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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.)

Background: Primary open-angle glaucoma (POAG), often associated with increased intraocular pressure (IOP), can lead to permanent damage of the optic nerve, concomitant visual field loss, and blindness. Latanoprost, a prostaglandin F2α analogue, reduces IOP and is used to treat glaucoma. In this clinical trial, we evaluated the efficacy of Latanoprost Polpharma, a generic preservative-free latanoprost 0.05 mg/ml eye drops solution, in lowering IOP when compared to the originator Xalatan ® (latanoprost 0.005% ophthalmic solution, Pfizer)., Methods: This was a Phase III, multicentre, randomized, investigator-masked, cross-over, comparative, non-inferiority trial carried out in 5 sites in Hungary and Russia. The primary endpoint was to evaluate the non-inferiority of the test product when compared to the reference product with respect to the differences in the mean diurnal IOP on Day 1 (baseline) and Day 29. The secondary endpoints included efficacy, ocular tolerance, safety, and usability. We recruited adult patients (18-75 years) with open-angle glaucoma or ocular hypertension., Results: Forty-nine patients were randomised and received at least one dose of the test or reference product. A virtually identical reduction of the mean diurnal IOP of 7.04 ± 2.14 mmHg or 7.17 ± 2.11 mmHg was found after treatment with test or reference product, respectively (N = 44). In the intention to treat analysis, the reduction was 7.29 ± 2.53 mmHg (95% CI: 6.55-8.04) or 7.43 ± 2.78 mm Hg (95%CI: 6.61-8.24) after treatment with test or reference product, respectively (N = 47). There were no serious adverse events., Conclusions: Latanoprost Polpharma was shown to be non-inferior to Xalatan ® . Both investigational products were equally well tolerated and safe. The data show a trend in favour of the test product with regards to the severity of hyperaemia and to the velocity of remission of ocular discomfort. Latanoprost Polpharma, being preservative-free, also avoids the cytotoxicity of benzalkonium chloride, the side effects of which may affect patient compliance and lower the quality of life., Trial Registration: The study had the ethical and regulatory approval from the National Institute of Pharmacy and Nutrition (OGYEI, OGYEI/41,779- 11/2018) and the Ethics Committee for Clinical Pharmacology (KFEB) of Hungary and from the Ministry of Healthcare of the Russian Federation (MOH of Russia) prior to the beginning of the study (642/25.12.2018) (clinical trial identification number: 848,300,144/0103/1 - POP03; IND number/EudraCT number: 2018-001727-39)., (© 2024. The Author(s).)

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.)

Aims: Hydroxychloroquine (HCQ) has a high variability and a long half-life in the human body. The purpose of this study was to evaluate the bioequivalence of a generic HCQ tablet (test preparation) versus a brand HCQ tablet (reference preparation) under fasting and fed conditions in a crossover design., Materials and Methods: This was an open-label, two-period randomized, single-dose, crossover study in 47 healthy Chinese subjects who were sequentially and randomly allocated either to the fed group (high-fat meal; n = 23) or the fasting group (n = 24). Participants in each group were randomized to the two arms to receive either a single 200-mg dose of the test preparation or a 200-mg dose of the reference preparation. The application of the two preparations in each patient was separated by a 28-day washout period, regarded as sufficiently long to avoid significant interference from residual drug in the body. Whole blood samples were collected over 72 hours after drug administration., Results: A total of 23 subjects completed both the fed and the fasting parts of the trial. There were no significant differences in C max , AUC 0-72h , and T 1/2 between the test and reference preparation (p < 0.05). Food had no significant effect on C max and T 1/2 (p < 0.05), but AUC 0-72h values were significantly reduced under fed condition compared to fasting condition (p < 0.05). The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) of C max and AUC 0-72h were 0.84 - 1.05 and 0.89 - 0.98 in the fed study, and 0.97 - 1.07 and 0.97 - 1.05 in the fasting study, respectively. The carryover effect due to non-zero blood concentrations resulted in higher AUC 0-72h values in the second period for both test and reference formulations and had no effect on the statistical results. No serious adverse events were reported., Conclusion: The investigation demonstrated that the test and reference preparations are bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese subjects.

