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Aim: To compare the efficacy of adding original moxonidine and its generics to previous ineffective antihypertensive therapy in patients with poorly controlled arterial hypertension (AH)., Material and Methods: This observational prospective non-randomized study included 120 patients with poorly controlled blood pressure on the previous antihypertensive therapy. All patients underwent clinical evaluation, including anthropometric and laboratory indexes, and 24-hour blood pressure monitoring (24-h BPM) at baseline and after 12 weeks of observation. Office systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) were recorded after 4 and 12 weeks of treatment. During the observation period, 4 equal groups were formed: group 1, Physiotens was added to the treatment; group 2, Moxonitex; group 3, Moxonidine SZ; and group 4, Moxonidine Canon. Statistical analysis was performed with the StatTech v.4.2.7 software (© OOO StatTech, Russia)., Results: After 4 weeks of therapy, the BP target was achieved significantly more frequently in group 1 (63% of patients) compared to groups 2 (36.7% of patients), 3 (16.7% of patients), and 4 (16.7% of patients) (p<0.05). At 12 weeks, office SBP, DBP, and HR were significantly decreased in all groups, but the decrease was significantly greater in group 1. The therapy was associated with a more pronounced decrease in all studied 24-h BPM parameters in the Physiotens group than in other groups, as well as with a significantly more frequent normalization of the 24-h BP profile, in 66.7% of patients vs. 46.7%, 33.4%, and 23.2% of patients in groups 2, 3, and 4, respectively., Conclusion: The treatment with original moxonidine demonstrated advantages over generic drugs in terms of achieving the BP goal, reducing office BP and HR, and improving 24-h BPM parameters.

Objectives: Although generic medicinal products are required to have the same qualitative and quantitative composition of the active substance as their reference originator product, patients and health care professionals express concerns about their interchangeability and safety. Therefore, the present study investigated the antimicrobial activity and pathogen mutation prevention of original and generic cefepime, linezolid and piperacillin/tazobactam against Staphylococcus aureus., Methods: Two generic formulations of cefepime, linezolid and piperacillin/tazobactam were tested against their respective originator products. Susceptibility testing was performed with twenty-one clinical isolates of S. aureus and ATCC-29213 using broth microdilution. Time kill curves (TKC) were performed with ATCC-29213 at drug concentrations above and below the respective minimum inhibitory concentrations (MIC). Mutation prevention concentration was determined for each drug formulation against ATCC-29213. All experiments were performed in triplicate. Mutant colonies from mutation prevention concentration (MPC) experiments were genotypically tested by sequence analysis., Results: MIC ratios between contiguous originator and generic drugs were similar for each isolate. No visual differences were observed in TKCs between originator and generic substances. The MPC did not differ between different formulations of the same substance. Although sequence analysis of mutant colonies revealed genomic differences compared with the original ATCC-29213, no differences in mutation frequencies were observed between clinical isolates and ATCC-29213 treated with originator or generic substances., Conclusions: Similar antimicrobial activity and pathogen mutation prevention was observed between contiguous substances. These results support the interchangeability of generic and originator drug formulations with the same active ingredient., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Application of drugs on skin with compromised barrier can significantly alter permeation of drugs with the possibility of increased adverse side effects or even toxicity. In this study, we tested in vitro delivery of diclofenac sodium from marketed brand and generic formulations across normal and compromised skin using microneedles and iontophoresis, alone and in combination. Ten tape strips on dermatomed human skin were used to create a compromised skin model, as demonstrated by changes in skin resistance and transepidermal water loss. Histology studies further confirmed creation of a compromised skin barrier. There was no significant difference between brand and generic formulations for delivery of diclofenac sodium into and across normal and compromised skin. Compromised skin showed higher total delivery (µg/sq.cm) of diclofenac sodium for all groups - microneedles (brand: 79.45 ± 8.81, generic: 92.15 ± 8.63), iontophoresis (brand: 233.13 ± 8.32, generic: 242.07 ± 11.17), combination (brand: 186.88 ± 6.76, generic: 193.8 ± 5.69) as compared to intact normal skin for same groups, microneedles (brand: 21.83 ± 1.96, generic: 20.38 ± 0.91), iontophoresis (brand: 149.78 ± 18.43, generic: 145.53 ± 12.61), and combination (brand: 80.97 ± 9.86, generic: 70.76 ± 6.56). These results indicate the effect of barrier integrity on delivery of diclofenac sodium which suggests increased absorption and systemic exposure of the drug across skin with compromised skin barrier., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Harsha T Garimella reports financial support was provided by National Institutes of Health]., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Advances in peptide and protein therapeutics increased the need for rapid and cost-effective polypeptide prototyping. While in vitro translation systems are well suited for fast and multiplexed polypeptide prototyping, they suffer from misfolding, aggregation and disulfide-bond scrambling of the translated products. Here we propose that efficient folding of in vitro produced disulfide-rich peptides and proteins can be achieved if performed in an aggregation-free and thermodynamically controlled folding environment. To this end, we modify an E. coli-based in vitro translation system to allow co-translational capture of translated products by affinity matrix. This process reduces protein aggregation and enables productive oxidative folding and recycling of misfolded states under thermodynamic control. In this study we show that the developed approach is likely to be generally applicable for prototyping of a wide variety of disulfide-constrained peptides, macrocyclic peptides with non-native bonds and antibody fragments in amounts sufficient for interaction analysis and biological activity assessment., (© 2022. The Author(s).)

