid-lowering therapy.

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference product of 10-mg ezetimibe (EZE) tablets in 24 healthy Japanese male volunteers under fasting conditions, obtaining sufficient evidence for the marketing approval of the new generic product. The bioequivalence study was conducted with an open-label, 2 × 2, single-dose, crossover design in which the test and reference products were administered to volunteers after fasting for ≥10 hours. Blood samples were collected 24 times before to 72 hours after the administration of the investigational drug. We evaluated the peak drug concentration and the area under the plasma concentration-time curve up to the last measured concentration of EZE, EZEG, and total EZE (EZE + ezetimibe glucuronide [EZEG]). The 90% confidence intervals of the geometric mean ratios for peak drug concentration and area under the plasma concentration-time curve up to the last measured concentration of the test and reference products fell within the bioequivalence limits of 0.80 to 1.25 for EZE, EZEG, and total EZE. The test and reference products were well tolerated, and no adverse events occurred during the study. The test product was bioequivalent to the reference product., (© 2023, The American College of Clinical Pharmacology.)

Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved in the United States and Europe as a treatment for patients with newly diagnosed chronic myeloid leukemia (CML)-chronic phase (CP) and patients with CML-CP or chronic myeloid leukemia-accelerated phase (CML-AP) who are resistant or intolerant to imatinib (a first-generation TKI). This study compared the bioequivalence and safety of the test nilotinib capsule and reference nilotinib capsule (Tasigna, Novartis) in healthy Chinese volunteers under fasting conditions for marketing authorization in China. The results of the study are reported for the first time. This was a single-dose, randomized, open-label, two-period, and cross-over study. Thirty healthy volunteers were randomly assigned to receive a single dose of a 200-mg test or reference capsule under fasting conditions in each period with a 10-day washout. Plasma samples were analyzed with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated with WinNonlin software. The geometric mean ratio and the corresponding 90% confidence intervals of C max , AUC 0-t , and AUC 0-∞ for nilotinib between the two fixed-dose combination formulations were within the bioequivalence acceptance range of 80%-125%, therefore the generic and branded formulations were bioequivalent in healthy Chinese volunteers., (© 2022, The American College of Clinical Pharmacology.)

Generic drugs may differ from brand-name drugs in nature and quantity of excipients. Hypersensitivity to generic drugs is a subject of growing importance given their key role in healthcare spending policies, however, a review of published data highlighted that relevant data is sparse. No scientific rationale has emerged for labelling patients allergic to all generic drugs, and hypersensitivity to generic drugs may rather be explored on a case-by-case basis. In the case of hypersensitivity without any change in medication, it is advisable to check for a switch from a brand-name to a generic drug, and if hypersensitivity to a generic drug is suspected, its composition must be checked.

What Is Known and Objectives: Despite the large body of evidence demonstrating equivalent efficacy and safety for branded drugs and their generic counterparts, some patients and providers have the perception that generics may be less safe and effective than branded agents. Authorized generics (AGs) are a category of generic drugs defined by the United States Food and Drug Administration (FDA) as being the same as the brand-name drug without the brand's name on the label and which may have minor differences, such as tablet or capsule markings for identification. Studies in which AGs are considered along with other generics may increase our understanding of factors that may influence perceptions about generics and shed light on areas where education may be impactful. The objectives of this paper are to provide information about AGs, review studies in which they have been evaluated and explore the role that AGs may fill in the individualized treatment of patients., Methods: A literature review was conducted on 30 September 2019 with follow-up search on 4 March 2020. The search was focussed on published papers and meeting abstracts that provided information on AGs with respect to medical and health outcomes of therapy as well as switching in individuals receiving branded, AG, or other generic agents. Information about patients' perceptions of generic medications and adherence to therapy was also included. Additional information, including relevant government sources, such as the FDA website and the Federal Trade Commission Report, was included as appropriate., Results: The literature specific to AGs is limited, but available data clearly highlight the importance of patient perception of generics as well as medication appearance as factors that may affect adherence and potentially more frequent switchbacks to branded agents from generics or AGs., What Is New and Conclusion: To our knowledge, this is the first narrative review to provide a summary of the published evidence about AGs with respect to clinical and health outcomes and switching. There is a need for more research and education regarding the use of AGs in clinical practice if they are to become more recognized as a potential treatment choice for patients. Generic medications play an important role in the healthcare system, and AGs may be able to provide an option to meet the specific needs of individual patients., (© 2021 John Wiley & Sons Ltd.)

Although the 3Rs are broadly applied in nonclinical testing, a better appreciation of the 3Rs is needed in the field of differentiated or value-added pharmaceutical generics because the minor changes in formulation, dosage form, indication, and application route often do not require additional safety testing. The US FDA and the EU EMA have comprehensive regulations for such drugs based on quality, therapeutic equivalence, and safety guidelines. However, no scientific publications on how the concept of replacement and reduction from 3Rs principles can be applied in the safety assessment of differentiated generics were found in the public domain. In this review, we discuss the application of 3Rs in nonclinical testing requirements for differentiated generics. Practical examples are provided in the form of case studies from regulated markets. We highlight the need for utilization of existing data to establish equivalence (differentiated generic vs innovator) in efficacy and safety. The case studies indicate that data requirements from animal experiments have been reduced to a large extent in some major markets without compromising quality and safety. In this context, we also highlight the problem that on a global scale, a true reduction of animal experiments will only be achieved when all countries adopt similar practices., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Generic drugs provide an opportunity for savings in drug expenditure since they are available at a lower cost and do not affect patients' health. A better understanding of pharmacists' knowledge, attitudes, and perception can promote the quality use of generic drugs. The objective of this study was to investigate the knowledge, attitudes, and perception of pharmacists from tertiary hospitals in China regarding generic drugs., Methods: A cross-sectional survey using a postal questionnaire was conducted, which was sent to 200 hospital pharmacists randomly selected from tertiary hospitals in Hubei Province. A total of 125 questionnaires out of 200 were received. Of the respondents, 80 were female and 45 were male., Results: The majority of respondents (87.2%) could clearly distinguish between original and generic drugs. Pharmacists agreed that generic drugs were less effective (52.8%) and produced more side effects (52%). Fortynine respondents thought that generic drug products were not adequately tested. Approximately 78% and 60% of the pharmacists indicated that generic substitution was not feasible for drugs with narrow therapeutic windows and drugs for critical diseases, respectively. Most of them supported the recommendation of generic drugs based on professional judgment., Conclusion: Our study showed that a considerable portion of Chinese hospital pharmacists hold negative perceptions of generic drugs. Interventions to improve pharmacists' knowledge of generic drugs are needed., (© 2021. Huazhong University of Science and Technology.)