Background and Objective: Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers., Methods: This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented., Results: In a fasting state, the bioequivalence of maximum plasma concentration (C max ) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, S WR > 0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC 0-t ) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC 0-∞ ) were evaluated by the average bioequivalence (ABE) method (S WR <  0.294). The geometric mean ratio (GMR) of T/R for C max was 106.49%, while the 95% upper confidence bound was <  0. The GMRs of AUC 0-t and AUC 0-∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of C max (S WR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC 0-t and AUC 0-∞ (S WR <  0.294). The GMR for C max was 99.80%, while the 95% upper confidence bound value was <  0. The GMRs of AUC 0-t and AUC 0-∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient., Conclusions: The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions., Trial Registration: Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023)., (© 2024. The Author(s).)

Background and Objective: Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR ® XR in healthy Chinese volunteers under fed conditions., Methods: A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC 0-t ) and the maximum observed concentration (C max )., Results: A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC 0-t and C max of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity., Conclusions: Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied., Clinical Trials Registration: This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021., (© 2024. The Author(s).)

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: The 2013 ACC/AHA Guideline was a paradigm shift in lipid management and identified the four statin-benefit groups. Many have studied the guideline's potential impact, but few have investigated its potential long-term impact on MACE. Furthermore, most studies also ignored the confounding effect from the earlier release of generic atorvastatin in Dec 2011., Methods: To evaluate the potential (long-term) impact of the 2013 ACC/AHA Guideline release in Nov 2013 in the U.S., we investigated the association of the 2013 ACC/AHA Guideline with the trend changes in 5-Year MACE survival and three other statin-related outcomes (statin use, optimal statin use, and statin adherence) while controlling for generic atorvastatin availability using interrupted time series analysis, called the Chow's test. Specifically, we conducted a retrospective study using U.S. nationwide de-identified claims and electronic health records from Optum Labs Database Warehouse (OLDW) to follow the trends of 5-Year MACE survival and statin-related outcomes among four statin-benefit groups that were identified in the 2013 ACC/AHA Guideline. Then, Chow's test was used to discern trend changes between generic atorvastatin availability and guideline potential impact., Results: 197,021 patients were included (ASCVD: 19,060; High-LDL: 33,907; Diabetes: 138,159; High-ASCVD-Risk: 5,895). After the guideline release, the long-term trend (slope) of 5-Year MACE Survival for the Diabetes group improved significantly (P = 0.002). Optimal statin use for the ASCVD group also showed immediate improvement (intercept) and long-term positive changes (slope) after the release (P < 0.001). Statin uses did not have significant trend changes and statin adherence remained unchanged in all statin-benefit groups. Although no other statistically significant trend changes were found, overall positive trend change or no changes were observed after the 2013 ACC/AHA Guideline release., Conclusions: The 2013 ACA/AHA Guideline release is associated with trend improvements in the long-term MACE Survival for Diabetes group and optimal statin use for ASCVD group. These significant associations might indicate a potential positive long-term impact of the 2013 ACA/AHA Guideline on better health outcomes for primary prevention groups and an immediate potential impact on statin prescribing behaviors in higher-at-risk groups. However, further investigation is required to confirm the causal effect of the 2013 ACA/AHA Guideline., (© 2024. The Author(s).)

Purpose: Levetiracetam is an antiepileptic drug known for its high tolerability, and severe adverse drug reactions are rare. We report the case of a severe cutaneous adverse drug reaction in a patient who was switched from brand-name to generic levetiracetam., Summary: A 29-year-old woman undergoing contrast-enhanced computed tomography developed lesions over her trunk starting 6 hours after imaging. Although initially diagnosed as an allergy to the radiocontrast agent, the condition progressively worsened into toxic epidermal necrolysis-drug reaction with eosinophilia and systemic symptoms overlap syndrome, despite adequate hydration and treatment. Investigation of the patient's medications revealed that she had been switched from brand-name to generic levetiracetam a week before the onset of symptoms. Levetiracetam was immediately discontinued, with the patient recovering after 2 weeks of intensive care. Adverse drug reaction analysis identified excipients in generic levetiracetam as the likely cause of the severe reaction., Conclusion: This is the first reported case of severe cutaneous drug allergy after a brand-to-generic switch for levetiracetam. Brand-to-generic switches of medications can potentially cause severe allergic reactions due to differences in excipients., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.)