Background: Generic antidepressants are approved on the market based on evidence of bioequivalence to their brand-name versions. We aimed to assess whether generic antidepressants exert equal effectiveness as their brand-name counterparts for treating patients with depressive disorders., Methods: In a nationwide, population-based cohort in Taiwan from 1997 through 2013, patients with a diagnosis of a depressive disorder aged between 18 and 65 years who were new users of antidepressant drugs were classified into either the brand-name group or the generic group. All patients were followed up until medication discontinuation or the end of the study period. We assessed the risk for hospitalization as a primary outcome and augmentation therapy, daily dose, medication discontinuation, or switching to another antidepressant as secondary outcomes., Results: A total of 277 651 brand-name users (35.8% male; mean age: 41.2 years) and 270 583 generic users (35.8% male; mean age: 41.0 years) were divided into 10 different antidepressant groups (fluoxetine, sertraline, paroxetine, escitalopram, citalopram, venlafaxine, mirtazapine, moclobemide, imipramine, and bupropion). We found that patients treated with the generic form of sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine, and bupropion demonstrated significantly higher risks of psychiatric hospitalization (adjusted hazard ratios ranged from 1.20-2.34), compared to their brand-name counterparts. The differences between brand-name antidepressants and their generic counterparts in secondary outcomes varied across different drugs., Conclusions: Compared to most generic antidepressants, brand-name drugs exhibited more protective effects on psychiatric hospitalization for depressive patients. These findings could serve as an important reference for clinicians when encountering patients with depressive disorder., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Importance: Whether the use of generic vs brand levothyroxine affects thyrotropin levels remains unclear., Objective: To compare the effectiveness of generic vs brand levothyroxine in achieving and maintaining normal thyrotropin levels among new users., Design, Setting, and Participants: This retrospective, 1:1 propensity score-matched longitudinal cohort study used the OptumLabs Data Warehouse administrative claims database linked to laboratory results from commercially insured and Medicare Advantage enrollees throughout the United States. Eligible patients were adults (aged ≥18 years) with thyrotropin levels ranging from 4.5 to 19.9 mIU/L who initiated use of generic or brand-name levothyroxine from January 1, 2008, to October 1, 2017. Data were analyzed from August 13, 2018, to October 25, 2019., Exposure: Patients received generic or brand-name levothyroxine., Main Outcomes and Measures: Proportion of patients with normal vs markedly abnormal thyrotropin levels (<0.1 or >10 mIU/L) within 3 months and with stable thyrotropin levels within 3 months after the thyrotropin value fell into the normal range., Results: A total of 17 598 patients were included (69.0% female; 74.0% White; mean [SD] age, 55.1 [16.0] years), of whom 15 299 filled generic and 2299 filled brand-name levothyroxine prescriptions during the study period. Among 4570 propensity score-matched patients (mean [SD] age, 50.3 [13.8] years; 3457 [75.6%] female; 3510 [76.8%] White), the proportion with normal thyrotropin levels within 3 months of filling levothyroxine prescriptions was similar for patients who received generic vs brand-name levothyroxine (1722 [75.4%; 95% CI, 71.9%-79.0%] vs 1757 [76.9%; 95% CI, 73.4%-80.6%]; P = .23), as was the proportion with markedly abnormal levels (94 [4.1%; 95% CI, 3.4%-5.0%] vs 88 [3.9%; 95% CI, 3.1%-4.7%]; P = .65). Among 1034 propensity score-matched patients who achieved a normal thyrotropin value within 3 months of initiation of levothyroxine, the proportion maintaining subsequent normal thyrotropin levels during the next 3 months was similar for patients receiving generic vs brand-name levothyroxine (427 [82.6%] vs 433 [83.8%]; P = .62)., Conclusions and Relevance: Initiation of generic vs brand-name levothyroxine formulations was associated with similar rates of normal and stable thyrotropin levels. These results suggest that generic levothyroxine as initial therapy for mild thyroid dysfunction is as effective as brand-name levothyroxine.