Docetaxel is a widely prescribed chemotherapy drug in oncology and post expiry of its patent, the drug has been marketed as a generic by multiple manufacturers. It is also classified as a narrow therapeutic window drug. Through enhanced permeability and retention effect, polymeric micelles can passively target agents to tumor tissue, thereby decreasing toxicity of the drug in normal tissue. However, various studies have raised concerns that generic docetaxel leads to greater incidences of toxicities among patients with cancer. Thus, we herein review the pharmaceutical challenges associated with different docetaxel formulations and provide insights into the dissimilarities in the quality and safety of branded and generic docetaxel formulations. Literature review reported that 90% of the generic formulations of docetaxel contain inadequate quantity of active drug and high levels of impurities. Higher amounts of solvents such as polysorbate 80 and ethanol in docetaxel formulation lead to severe toxicities such as febrile neutropenia, hematological, and cutaneous toxicities. In most of the studies, even minor changes in excipients, solvents, unbound fraction of docetaxel were associated with adverse events, while in few, the source of docetaxel remained unidentified. One study reported incidence of febrile neutropenia due to a switch in the formulation from branded to generic. The quality, safety, and efficacy of medicines will directly affect the life of patients, and therefore, use of docetaxel formulations that guarantee safety of patients are the necessity of the hour. Being an injectable anti-cancer drug, it is important to determine the consistency of the various formulations of docetaxel globally, conduct bioequivalence studies as per the regulatory standards, taking into account the permissible limits of the excipients or the presence of such unapproved excipients.

Objectives: The aim of this study was to examine the cost-effectiveness of branded and authorized generic (AG) celecoxib for chronic pain patients with osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain (LBP), using real-world cost information for loxoprofen and pharmacotherapy for gastrointestinal bleeding., Methods: This cost-effectiveness analysis was performed as a long-term simulation using the Markov model from the Japanese public healthcare payer's perspective. The analysis was conducted using loxoprofen with real-world weighted price by branded/generic distribution (hereinafter, loxoprofen with weighted price) as a comparator. In the model, we simulated the prognosis of patients with chronic pain by OA, RA, and LBP treated with loxoprofen or celecoxib, over a lifetime period., Results: A cost-increase of 129,688 JPY (1,245.00 USD) for branded celecoxib and a cost-reduction of 6,268 JPY (60.17 USD) for AG celecoxib were recognized per patient in lifetime horizon, compared to loxoprofen with weighted price. No case was recognized to reverse the results of cost-saving by AG celecoxib in one-way sensitivity analysis. The incremental cost-effectiveness ratio of branded celecoxib attained 5,403,667 JPY/QALY (51,875.20 USD/QALY), compared to loxoprofen with the weighted price., Conclusion: The current cost-effectiveness analysis for AG celecoxib revealed its good value for costs, considering the patients' future risk of gastrointestinal injury; also, the impact on costs due to AG celecoxib against loxoprofen will be small. It implies that the disadvantage of AG celecoxib being slightly more expensive than generic loxoprofen could be offset by the good cost-effectiveness during the prognosis., Competing Interests: Yusuke Karasawa and Kazutaka Nozawa are employees of Viatris Pharmaceuticals Japan Inc. Shigeki Zeniya and Tatsunori Murata are employees of CRECON Medical Assessment Inc. Satoshi Soen has received consulting fees, speaking fees, and/or honoraria from Asahi Kasei Pharma, Astellas, Amgen, Daiichi-Sankyo, Eli-Lilly Japan, and UCB Japan. Choitsu Sakamoto has received lecture rewards from Pfizer Japan and Astellas. Isao Kamae declares no conflicts of interest associated with this manuscript. The competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

The present study assessed the pharmacokinetics and bioequivalence of a single 10-mg dose of a generic and the branded formulation (Ocaliva) of obeticholic acid (OCA) in healthy Chinese subjects under fasting and fed conditions. The possible effects of food and sex on the pharmacokinetics of OCA and its 2 active metabolites (glyco-OCA and tauro-OCA) were evaluated. Plasma concentrations of OCA and its 2 active metabolites were measured by liquid chromatography-tandem mass spectrometry. The 90%CIs of the ratios of the test and reference formulations for C max , AUC 0-t , and AUC 0-∞ of OCA, glyco-OCA, and tauro-OCA were contained entirely within the 80% to 125% range required for bioequivalence under fasting and fed conditions. Plasma exposure of OCA was 30% to 36% higher under fed compared with fasting conditions. Plasma exposure of OCA, glyco-OCA, and tauro-OCA was 39% to 66%, 22% to 58%, and 37% to 84% higher, respectively, in women compared with men under fasting and fed conditions. In conclusion, OCA was well tolerated in healthy Chinese subjects under fasting and fed conditions. The single 10-mg dose of a generic OCA formulation was bioequivalent to Ocaliva. Food and sex impacted the pharmacokinetics of OCA and/or its 2 active metabolites. Further studies are required to determine if these effects are clinically relevant., (© 2021, The American College of Clinical Pharmacology.)