Background: On May 2017, two generic drugs for fingolimod were introduced into the market in Israel, and most MS patients treated with Gilenya® (Novartis) were switched to fingolimod (Teva), or to Finolim (Rafa). In this study we analyzed the consequences of switching to generic fingolimod in a single MS center., Methods: Study population included relapsing MS patients who were treated with Gilenya® for at least two year before May 2017, switched to generic fingolimod and remained on treatment for at least 2 years thereafter. Data before and after the switch were compared., Results: Twenty-seven patients fulfilled the inclusion criteria (F = 20, RRMS=20, SPMS=7, average age 49±11.4 years, average disease duration=16.6 ± 7.6 years). Seventeen patients had to be switched back to the original Gilenya® due to intolerable new or worsening clinical adverse events (n = 9), clinical relapse (n = 1), clinical relapse with adverse events (n = 3), elevation of liver enzymes > X3 ULN (n = 3) and elevation of amylase (n = 1). Expanded Disability Status Scale (EDSS) score increased in 4 patients during the year before the switch, and in 12 patients during the year of treatment with generic fingolimod (p = 0.036)., Conclusion: The tolerability, retention rate and probably efficacy of generic fingolimod seems to be lower than the original Gilenya®., Competing Interests: Declaration of Competing Interest The authors declared no conflict of interest, (Copyright © 2023. Published by Elsevier B.V.)

Biosimilars (BS) are promoted worldwide because of the high cost of biologics. However, patients are apprehensive about switching to BS. For some diseases, several factors, which may be disease-dependent, influence patients' acceptance of switching to BS. Herein, we evaluated whether factors influencing acceptance for switching were disease-dependent among Japanese patients with different diseases. This cross-sectional study involved pharmacists' interviews with patients who used or planned to use biologics. Demographic and clinical characteristics were retrospectively investigated using the patients' medical records. Multivariate logistic regression showed that switch refusal was associated with a history of adverse reactions to biologics (odds ratio [95% confidence interval (CI)] = 3.38 [1.35-8.44]), history of complaints related to disease activity (3.57 [1.53-8.32]), and unacceptability of generic drugs (7.62 [2.70-21.60]). Subgroup analyses suggested that the unacceptability of generic drugs was a common factor, regardless of the disease. Concomitantly, histories of adverse reactions to biologics and complaints related to disease activity were disease-dependent factors. Healthcare professionals should help patients in selecting BS, considering these factors according to the disease.

Generic medication is a product that contains the same active substance and pharmaceutical characteristics as brand-name medications. Generic medications are cost-effective and comparable to brand-name medications in terms of clinical endpoints. However, the use of generic medications instead of brand-name medications is a debatable issue among patients and healthcare providers. Two patients with essential hypertension experienced side effects after switching to different generic antihypertensives (one generic medication to another generic medication). Adverse drug reactions, including, hypersensitivity, side effects, and intolerance, should be identified through present and past medical history and clinical characteristics. The adverse drug reactions in both patients were more likely to be side effects of the medications after switching to different generic antihypertensives produced by different companies (patient 1: enalapril and patient 2: amlodipine). The side effects were possibly caused by the different inactive ingredients or excipients. These two case reports emphasise the importance of monitoring adverse drug reactions throughout the course of treatment and communicating with patients prior to switching to a new generic medication.

Background: During the 1900s, tacrolimus became the mainstay immunosuppressive agent to prevent rejection after kidney transplant. Subsequently, an extended-release tacrolimus (ER-Tac) formulation was developed to improve adherence, and its generic version has been marketed over the last years. This study examines the differences in efficacy and safety between the generic ER-Tac (Conferoport) and the reference brand-name drug (Advagraf)., Methods: Prospective, randomized and parallel single-center study (May 2020 to June 2021) with 52 kidney transplant recipients who were randomly assigned to 1 of the following groups: study group (Conferoport, n = 31) and control group (Advagraf, n = 21). The variables of interest were collected and analyzed to compare tacrolimus efficacy and safety between them. Demographic characteristics of the patients and clinical donor data were homogeneous in both groups (P > .05)., Results: No statistically significant differences were found among treatments regarding dosage used, levels, creatinine, and proteinuria (P > .05), with these variables presenting a downward trend during follow-up and, consequently, the improvement of graft function. Analyses also revealed the absence of differences concerning the incidence of acute rejection and intrapatient variability (coefficient of variation) throughout the first year of evolution between both formulations (P > .05). A total of 5 graft losses occurred, 2 resulting from patient death., Conclusions: In our experience, we found no significant differences between the measured parameters in relation to the efficacy and safety profile of both drugs, with generic ER-Tac being an alternative comparable with the reference brand-name ER-Tac., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)