Background: Generic medicines are similar to innovator medicine in terms of safety, quality, efficacy, dosage form, strength, and route of administration. They have the same therapeutic use to innovator medicines and available at a far lower price. However, health professionals' poor knowledge and attitude may limit its utilization. The present study aimed at assessing the knowledge, attitude, and practice of pharmacy professionals towards generic medicines in Harar city, Eastern Ethiopia., Methods: A cross-sectional survey was conducted among community pharmacists in Harar city. A self-administered thirty-three item questionnaire on Knowledge, attitude, and practice of community pharmacists was utilized. Logistic regression analysis was performed to predict the determinants of knowledge and attitude of pharmacists. An odds ratio at 95% confidence interval along with a p-value < 0.05 was considered significant., Results: Among 80 community pharmacists' approached, 74 completed the survey, providing a response rate of 92.5%. Sixty-seven percent of the respondents knew that generic drugs are bioequivalent to brand drugs and claimed generic medicines are cheaper (86.5%). Nearly half (48.6%) of participants believe that generic medicines are less effective and slower in the onset of action (58.1%). More than half (54.1%) of study participants revealed their lack of belief in generic medicine as a factor hindering the selection and dispensing of generic medicines. In multivariate logistic regression, experience in community pharmacy practice (Adjusted odds ratio (AOR = 2.18, 95%CI: 1.21-63.1) and Sex (AOR = 3.88, 95%CI: 2.12-39.62) were significantly associated with knowledge and attitude toward generic medicines, respectively., Conclusion: The current study revealed that there is a gap in the knowledge and attitude of community pharmacists towards generic and brand drugs. More than averages of the respondents have known the concept of generic medicine including their right to perform generic substitution and had a positive attitude toward generics. Female pharmacists were more likely to have a positive attitude and the overall knowledge was higher in those who have more than 5 years of work experience., Competing Interests: the authors have declared that no competing interests exist.

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: Few studies have been investigated the in vivo efficacy of generic vancomycin products available outside of the United States. In this study, we aimed to compare the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of five generic vancomycin products available in Korea with those of the innovator., Materials and Methods: The in vitro vancomycin purity of each product was examined using high-pressure liquid chromatography. Single-dose PK analyses were performed using neutropenic mice. The in vivo efficacy of vancomycin products was compared with that of the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a thigh-infection model with neutropenic mice., Results: Generic products had a lower proportion of vancomycin B (range: 90.3-93.8%) and a higher proportion of impurities (range: 6.2-9.7%) than the innovator (94.5% and 5.5%, respectively). In an in vivo single-dose PK study, the maximum concentration (C max ) values of each generic were lower than that of the innovator, and the geographic mean area under the curve ratios of four generics were significantly lower than that of the innovator (all p <0.1). In the thigh-infection model, the maximum efficacies of generic products reflected in maximal effect (E max ) values were not significantly different from the innovator. However, the PD profile curves of some generic products differed significantly from that of the innovator in mice injected with a high level of Mu3 (all p ≤0.05)., Conclusion: Some generic vancomycin products available in Korea showed inferior PK and PD profiles, especially in mice infected with hetero-vancomycin-resistant Staphylococcus aureus., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Background Indonesian Ministry of Health advocate doctors, especially in government-owned healthcare facility, to prescribe generic drugs including amoxicillin. Although BPOM (the National Agency of Drug and Food Control) already guarantees that the generic amoxicillin and the branded one were interchangeable, lack of confidence in generic drugs still remains among patients, pharmacists, and doctors. This issue supported by lack of publication confirmed the therapeutic equivalence of branded and generic drugs. This study aims to evaluate and compare the in vitro microbiological assay of different generic and branded amoxicillin that are available in Indonesian market, especially those used in government-owned healthcare facilities. Methods Microbiological assays for five samples of amoxicillin tablet containing 500 mg amoxicillin available in Indonesia were determined using a method from Indonesia Pharmacopeia. Samples were coded as Products A to E. The assay was carried out by measuring the diameter of the inhibition zones in the plate agar incubated with Escherichia coli and Staphylococcus aureus. The obtained data were evaluated to determine the sample potency and compared with the amoxicillin reference standard. Results Minor and insignificant differences (p > 0.05) were found in the diameters of the inhibition zones. Potency ratio measured both in E. coli and S. aureus were all between 95% and 105%. The lowest of the tested samples were from Product C, which resulted to ratio potencies of 96.3% and 95.5% in E. coli and S. aureus, respectively. Conclusions All five samples were in the range of the acceptance criteria. Therefore, from the view of the microbiological assay, these products are in equivalence in quality and are interchangeable.