This study aimed to evaluate the bioequivalence of 2 pantoprazole sodium enteric-coated tablet formulations, a generic formulation and a branded formulation, and to investigate their pharmacokinetic and safety profiles. The study was designed as a single-center, randomized, open-label, single-dose, dual-period, and 2-sequence crossover trial, and was divided into fasting and postprandial human bioequivalence trials. In the first trial, 36 subjects were fasted overnight before they were given generic or branded tablets (during 2 separate administration periods). Separately, 42 subjects were provided a high-fat meal 1 hour before the drugs were administered. Blood specimens of each subject were obtained up to 24 hours after drug administration. No significant differences were observed between the pharmacokinetic profiles of the generic and branded pantoprazole sodium enteric-coated tablets. Bioequivalence was evaluated using 90% confidence intervals for the ratio of test/reference log area under the concentration-time curve over 24 hours, log area under the concentration-time curve to infinity (AUC 0-∞ ), and log peak concentration (C max ). The 90% confidence intervals of the least squares geometric mean ratio of C max , area under the concentration-time curve from time zero to the last measurable concentration (AUC 0-t ), and AUC 0-∞ of 36 subjects in the fasting trial and of 40 of 41 subjects in the postprandial trial (C max [41], AUC 0-t [41], and AUC 0-∞ [40]) were in accordance with the bioequivalence criteria. No severe adverse effects were detected. The generic and branded pantoprazole sodium enteric-coated tablets were considered bioequivalent with similar safety profiles., (© 2020, The American College of Clinical Pharmacology.)

The purpose of this study was to evaluate the bioequivalence of a generic immediate-release tofacitinib tablet versus a brand-named immediate-release tofacitinib tablet under fasting and fed conditions, and the food effect on pharmacokinetic profiles of the both formulations. This randomized, open-label, 2-period, crossover, bioequivalence study included 52 healthy Chinese subjects (fasting cohort: n = 26; fed cohort: n = 26). The subjects were assigned to receive a single 5-mg dose of generic or brand-named tofacitinib. Blood samples were collected at predosing and up to 14 hours after dosing. Tofacitinib concentrations in plasma were analyzed by high-performance liquid chromatography-tandem mass spectrometry. Safety was monitored. There were no significant differences in maximum plasma concentration, area under the plasma concentration-time curve from time zero to time t (AUC 0-t ), AUC from time zero to infinity (AUC 0-∞ ) , and terminal elimination half-life between the test and reference formulations (all P > .05); high-fat food had no significant effect on AUC 0-t , AUC 0-∞, or terminal elimination half-life of immediate-release tofacitinib tablets (all P > .05). The 90% confidence intervals of the test/reference ratios of log-transformed maximum plasma concentration, AUC 0-t , and AUC 0-∞ were within the range of 80% to 125% under both fasting and fed conditions. No serious adverse events were reported. The 2 formulations of immediate-release tofacitinib tablets are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese volunteers. Food had no clinically relevant effects on drug exposure of tofacitinib., (© 2020, The American College of Clinical Pharmacology.)

Generally, bioequivalence (BE) studies of drug products for pediatric patients are conducted in adults due to ethical reasons. Given the lack of direct BE assessment in pediatric populations, the aim of this work is to develop a database of BE and relative bioavailability (relative BA) studies conducted in pediatric populations and to enable the identification of risk factors associated with certain drug substances or products that may lead to failed BE or different pharmacokinetic (PK) parameters in relative BA studies in pediatrics. A literature search from 1965 to 2020 was conducted in PubMed, Cochrane Library, and Google Scholar to identify BE studies conducted in pediatric populations and relative BA studies conducted in pediatric populations. Overall, 79 studies covering 37 active pharmaceutical ingredients (APIs) were included in the database: 4 bioequivalence studies with data that passed BE evaluations; 2 studies showed bioinequivalence results; 34 relative BA studies showing comparable PK parameters, and 39 relative BA studies showing differences in PK parameters between test and reference products. Based on the above studies, common putative risk factors associated with differences in relative bioavailability (DRBA) in pediatric populations include age-related absorption effects, high inter-individual variability, and poor study design. A database containing 79 clinical studies on BE or relative BA in pediatrics has been developed. Putative risk factors associated with DRBA in pediatric populations are summarized.

The objective of the present study was to evaluate the bioequivalence between generic and branded metformin extended-release (ER) tablets in Chinese subjects. We tested bioequivalence in vitro and in vivo using a comparative dissolution study and a comparative pharmacokinetic trial. Safety assessments were conducted throughout the entire trial period. The dissolution profiles of the generic formulation expressed obvious extended-release properties, similar to those of the branded formulation (f 2 > 60.0%). Consistent with the result of the in vitro study, no remarkable differences were found in terms of pharmacokinetic profiles between generic and branded formulations. The 90% confidence intervals of Ln AUC 0-36 h , Ln AUC 0-∞ , and Ln C max from generic formulation versus branded formulation were 91.4% to 105.0%, 91.3% to 104.7%, and 101.2% to 119.4%, respectively. During the entire trial period, 4 subjects experienced 11 adverse events. All these were mild and spontaneously resolved. The results obtained from the present study suggest that the generic and branded metformin ER tablets were bioequivalent in Chinese subjects., (© 2020, The American College of Clinical Pharmacology.)