Background: Brand-name dasatinib was approved for newly diagnosed chronic myeloid leukemia-chronic phase (CML-CP) patients due to its deeper and faster molecular response than imatinib. Generics, as the alternative, low-cost forms, are much in demand. This study aimed to evaluate the efficacy and safety of generic dasatinib (Yinishu) as a first-line treatment in CML-CP., Materials and Methods: This was a prospective, multicenter, single-arm study from May 2016 to October 2018 with a 2-year follow-up analysis. All patients were given 100 mg/d (initial dose) of the generic dasatinib once a day. The primary endpoint was the major molecular response (MMR) calculated based on the BCR-ABL1 gene mutation rate of ≤ .1% at 12 months., Results: Among 55 patients in CP observed for at least 3 months, 80.4% achieved MMR at 12 months. The cumulative MR4.5 was 58.2% by 24 months. Responses occurred rapidly, with 69.1% of patients achieving complete cytogenetic response (CCyR) by 3 months and 70.9% achieving CCyR by 6 months. The estimated 2-year PFS and OS were both 96%, with a median follow-up time of 24 months. Grade 3 neutropenia occurred in 8.5% of patients, and thrombocytopenia occurred in 11.9% of patients. Nonhematologic toxicity was usually mild and manageable. Pleural effusion occurred in 20.3% of patients, and only 1 patient (1.7%) had a grade 3 pleural effusion. No grade 4 adverse events were observed., Conclusion: Generic dasatinib is an effective option for newly diagnosed CML-CP patients, producing an MMR early in a greater number of patients during their therapy., (Copyright © 2022. Published by Elsevier Inc.)

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.

Background: Carbamazepine is an anticonvulsant largely used in the treatment of epilepsy. The use of generic antiepileptic drugs (AEDs) is controversial because of the eventual possibility to loss seizures control. The aim of our study was to compare the concentration over dose ratio of two products containing carbamazepine, the innovator (Tégrétol®-NOVARTIS) and the generic (Taver®-MEDOCHEMIE)., Methods: It is a retrospective study (2009-2016) including 32 patients treated with carbamazepine. Patients were treated initially by innovator then switched to generic or vice versa. All patients have at least one level of carbamazepine plasma concentration (C 0 ) with the innovator or the generic formulation. Monitoring of carabamazepine was made using immunoassay method (ARCHITECT-ABOTT®)., Results: The mean age of our patients was 28.4 years and ranged from 2 to 55 years. The sex ratio M/F was 1.46. The mean ratio C 0 /dose for the innovator group was 0.723 (min/max: 0.017/1.73), and the mean ratio C 0 /dose for the generic group was also 0.607 (min/max: 0.064/1.68). There was no statistically significant difference between both groups (P=0.16)., Conclusion: Our results confirm the difference between the innovator and the generic formulation of carbamazepine. So, switching from innovator to generic seems to be safe and exposure to carbamazepine remains the same., (Copyright © 2022 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To pursue explanations for compromised efficacy and induction of side-effects in some generic brands of lamotrigine distributed in Australia., Method: Bioassays of the non-generic and five generic lamotrigine tablets were undertaken (also after exposure to heat and cold), as well as assays of two generic drugs generating concerning side-effects in two patients, while enquiries were made of manufacturing companies., Results: Mass spectrometry of the six tested products showed comparable properties and no compromising when those tablets were heated and cooled, while analyses of the products taken by the two patients reporting significant side-effects showed an increase in the peak area lamotrigine concentration., Conclusions: We failed to identify any intrinsically compromised product in our comparison analyses of the six preparations. We consider alternate explanations for an issue leading to widespread international reporting of distinct side-effects and deaths following brand switching, with analyses of the two problematic preparations supporting a 'faulty' batch explanation.

Objectives: To assess patient characteristics, treatment patterns, and patient-reported outcomes (PROs) associated with authorized generics (AGs) and independent generics (IGs) use., Methods: Prescription claims and National Health and Wellness Survey (NHWS) data were linked. Adults with billable national drug code (AG or IG), NHWS completion from June 2015 to July 2019, AG or IG on-hand at NHWS completion, and continuous insurance eligibility in 12 months pre- and post-NHWS completion were included. To be included, all unique medication formulations had to have at least one AG and one IG observation. PRO index date was NHWS completion; claims index date was defined as the first prescription claim identified during the 180-day period prior to NHWS completion for the same active ingredient and formulation type that was on-hand at NHWS completion., Results: Patients ( N  = 20,229; 17.2% AG users) in six therapeutic areas (attention deficit-hyperactivity disorder [ADHD], antidepressants, beta blockers [BBs], calcium channel blockers [CCBs], statins, and thyroid) were included. Generally, AG (vs. IG) users were younger and differed in regional access and insurance type (all, p  < .05). In multivariable analysis, significant differences were observed for presenteeism and overall work impairment (BBs), healthcare provider visits (BBs), and indirect costs (thyroid) (all, p  < .05). AG and IG users differed in persistence (ADHD and statins; both, p  < .05) and switch (BBs and CCBs; both, p  < .01) rates., Conclusions: PRO differences were often small in magnitude and varied by therapeutic area. The impact of switching should consider observed PRO differences, patient preferences, and market availability of AG and IG alternatives.

Background/aims: Entecavir (ETV) can suppress chronic hepatitis B (CHB) virus replication as a standard of treatment drugs. For the treatment of CHB, affordable generic drugs may be more widely used in developing and undeveloped countries. However, there is little real-world data regarding the clinical efficacy of switching from entecavir-brand-name drugs (ETV-Brand) to entecavir generic drugs (ETV-Generic) with 0.5 mg once daily. The aim of the study was to evaluate the antiviral activity and safety of ETV-Generic in comparison to ETV-Brand in CHB-patients., Methods: In this single-center, retrospective, 175 treatment-naïve-CHB-patients were assigned to receive 0.5 mg of ETV-Brand per day for a least 2 years and then switched to ETV-Generic for 6 months for analysis. The primary efficacy endpoint was a sustained virological response in comparison of the rate of undetectable serum Hepatitis B deoxyribonucleic acid (HBV DNA) as the sustained virologic response at baseline and 6 months after switching. Secondary efficacy endpoints were the comparison of the alanine aminotransferase (ALT) levels between before and after switching and ALT normalization. Renal safety consideration was reported on changing the estimated glomerular filtration rate., Results: From baseline to 6 months, the rate of undetectable HBV DNA and ALT levels remained stable as compared ETV-Brand period with ETV-Generic for 6 months. The rate of undetectable HBV DNA were 81.1%in ETV-Brand versus 88.0%in ETV-Generic (p = 0.05 CI 0.1-13.5%). ALT levels were 27.2 IU/L (CI 24.8-29.6 IU/L) in ETV-Brand versus 26.2 IU/L (CI 24.0-28.4 IU/L) in ETV-Generic (p = 0.55). Both endpoints were not significantly different between ETV-Brand and ETV-Generic treatments. Kidney function did not significantly differ from ETV-Brand (80.8, interquartile range [IQR]: 66.6-95.3 mL/min/1.73 m 2 ) to ETV-Generic treatment period (80.3, IQR: 65.6-93.5 mL/min/1.73 m 2 )., Conclusion: In treatment-naïve CHB-patients, the efficacy and safety profiles of switching from ETV-Brand to ETV-Generic showed no difference. Concluding the ETV-Generic comes to exciting virologic responses and rare adverse events., (© 2022. The Author(s).)