Background: To evaluate the bioequivalence between test and reference formulations of perindopril tert-butylamine under fasting and fed conditions and to assess their pharmacokinetic (PK) and safety profiles., Method: A randomized, open-label, single-dose, crossover trial was conducted in healthy Chinese subjects. Test or reference perindopril tert-butylamine tablets (4 mg) were randomly given to subjects under fasting (2-period crossover, with an administration sequence of test tablet (T), reference tablet (R) or RT) and fed (4-period crossover, with an administration sequence of TRTR or RTRT) conditions, while each single administration was followed by a 14-day washout period. The plasma concentrations and corresponding non-compartmental PK parameters of perindopril and perindoprilat were determined. The two formulations were considered to be bioequivalent if the 90 % confidence intervals (CIs) of the geometric mean (GM) ratio (test/reference) for C max , AUC 0-t , and AUC 0-∞ (perindopril) was both within the range of 80-125 %. Safety assessments including vital signs, physical examination, laboratory examination, 12-lead ECG and reports of treatment emergent adverse events (TEAEs) were carefully documented., Results: A total of 64 subjects (32 in each trial) were randomized and all completed the trials. Regardless of fasting or fed trials, the PK characteristics of perindopril and perindoprilat for the test formulation were similar to those of the reference formulation (all P > 0.05). The 90 % CIs of the geometric mean (GM) ratio for C max , AUC 0-t, and AUC 0-∞ , respectively, were 92.86-106.81 %, 98.44-102.88 % and 98.48-103.02 % under the fasting condition and 90.64-110.04 %, 96.95-101.90 % and 96.83-101.78 % under the fed condition, which were both within the pre-specified range of 80-125 %. A total of 10 (31.3 %) fasted subjects and 11 (34.4 %) fed subjects experienced 11 and 24 TEAEs, respectively, all of which were within the severity of grade 1. The incidence of TEAEs and drug-related TEAEs were similar between test and reference formulations (all P > 0.05) and no serious TEAEs or deaths occurred during the trials., Conclusions: The test and reference formulations of perindopril tert-butylamine tablets (4 mg) were bioequivalent and well tolerated in healthy Chinese subjects under fasting and fed conditions., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Lenalidomide is an effective immunomodulatory derivative drug used in the treatment of multiple myeloma (MM). It is available in original and generic forms in Turkey, but there is no clinical study that has compared the effectiveness and adverse events (AEs) of the generic and original forms of lenalidomide. We compared the effectivity and AEs of generic and original lenalidomide in patients with relapsed/refractory MM (RRMM)., Materials and Methods: Patients with RRMM using original or generic lenalidomide were evaluated retrospectively. Overall response (OR), complete response (CR), very good partial response (VGPR), partial response (PR), stable disease, and progressive disease rates and hematologic and nonhematologic AEs were evaluated in these RRMM patients. The results were described as numbers, frequencies, and percentages and were analyzed using PASW 19.0 for Windows with chi-square and Fisher exact tests., Results: The number of patients using original lenalidomide was 55 and the number of patients using generic lenalidomide was 43. The OR rate was 67.2% for patients using original lenalidomide and 60.4% for those on generic lenalidomide. CR and VGPR rates were 14.5% and 45.4% in the original group while the CR and VGPR rates were 20.9% and 18.6%, respectively, in patients using generic lenalidomide. Hematologic AEs were similar in the two groups while some nonhematologic AEs were less common in the original lenalidomide group than the generic group. Only pyrexia as a grade 3-4 AE was more common in the original lenalidomide than the generic lenalidomide group., Conclusion: This study showed that the generic form of lenalidomide has similar efficacy with the original form of lenalidomide in the treatment of RRMM. The AEs of original lenalidomide were generally fewer than those of generic lenalidomide. Further studies involving a larger number of patients with RRMM would be useful for comparing the efficacy and AEs of original and generic lenalidomide.

Optimum use of generic products would require equivalence, not only in terms of quality, safety, and efficacy in clinical studies, but also patient acceptability to not jeopardize treatment success because of non-adherence which would de facto limit the potential cost saving anticipated by their use. Although acceptability is a requirement for the authorization of pediatric innovator products, a survey of European Union (EU) regulatory authorities showed that few have a formal process for assessing patient acceptability of generic products during the registration processes. The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) focus on unifying guidance for the development and scrutiny of generics but should include acceptability alongside the other factors being considered for harmonization., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Nateglinide or N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine is a drug with a rapid hypoglycemic effect that is mainly used in the treatment of type 2 diabetes. Very few studies have assessed bioequivalence based on feeding status. This study aimed to assess the pharmacokinetic bioequivalence and safety of nateglinide-containing tablets (0.12 g) in healthy Chinese volunteers under fasting and fed conditions., Methods: The studies were performed in 2017-2018 in the Phase I Clinical Trial Ward of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China. Eligible Chinese volunteers received a single 0.12-g dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. Blood samples were collected at various time intervals, and plasma nateglinide concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Then, the adverse events, laboratory test results, vital signs, and physical exam findings were compared between the 2 groups., Results: The ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf of the tested to reference preparations under fasting conditions were 105.03% (90% confidence interval [CI]: 99.53-110.83%), 104.02% (90% CI: 101.37-106.74%), and 104.04% (90% CI: 101.38-106.77%), respectively. The same ratios under fed conditions were 96.55% (90% CI: 85.80-108.65%), 103.08% (90% CI: 100.07-106.18%), and 103.07% (90% CI: 100.21-106.01%), respectively. The 90% CI values for Cmax, AUC0-t, and AUC0-inf fell within the accepted range of bioequivalence (80.00-125.0%). Common adverse events included hypoglycemia, heart rate increase, palpitation, sweating, dizziness, and diarrhea., Conclusions: The test formulation (0.12 g) met the CFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated by healthy Chinese subjects., Trial Registration: This trial has been registered in the Chinese Clinical trial registry (ChiCTR2000030694), March 10, 2020., (© 2021 S. Karger AG, Basel.)

Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1-16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4-22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4-4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects.

Background: Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive rise in pulmonary vascular resistance. Ambrisentan is an oral, propanoic acid based-endothelin receptor antagonist (ERA), selective for the endothelin type-A receptor, which is approved for the treatment of PAH. The Colombia National Food and Drug Surveillance Institute regulatory criteria require demonstrating that the proposed generic product is bioequivalent to its reference-listed drug to obtain marketing approval., Objectives: The purpose of this study was to test the bioequivalence, pharmacokinetics, and tolerability of ambrisentan 10 mg tablets., Methods: In this open-label, randomized, oral single-dose, two-way crossover bioequivalence study, 26 Mexican adult healthy male subjects received either the generic product of ambrisentan 10 mg or the reference product Volibris ® (ambrisentan) 10 mg tablets during each study period under fasting conditions. There was a 7-day washout period between each dosing. Ambrisentan concentrations in plasma samples were quantified using a validated ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method. Blood samples were collected up to 72 h post-dose in each study period. The primary end points were maximum plasma concentration (C max ) and area under the plasma concentration-time (AUC 0-t ) curve between 0 and 72 h for ambrisentan., Results: The ratios (90% CI) of geometric mean for ambrisentan were 104.3% (97.12-111.98%) and 100.2% (95.56-104.72%). These pharmacokinetic parameter values lie within the INVIMA-specified bioequivalence limits of 80%-125%. Nervous system disorders were the most common adverse events (AEs). All AEs were mild to moderate in nature and were resolved after follow-up or pharmacologic treatment. Both products were safe and well tolerated., Conclusions: The test product ambrisentan 10 mg tablets is bioequivalent to the reference product Volibris ® (ambrisentan) 10 mg tablets. Both treatments were well tolerated in the Mexican male population of this study., Trial Registration: COFEPRIS National Clinical Trials Registry number 183300410B0367/2018.