More than thirty antiseizure medications (ASMs) are available for treating epilepsy. ASMs differ in their potency and efficacy in controlling seizures by acting on diverse targets in the brain, often with variable pharmacokinetics. Moreover, nearly 30% of people with epilepsy have drug-resistant or intractable seizures. Generic substitution of ASMs is a complex issue. It is thought that frequent generic substitution in people with epilepsy may cause problems because the U.S. Food and Drug Administration (FDA) rules allow too much variability across products. The standard bioequivalence range (80% to 125%) appears too broad for many ASMs, especially those exhibiting little separation between therapeutic and toxic levels. Hence, sub-therapeutic concentration may lead to therapeutic failure with seizure recurrence, which could be life threatening. A supra-therapeutic level could result in adverse effects or compliance issues. There are reported issues with generic substitutions of phenytoin, topiramate, levetiracetam, carbamazepine, and lamotrigine. There is discussion in the epilepsy community about additional guidelines, including designation of generic ASMs as Narrow Therapeutic Index (NTI) drugs and how patient education plays a role in generic substitution. Overall, based on the published evidence on specific generic ASMs, FDA bioequivalence standards are not the cause of problems with generic ASM substitution. Rather, it is imperative that physicians and pharmacists provide adequate patient education on what to expect when switching to generic ASMs, including changes in medication shape and color. Another suggestion would be to consider that all ASMs be considered for inclusion in NTI class to prevent the clinical outcome issues associated with generic ASM switching. SIGNIFICANCE STATEMENT: There are critical aspects to consider when switching from a brand name antiseizure medication (ASM) when a generic becomes available or switching between generics. Generic ASMs are interchanged with little consideration of differences in therapeutic equivalence and other clinical factors. This article describes key issues on generic substitution of ASMs and highlights critical pharmacotherapeutic issues associated with generic ASMs., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

This retrospective multi-institutional database analysis aimed to evaluate the blood-pressure-lowering efficacy and clinical outcomes of a generic versus brand-name nifedipine for hypertension management. A total of 12 693 patients who were prescribed a generic or brand-name nifedipine between January 1, 2011, and December 31, 2018, were identified from the Chang Gung Research Database of Chang Gung Memorial Hospitals, Taiwan. Among them, 2112 (21.4%) were prescribed generic nifedipine. After propensity score matching, both the generic and brand-name groups consisted of 2102 patients. At a mean follow-up of 3 years, the changes in office systolic (p for interaction = .791) and diastolic blood pressure (p for interaction = .689) did not differ significantly between the patients who received the generic and the brand-name nifedipine. There was no significant difference between the two study groups regarding the composite of all-cause mortality, acute myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure (hazard ratio 0.98, 95% confidence interval 0.85-1.13; p = .774). In conclusion, the generic nifedipine was comparable to its brand-name counterpart regarding office blood pressure reduction and the composite cardiovascular outcome for the treatment of patients with hypertension., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

The aim of this study was to evaluate the pharmacokinetic bioequivalence of a generic budesonide nasal spray and a branded product in healthy Chinese subjects under fasting condition. A single-center, single-dose, randomized, open-label, crossover study was conducted in 32 healthy Chinese subjects under fasting condition. The subjects were administered 256 μg of generic budesonide nasal spray (test drug) or branded budesonide nasal spray (RHINOCORT AQUA, reference drug), respectively. For each period, the subjects were administered with 64 μg of budesonide per spray and 2 sprays for each nostril followed by a washout period of 7 days. Plasma concentration of budesonide was determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic (PK) parameters were calculated, and the bioequivalence was compared using the noncompartment model with the Phoenix WinNonlin 7.0 program. Results show that the 90% confidence intervals of the test/reference ratios of maximum concentration, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity for the budesonide concentration were 84.8% to 102.7%, 84.6% to 94.4%, and 85.4% to 95.2%, respectively, all fall within the bioequivalent range of 80% to 125%. The test and reference budesonide nasal sprays were PK bioequivalents in healthy Chinese subjects with comparable PK parameters. No serious adverse events were reported, and the 2 products have a good and similar safety profile., (© 2021, The American College of Clinical Pharmacology.)