Chemo-induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first-line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, hematological safety profile, and impact on survival following the initiation of either the brand-name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma. Patients were treated with TMZ at 75 mg/m 2 per day during six weeks, concomitantly with radiotherapy. Platelet concentration was collected each week. Primary endpoint was to perform a linear mixed-effect model of platelet concentration kinetic over weeks. A total of 147 patients were included as follows: 96 received the brand-name TMZ, and 51 received a generic TMZ formulation. Exposition to the generic was a significant variable that negatively influenced the platelet kinetics in the radiotherapy and concomitant TMZ phase, P = 0.02. Grade ≥3 chemo-induced thrombocytopenia was more frequent in the generic group: 19.6% [95% CI 8.7-30.5%] vs 3.1% [0-6.6%], P = 0.001. Exposition to the generic formulation of TMZ led to increase early treatment discontinuation due to TMZ-induced thrombocytopenia and was a worsening independent prognostic factor on overall survival: adjusted HR 1.83 [1.21-2.8], P = 0.031. These data suggest that exposition to a generic formulation of TMZ vs the brand-name product is associated with higher early platelet decrease leading to clinically relevant impacts on treatment schedule in glioblastoma. Further prospective trials are needed to confirm these results., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

The objectives of the present study were to evaluate the bioequivalence of 2 tablet formulations of prucalopride, generic and branded, and to investigate relevant pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, fasting, single-dose, crossover, and dual-period trial. After overnight fasting, 12 subjects were given prucalopride tablets via oral administration, and blood specimens were obtained up to 96 hours after dosing. Prucalopride concentrations in plasma were measured using ultraprecision liquid chromatography-tandem mass spectrometry followed by calculation of pharmacokinetic parameters. The safety of prucalopride was assessed throughout the study. The pharmacokinetics of prucalopride can be defined as a 2-compartment model with a long elimination phase. No significant differences were observed between the pharmacokinetic profiles of the generic and branded prucalopride tablets. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve over 96 hours, log area under the concentration-time curve to infinity, and log peak concentration from generic and branded tablets, which were 100.06-109.94%, 100.63-110.32%, and 95.84-113.08%, respectively. During administration of the medication, there were 18 adverse events in 6 subjects in the test formulation group and 19 cases of adverse events in 6 subjects in the reference formulation group (P > .05). No severe adverse effects were detected. These results suggest that generic and branded prucalopride tablets are bioequivalent and show similar safety profiles., (© 2019, The American College of Clinical Pharmacology.)

Aims: Generic medicinal products (GMPs) are low-priced copies of off-patent medicines that reduce healthcare costs and broaden access to healthcare. Thus, healthcare authorities, professionals, and providers recommend their use. In recent years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved hundreds of GMPs based on specific bioequivalent trials. The question is whether the brand name drugs and GMPs or the different GMPs similar in purity, efficacy, and safety., Methods and Results: We have reviewed the progressive increasing recalls and warning letters of cardiovascular GMPs issued recently by the FDA/EMA. Both Agencies found numerous irregularities in the purity, safety, effectiveness, and current good manufacturing practices in some GMPs widely used in cardiovascular therapy. This evidence and the recent identification of nitrosamine impurities classified as probable human carcinogens in several angiotensin receptor blockers confirm that the presence of low-quality/substandard GMPs represents a serious public health problem with significant impact on national clinical and economic burden., Conclusion: A global strategy that unifies the efforts of all the stakeholders, including drug manufacturers, healthcare providers, governments, health professionals, patients, and judicial systems are needed to protect the drug chain supply and ensure that only high-quality GMPs are available for use., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Introduction: To compare the efficacy and safety of generic and branded imatinib in adults with newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP), we retrospectively reviewed data from patients CML-CP who received generic or branded imatinib., Patients and Methods: A propensity score matching (PSM) study was performed. A Cox regression model was used to identify factors associated with responses and outcomes., Results: Four hundred forty-two adults receiving generic imatinib (n = 236) or Glivec (Novartis, Basel, Switzerland; n = 206) were included. There were more patients with rural household registration (P < .001), lower education level (P < .001), divorced or widowed status (P = .009), higher white blood cell counts (P = .019), splenomegaly (P < .001), and longer intervals from diagnosis to imatinib initiation (P = .033) in the generic cohort. During the follow-up, there was no significant difference between the 2 cohorts in the 4-year probabilities of achieving a complete cytogenetic response (97.0% vs. 97.3%; P = .736), major molecular response (87.8% vs. 90.1%; P = .113), and molecular response 4.5 (32.5% vs. 38.8%; P = .186), as well as failure-free survival (77.3% vs. 81.4%; P = .313), progression-free survival (94.4% vs. 95.8%; P = .489), and overall survival (96.8% vs. 98.3%; P = .088). Multivariate analyses showed that the drug type was not associated with responses and outcomes. After the PSM procedure, 177 pairs of patients with comparable baseline characteristics were reanalyzed. Multivariate analyses confirmed that generic or branded imatinib used as first-line therapy was not associated with either responses or outcomes., Conclusion: Sociodemographic characteristics might influence the tyrosine kinase inhibitor that patients chose. Generic and branded imatinib as first-line therapy had comparable efficacy and safety in CML-CP patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.)

Background: Previous systematic reviews (2008; 2016) concluded similarity in outcomes between brand-name and generic drugs in cardiology, but they included ≥ 50% comparative bioavailability studies, not designed or powered to detect a difference in efficacy or safety between drug types. We aimed to summarise best-evidence regarding the effectiveness and safety of generic versus brand-name drugs used in cardiology., Methods: For this systematic review of the literature, scientific databases (MEDLINE and EMBASE) were searched from January 1984 to October 2018. Original research reports comparing the clinical impact of brand-name versus generic cardiovascular drugs on humans treated in a real-life setting, were selected. Meta-analyses and subgroup analyses were performed. Heterogeneity (I 2 ) and risk of bias were tested., Results: Among the 3148 screened abstracts, 72 met the inclusion criteria (n ≥ 1,000,000 patients, mean age 65 ± 10 years; 42% women). A total of 60% of studies showed no difference between drug types, while 26% concluded that the brand-name drug was more effective or safe, 13% were inconclusive and only 1% concluded that generics did better. The overall crude risk ratio of all-cause hospital visits for generic versus brand-name drug was 1.14 (95% confidence interval: 1.06-1.23; I 2 : 98%), while it was 1.05 (0.98-1.14; I 2 : 68%) for cardiovascular hospital visits. The crude risk ratio was not statistically significant for randomised controlled trials only (n = 4; 0.92 [0.63-1.34], I 2 : 35%)., Conclusion: The crude risk of hospital visits was higher for patients exposed to generic compared to brand-name cardiovascular drugs. However, the evidence is insufficient and too heterogeneous to draw any firm conclusion regarding the effectiveness and safety of generic drugs in cardiology.

To assess bioequivalence of a generic dabigatran etexilate capsule in healthy Chinese subjects under fasting and fed conditions. This was an open-label, single-center, randomized four-period crossover study with a 7-day washout period. A single oral dose of 150 mg generic dabigatran etexilate capsule (test drug) or a commercial dabigatran etexilate capsule (Pradaxa ® , reference drug) was given to healthy volunteers under the fasting and fed conditions. Plasma concentrations of total and free dabigatran were detected using a validated HPLC-MS/MS method. A noncompartmental method was used for pharmacokinetic analysis and established coagulation assays were applied for pharmacodynamic analysis. The 90% CIs of the test/reference ratios of C max , AUC 0-t , and AUC 0-∞ for the total dabigatran concentration were 92.57%-106.58%, 91.63%-106.32%, and 92.54%-106.17%, respectively, under fasting condition, and 99.30%-110.74%, 98.58%-105.37%, and 97.75%-103.99%, respectively, under fed conditions. The 90% CIs of the ratios of the parameters for the free dabigatran were 93.18%-106.98%, 92.13%-107.10%, 92.89%-106.48%, respectively, under fasting condition, and 100.05%-110.89%, 99.37%-106.23%, 97.59%-103.98%, respectively, under the fed condition. Additionally, the upper limit of the 90% CIs for σWT/σWR was below 2.5. There were no significant differences in the coagulation parameters including thrombin clotting time, activated partial thromboplastin time, and anti-IIa activity between the two preparations. The generic dabigatran etexilate capsule is bioequivalent to the brand-named product in healthy Chinese volunteers under fasting and fed conditions. The two products have comparable pharmacodynamic parameters, with a good safety profile. In addition, food intake influences absorption of both products in a similar way., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Purpose: The purpose of the study was to assess if any antiepileptic drug (AED) was associated with patients being generic brittle (GB) and if any specific AED caused - and was not merely associated with - more frequent switch problems., Methods: Chi square and binary logistical regression analysis were performed, using a previously described study in patients with epilepsy who were routinely followed at the University of Maryland epilepsy outpatient clinic in Baltimore, Maryland. Determination of generic brittleness mirrored clinical practice and included patient opinion about generic formulations, usually based on a history of worsened seizures or side effects with prior AED formulation switching. The dataset included a total of 148 patients, who took 30 different AED formulations. Patients collectively took 530 AED formulation products., Results: Taking lamotrigine immediate release (IR) tablets was associated with a greater probability of being GB and tended to cause more frequent switch problems. Interestingly, six AEDs - Vimpat tablet, carbamazepine IR tablet, phenobarbital (any formulation), gabapentin capsule, Lyrica capsules, and phenytoin (any formulation) - were associated with a reduced probability of being GB, although perhaps not through greater efficacy and tolerability, or better formulation quality. Since tablet and capsule appearance may influence patient perceptions and clinical outcomes, it was observed that the six AEDs less associated with being GB also tended to have fewer generics, and hence possibly lessen treatment uncertainties from the patient perspective. A patient taking more AEDs had significantly increased odds of having a switch problem. An additional observation was that, when a generic was available for their most problematic AED, GB patients took a generic AED only 50% of the time, while not GB patients took a generic AED all the time., Conclusions: Taking lamotrigine IR tablets was associated with a greater probability of being GB and tended to cause more frequent switch problems than other AEDs in this cohort of patients. Six AEDs were associated with a reduced probability of being GB. The lower number of different generics for these six drugs may result in greater patient certainty in medication identity, due to greater consistency in medication color, shape, and size, and hence less generic skepticism or generic brittleness. Also, patients taking more AEDs showed increased odds of a switch problem., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Adherence and persistence with diabetes medication play an important role in glycemic control and may differ by medication class. However, there is a lack of research comparing diabetes medications in patients with renal impairment, despite the challenges and higher burden associated with managing this population., Objective: To compare adherence and persistence among patients with type 2 diabetes mellitus (T2DM) and nondialysis chronic kidney disease (CKD) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors versus pioglitazone., Methods: This retrospective cohort study used Truven MarketScan administrative claims databases from 2009 to 2015. One-year adherence for patients with T2DM and nondialysis CKD who initiated therapy with either a DPP-4 inhibitor or pioglitazone was measured by proportion of days covered (PDC) following an initial dispensing, and PDC ≥ 0.80 was coded as adherent. Persistence was calculated as the days between the index date and last day with the index medication on hand, based on the end of the last days supply or the end of follow-up (i.e., 365 days), whichever occurred first. Multivariate logistic regression and Cox proportional hazards models were used to estimate confounder-adjusted differences between the groups for adherence and persistence., Results: The final cohort included 9,019 patients (DPP-4 inhibitors: 7,002; pioglitazone: 2,017). In the adjusted analysis, DPP-4 inhibitor users demonstrated a 1.41 (95% CI = 1.25-1.59) higher odds of being adherent compared with pioglitazone users. Overall adjusted HR for persistence was 0.74 (95% CI = 0.69-0.79), which favored DPP-4 inhibitors compared with pioglitazone. Relative to 2010, persistence with pioglitazone decreased in 2011-2012 and then increased in 2013-2014. In the subgroup analysis, DPP-4 inhibitors first had lower (2010: OR = 0.78, 95% CI = 0.70-0.87; 2011-2012: OR = 0.60, 95% CI = 0.54-0.66) and then similar (2013-2014: OR = 1.03, 95% CI = 0.88-1.19) hazards of nonpersistence compared with pioglitazone., Conclusions: Among patients with T2DM and nondialysis CKD, the use of DPP-4 inhibitors was associated with better adherence compared with pioglitazone. However, following the approval of generic pioglitazone and associated lower cost sharing after 2012, the magnitude of difference in adherence between the medication classes reduced. Similarly, safety warnings in 2011 and approval of generic products in 2012 may have affected pioglitazone persistence, leading to first higher and then similar hazards for nonpersistence with pioglitazone as compared with DPP-4 inhibitors. These shifts in the results for pioglitazone warrant further investigation and close monitoring of the population initiating this medication., Disclosures: No funding was received for this study. The authors have no conflicts of interest to disclose. An abstract for this study was presented as a podium presentation at the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) 2019 Annual Meeting; May 18-22, 2019; New Orleans, LA.