Purpose: In a prior bioequivalence study, generic brittle (GB) patients with epilepsy who were considered at risk of worsened seizures or drug side effects from switching antiepileptic drug (AED) formulations demonstrated no significant difference in their drug levels when switched between a brand and generic AED. An alternative basis for being GB may relate to having a personality or mindset that predisposes to poor outcomes from a formulation switch. The objective of this study was to explore whether GB patients with epilepsy could be differentiated from not GB patients based on standardized measures of personality, mood, outlook, and beliefs., Methods: This was an exploratory, observational, case-control, non-therapeutic study in patients with epilepsy. Patient interviews were conducted, and histories were collected, yielding each patient (n = 148) to be determined as GB or not GB. Eight neuropsychiatry tests were administered to n = 127 of these patients. Tests included Neuroticism Extraversion Openness Personality Inventory 3 (NEO-PI 3), Life Orientation Test-Revised (LOT-R), Quality of Life in Epilepsy Inventory-89 (QOLIE-89), Adverse Childhood Experiences Score (ACE), Physical Symptoms Questionnaire or Patient Health Questionnaire-15 (PHQ-15), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), and the Beliefs About Medicines Questionnaire Epilepsy (BMQ-Epilepsy). A total of 23 Chi squared analyses, along with logistical regression, were performed to assess which tests and sub-elements associated with GB status., Results: None of the neuropsychiatry tests or their sub-elements differentiated GB patients from not GB patients. Results implicate that standardized measures of personality, mood, outlook, and beliefs about their healthcare do not differ between GB and not GB patients with epilepsy, possibly because generic brittleness is caused by factors that neuropsychiatry tests do not measure., Conclusions: We hypothesized that being GB may relate to having a personality or mindset that predisposes patients to attributing poor outcomes to a formulation switch. However, findings here in patients with epilepsy did not uncover neuropsychiatric factors that predict which patients were GB and which were not GB., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.)

Aim: This study aimed to compare the incidence of infusion site reactions (ISRs) induced by intravenous administration of brand-name and generic vinorelbine (VNR) for treating non-small cell lung cancer., Method: This single-centre retrospective cohort study was conducted by medical chart review of VNR infusions. ISRs were defined as symptoms around the infusion site, including pain, redness and swelling. ISRs requiring treatment were defined as ISRs requiring treatments including steroid ointments, vein repuncture and local steroid injections., Results: In all, 1973 VNR infusions were administered to 340 patients (brand-name 141 patients, generic 199 patients). ISRs and ISRs requiring treatment were observed in 161 and 100 patients, respectively. The ISR incidence per patient and per injection was significantly higher in generic VNR-treated patients than in brand-name VNR-treated patients (53.3% vs 39.0%, P = 0.0112 and 15.0% vs 9.9%, P = 0.0008, respectively). The frequency of ISRs requiring treatment was also significantly higher in the generic group (per patient 36.7% vs 19.2%, P = 0.0005; per injection 11.3% vs 5.5%, P < 0.0001). Multivariate analysis revealed that generic VNR was significantly associated with an increased risk of ISRs (per patient adjusted odds ratio [AOR] 1.775, P = 0.0155; per injection AOR 1.672, P = 0.004) and ISRs requiring treatment (per patient AOR 2.422, P = 0.0012; per injection AOR 2.286, P = 0.001)., Conclusion: Intravenous infusion of generic VNR was associated with an increased risk of ISRs. Further research is needed to elucidate the mechanism underlying the increased incidence of ISRs with generic VNR., (© 2020 The British Pharmacological Society.)

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.)

Background/aims: Clinical equivalence of generic antiviral agents for chronic hepatitis B (CHB) has not been demonstrated, particularly in cases with previous antiviral resistance. Entecavir 1 mg is prescribed frequently as a mono- or combination therapy in antiviral-resistant CHB patients. This study evaluated the efficacy and safety of switching to generic entecavir 1 mg (Baracle ® ) in CHB patients taking brand-name entecavir 1 mg (Baraclude ® ) alone or in combination with other nucleotide analogs after the development of antiviral resistance., Methods: This study was a single-arm prospective study. The primary endpoint was undetectable HBV DNA (<20 IU/mL) at 12 months after switching treatment. The biochemical and serologic responses, virologic breakthrough, and antiviral resistance rates were also evaluated., Results: Forty CHB patients with undetectable HBV DNA through the brand-name entecavir 1 mg treatment as a mono- or combination therapy after developing antiviral resistance to nucleos(t)ide analogs were enrolled in this study. No significant difference in the HBV DNA non-detection rate was observed between the baseline and 12 months after switching therapy (p=0.324). Furthermore, non-inferiority of the generic entecavir 1 mg to the brand-name entecavir 1 mg with 10% margin in maintaining undetectable HBV DNA was demonstrated (95% CI -2.80 to 8.20%). Similarly, no difference in the biochemical response rate was observed after switching therapy. Serum hepatitis B e antigen loss was observed in 12.5%. No virologic breakthrough was reported., Conclusions: Generic entecavir 1 mg is a reasonable alternative to the brand-name entecavir 1 mg in antiviral-resistant CHB patients with viral suppression.

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.)

Introduction: use of generic drugs is common. However, there is still concern among patients and physicians that brand name drugs are more efficient. The aim of the study was to compare efficacy and tolerance between two forms of cisatracurium: brand name versus generic name., Methods: it´s a crossover, randomized, double-blind physiological trial. Patients admitted for hypoxemic acute respiratory failure with PaO2/FIO2 < 200mmHg despite optimized ventilation and sedation thus requiring non-depolarizing neuromuscular blocking agents (NMBAs), were enrolled. Patients received consecutively, in a random order, cisatracurium brand name (Nimbex®) and generic (Cisatrex®) over two-hour period separated by one-hour washout period. Neuromuscular function was monitored by a calibrated train-of-four (TOF) stimulation device. Paralysis time delay to reach TOF of 2/4, recovery kinetics and tolerance were monitored. The number needed to demonstrate a significant difference in time delays to reach a TOF of 2/4 between the two forms of cisatracurium was estimated at 22 patients., Results: twenty-two patients were included. Eight (36.4%) had acute respiratory distress syndrome; 8(36.4%), acute exacerbation of chronic obstructive pulmonary disease and 3(13.6%), status asthmaticus. Median [IQR] SAPS II at admission, 28.5 [22, 41]. PaO2/FIO2, 121 [81, 156] mmHg. Paralysis time delays were respectively, 80 [50, 112] vs. 87 [65, 115] minutes, in Nimbex® group and Cisatrex® group; (p=0.579). Within the recovery period, the between two-studied drugs´ difference in TOF was at 0.25±0.96; p=0.64. There were no significant hemodynamic differences., Conclusion: the present study revealed no significant differences in efficacy nor in tolerance between cisatracurium brand name Nimbex® and generic name Cisatrex® in hypoxemic ventilated patients., Competing Interests: The authors declare no competing interests., (Copyright: Nesrine Fraj et al.)

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.

Data regarding the long-term outcomes of generic antihypertensive drugs are limited. This nationwide retrospective database analysis aimed to evaluate the efficacy and safety of a generic versus brand-name nifedipine for hypertension treatment. Patients who were prescribed generic or brand-name nifedipine between January 1, 2008, and December 31, 2013, were identified from the National Health Insurance Research Database of Taiwan. The efficacy outcomes included all-cause mortality and the composite cardiovascular (CV) outcome, including CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and hospitalization for heart failure. Safety outcomes included headache, peripheral edema, constipation, acute kidney injury, hypotension, syncope, new diagnosis of cancer, and cancer death. Among the 98 335 patients who were eligible for analysis, 21 087 (21.4%) were prescribed generic nifedipine. Both the generic and the brand-name groups included 21 087 patients after propensity score matching. At a mean follow-up of 4.1 years, the generic nifedipine was comparable to the brand-name drug with regard to all-cause mortality (7.2% vs. 7.1%; hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.95-1.09) and the composite CV outcomes (11.6% vs. 11.9%; HR 0.97; 95% CI 0.92-1.03). The generic nifedipine was associated with higher rates of headache, peripheral edema, and constipation but a modest reduction in the risk of newly diagnosed cancer (7.1% vs. 7.8%; subdistribution HR 0.90, 95% CI 0.84-0.97). The risks of acute kidney injury, hypotension, syncope, and cancer death were not significantly different between the two groups. In conclusion, the generic nifedipine was comparable to the brand-name drug with regard to the risks of all-cause mortality and the composite CV outcome. The finding of cancer risk could be chance and should be interpreted with caution., (© 2020 Wiley Periodicals LLC.)