Introduction: Imatinib is standard therapy for patients with chronic myeloid leukemia (CML). In February 2016, a generic formulation entered the US market. Physicians and patients are frequently concerned about whether switching from original to generic drugs may affect the efficacy and/or safety., Materials and Methods: This is an observational retrospective study using medical charts of patients diagnosed with CML in the chronic phase who were treated with original imatinib from the year 2000 to 2017 and who were subsequently switched to generic imatinib., Results: In this study, 38 patients have switched to generic imatinib. Before the switch, responses were assessed on all patients, all of them were in CCyR and 36 (95%) were in MMR, including 28 (74%) with MR4.5. Patients have received generic imatinib for a median of 19.4 (range, 3.4-46.3) months. Molecular responses after switching were stable in 89%, improved in 8%, and worsened in 3% of patients. After switching, 15 (39%) patients reported new or worsening adverse events, including 5 (13%) patients with edema, 8 (21%) muscle cramps, 7 (18%) nausea, 6 (16%) diarrhea, and 5 (13%) fatigue., Discussion: Bioequivalence studies demonstrated the same rate and extent of absorption of generic imatinib compared to the original form, which led to the FDA approval. In our observational series, most of the patients maintained their responses and none lost MMR. Adverse events noted were mild and well tolerated., Conclusion: A change from original to generic imatinib appears to maintain efficacy and be generally safe. More patients and longer follow-up are required to confirm these observations., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method. The safety/tolerability assessment consisted of documenting adverse events, vital signs, electrocardiogram, and laboratory test results. Sofosbuvir was well tolerated. Major PK parameters of the generic formulation of sofosbuvir were similar to those found in previous reports. These data support further clinical evaluation of this generic formulation of sofosbuvir., (© 2019, The American College of Clinical Pharmacology.)

Aims: While several generic preparations of levodopa/carbidopa and levodopa/benserazide (LBD) are currently available, pharmacokinetic (PK) equivalence and therapeutic equivalence studies with levodopa generics are not available in Italy. Lack of data on generic formulations is a critical factor for their limited use in this country and often lead patients to refuse the generic version of the branded drug., Methods: An experimental, 2-centre, randomized, double-blind, 2-sequence, noninferiority cross-over study was designed to evaluate both the PK equivalence and clinical equivalence of multiple doses of the generic preparation of LDB, Teva Italia, compared to the originator (Madopar). Forty-three out-patients with a diagnosis of idiopathic Parkinson's disease on LDB, were recruited and randomly assigned to 1 of 2 study sequences: generic-originator or originator-generic. Clinical evaluations were performed at the end of each study period. A PK study with an LDB fixed dose (100 + 25 mg) was performed in a subpopulation of 14 subjects., Results: Clinical data showed a reduction of 0.49 and 1.54 in the mean UPDRS III scores for the LDB and the originator, respectively. The 95% CIs [-2.21: 0.11] of the mean difference original vs LDB are smaller than the clinically significant difference of 3 UPDRS III points, supporting the conclusion that the treatment with LDB is not inferior to the originator. No statistically significant differences were found with respect to area under the curve to last dose, half-life, maximum concentration, time to maximum concentration and last observed concentration., Conclusion: These findings prove the therapeutic clinical equivalence as well the PK equivalence of the generic LDB and the originator (Madopar)., (© 2019 The British Pharmacological Society.)

Purpose: The aim of this study is to assess the bioequivalence of a new generic formulation and the branded formulation of levocetirizine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and food-intake effect on the pharmacokinetic properties is also evaluated., Patients and Methods: Volunteers were randomly allocated into two groups to receive a single oral dose of generic formulation and branded formulation under fasting or fed conditions, respectively. Blood samples were collected at designated time points. Plasma concentrations of levocetirizine were determined by UFLC-MS/MS. Safety evaluations were carried out through the study. The main pharmacokinetic parameters of the two formulations of levocetirizine were calculated using non-compartmental analysis incorporated in WinNonlin ® 7.0 software., Results: Forty-nine volunteers were enrolled; 46 completed the studies. Under fasting and fed conditions, the 90% confidence intervals for the geometric mean of generic/branded ratios were in the range of 94.75-107.24% and 99.98-114.69% for the maximum observed concentration, and 97.13-102.50% and 98.36-103.98% for the area under the concentration-time curve. As a result of food intake before administration, the reduced rate and extent of absorption of levocetirizine were observed. Both formulations were generally well tolerated, with no serious adverse reactions reported., Conclusion: The two formulations demonstrated essentially identical pharmacokinetic profiles and were all well within the FDA/CFDA bioequivalence standards. Meanwhile, food intake can delay the absorption rate and reduced the bioavailability of levocetirizine in healthy Chinese volunteers., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Cheng et al.)

Objectives : The economic crisis in Greece has triggered an extensive public debate about the use of generic drugs (generics). Despite their cost-saving potential, generic market penetration remains very low. This raises questions on awareness of, perception on and preference for generics by health-care professionals and patients. This is a descriptive study on the level of knowledge and attitudes towards generics of final year pharmacy school students in Greece. Methods : An electronic questionnaire was distributed to 173 senior pharmacy school students in three Universities in Greece. Responses were submitted electronically. Results : The majority of students knew that generics contain the same active ingredient as the originator products and are cheaper. Students were somehow concerned with safety and efficacy of generics. The majority of students agreed that pharmacists should probably recommend the use of generics, and indicated that prescribing and dispensing practices would largely depend on the profit margin. Despite more than half of the students expressing a positive attitude towards generics, they were inadequately educated on their features. Conclusion : It is critical to improve knowledge of and preference for generics amongst health-care professionals from early on if to build the trust required to increase generic market penetration and achieve measurable savings in pharmaceutical expenditure.

Aims: Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful., Methods and Results: We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square (χ2). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32-0.43; χ2=369.7; P<0.0001] for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37-0.45; χ2=286.2; P<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0-1.25; χ2=3.5; P<0.06). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33-1.57; χ2=75.8; P<0.0001), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0-1.44; χ2=3.75; P<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation., Conclusion: The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Real-world spontaneous adverse event reports and administrative health care data were utilized as one part of a multipronged approach to verify surveillance signals related to generic drug formulations. This study used metoprolol succinate extended release as a historic case example from which to develop an analytic framework. The US Food and Drug Administration Adverse Event Reporting System was utilized for disproportionality analyses and to identify outcomes of interest. Claims data were analyzed for generic uptake, proportion of prescriptions with "dispense as written" orders, time to discontinuation or switching, and relative rates of clinical events. Adverse Event Reporting System data showed that the Medical Dictionary for Regulatory Activities terms for product quality were higher for generic metoprolol cases and that a number of clinical events were increased that could be side effects of high or low variability in drug levels. Compared to amlodipine-benazepril, which also had a first-approved generic at the same time, market share data showed that metoprolol succinate had lower utilization and more prescriptions written as dispense as written. Switching and discontinuation were generally higher for metoprolol users compared to amlodipine-benazepril users. Finally, clinical event rates were generally higher for generic versus brand metoprolol but lower for the same comparison for amlodipine-benazepril users. In the claims-based analyses, the 90-day period immediately after generic entry provided stronger signal capture than using the entire study period. This analytic framework can be implemented to actively monitor new generic formulations for potential bioequivalence failures. Signals from these analyses require confirmation (eg, via pharmacometric analyses) to be informative for regulatory action., (© 2019, The American College of Clinical Pharmacology.)

Background: Clopidogrel has been widely used to prevent atherothrombotic events. Since 2011, pharmacists have offered their patients the opportunity to switch to generic clopidogrel, an economic alternative. Whether bioequivalence of generic cardiovascular drugs translates into clinical equivalence at a population level remains unclear and needs to be further documented., Objective: We aimed to evaluate the impact of generic clopidogrel commercialization on adverse events (AEs): hospitalizations or emergency room (ER) consultations., Methods: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. We included all patients ≥ 66 years old who were users of the brand-name clopidogrel or a generic version (n = 6) 24 months before and up to 12 months after generics commercialization. Rates of AEs were computed, and periods before and after generics commercialization were analyzed by segmented regression models along with exploratory analyses (generic vs. brand name). Sensitivity analyses were also performed using stratification of the time series by (1) sex, (2) the number of prevalent cardiovascular comorbidities, and (3) socioeconomic status., Results: Time series were constituted of 89,525 clopidogrel users (mean age 78 years, 45% women, 71% ischemic heart disease, 34% stroke). For all users, there was a mean rate of 157 AEs per 1000 user-months, stable trend before (-0.1% [95% confidence interval -0.3 to 0.1] and after (0.0% [- 0.5 to 0.6]) generics commercialization. In exploratory analyses, once generic clopidogrel versions were commercialized, rates of AEs were 19.2% (95% CI 11.7-26.7) higher for generic versus brand-name users. This difference persisted up to 1 year. Sensitivity analyses yielded similar results., Conclusions: The population treated with clopidogrel had similar rates of hospitalizations or ER consultations before and after generics commercialization. However, differences in rates of hospitalizations or ER consultations between generic and brand-name clopidogrel users may represent a drug safety signal which remains to be validated. Using a different study design, permitting adjustment for potential confounders, could be useful in this regard.

Objective: To determine whether levothyroxine (L-T4) preparation (generic vs brand) affected hospitalization for cardiovascular events., Patients and Methods: We performed a retrospective analysis using a large administrative claims database, OptumLabs Data Warehouse, creating two 1-to-1 propensity score-matched cohorts initiating generic or brand L-T4. Patients were followed for a mean of 1.0±1.2 years (range, 0-9.3 years). We included 87,902 propensity score-matched patients (43,951 patients per cohort) initiating generic or brand L-T4. Variables included in matching were age, sex, race/ethnicity, residence region, selected comorbidities, and Charlson-Deyo comorbidity score. Patients with previous use of any thyroid preparation, amiodarone, or lithium were excluded. Primary outcomes were the event rates for hospitalizations for incident atrial fibrillation, myocardial infarction, congestive heart failure, or stroke., Results: In the generic L-T4 cohort, 35,242 (80.2%) were women and 7327 (16.7%) were 65 years of age or older; in the brand L-T4 cohort, 34,633 (78.8%) were women and 8092 (18.4%) were 65 years of age or older. We found no differences in event rates (events per 1000 person-years) for 4 outcomes comparing generic and brand L-T4 therapy: (1) atrial fibrillation (1.82 vs 2.19; hazard ratio [HR], 1.22; 95% CI, 0.90-1.65; P=.19); (2) myocardial infarction (2.12 vs 1.83; HR, 0.86; 95% CI, 0.64-1.17; P=.35); (3) congestive heart failure (2.27 vs 2.00; HR, 0.88; 95% CI, 0.66-1.18; P=.41); and (4) stroke (3.10 vs 2.38; HR, 0.77; 95% CI, 0.59-1.00; P=.05). Stratification by age group revealed no differences., Conclusion: In patients with newly treated hypothyroidism, cardiovascular event rates were similar for generic and brand L-T4., (Copyright © 2019. Published by Elsevier Inc.)