Topic: An evaluation of the efficacy and tolerability of generic prostaglandin analogues (PGAs) compared with their original counterpart., Clinical Relevance: This systematic review was initiated to enlighten ophthalmologists and patients in the use of original and generic ophthalmic solutions., Methods: A literature search was conducted on PubMed, EMBASE, MEDLINE, Clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform, along with a manual search, from the marketing of the first PGA, latanoprost, in 1995 to the present. Randomized controlled trials comparing an original PGA with its generic counterpart were included. The last literature search was conducted in June 2019. Risk of bias was assessed by 2 independent reviewers using the Cochrane Handbook for Systematic Reviews Tool. The primary outcome was reduction of intraocular pressure (IOP) from baseline. Secondary outcomes included tolerability, ocular surface health, quality of life, disease progression, and cost-effectiveness. Meta-analysis of the primary outcome was planned., Results: Of 385 screened articles, 6 were included in a broad characterization and in the meta-analysis. A total of 619 patients were enrolled. The duration of the studies ranged from 3 to 16 weeks. Meta-analysis of all 6 studies denied any clinically significant difference in efficacy, and the 95% confidence interval included nil (-0.50 to 0.04 mmHg). The evidence was of moderate certainty because of unclear or high risk of bias in all studies. There were no reported differences in tolerability., Conclusions: Trials comparing original and generic PGAs did not show a clinically significant difference in IOP-lowering effect or tolerability. However, the quality of the trials is suboptimal. Overall, there is uncertainty, and further research is needed to confirm equivalence., (Copyright © 2019 American Academy of Ophthalmology. All rights reserved.)

Objective: Branded medicines have a greater placebo effect, resulting in a heightened therapeutic response, whereas generics are associated with greater side effect reporting. These two studies investigated whether enhancing the appearance of a generic medicine could increase placebo and decrease nocebo responding. Design: Two experimental studies allegedly examining the effect of β-blockers (actually placebos) for pre-examination anxiety. In Study 1, participants received either a generic β-blocker with enhanced packaging, a plainly packaged generic or a branded β-blocker. Study 2 compared an enhanced packaging generic to a plainly packaged generic β-blocker. Main outcomes measures: Blood pressure, heart rate, anxiety and the number of symptoms and side effects reported. Results: Study 1 found no differences between the three groups for blood pressure, heart rate, or anxiety. Study 2 showed similar results but a significant difference in anxiety was found with the plain generic group experiencing a greater reduction in anxiety than the enhanced generic group. No differences in symptoms or side effects were found in either study. Conclusions: While the sample characteristics and familiarity of the medicines may have influenced the findings, we found no evidence that enhancing the branding of generic medicines improved response to the medication or reduced side effects.

Background: Locally produced generic drugs offer a cost-effective alternative to imported drugs to treat patients in Ethiopia. However, due to a lack of bioequivalence testing, additional assurance tests are needed to build trust in cheaper, locally made drugs. By testing bioequivalence of local drugs to gold standard, N-of-1 tests have the potential to promote patient centred quality use of medicines., Method: We sought to assess the acceptability of, and explore barriers to, conducting N-of-1 tests to evaluate local medicines in a resource limited clinical setting. We conducted a descriptive qualitative study, analysing four focus group discussions and five key informant interviews. Participants were senior drug regulatory authority members, institutional review board members, physicians and patients. All interviews were audio taped and transcribed verbatim. Patient interviews were conducted in Amharic and translated to English prior to analysis. Data analysis used an inductive, thematic process., Results: Five major themes were identified; (1) Appropriateness of N-of-1 tests to determine the therapeutic equivalence of local drugs, (2) N-of-1 therapeutic equivalence tests: clinical care or research? (3) Ethical and regulatory requirements (IRB), (4) Potential barriers to implementing N-of-1 tests and (5) Possible solutions to identified challenges. The study demonstrated considerable support for using N-of-1 tests for clinical equivalence studies between local and imported medicines, but important impediments were very likely to impact the feasibility of conducting N-of-1 tests in Ethiopia. Key informants from the regulatory authority did not support additional tests of local drugs. There were also mixed opinions regarding ethical requirements for conducting N-of-1 tests. The Institutional Review Board (IRB) members believed that IRB approval was sufficient to conduct N-of-1 tests, however, the regulatory authority members considered that N-of-1 tests constituted a clinical trial, and required approval at the regulatory level., Conclusion: This study showed that there were key uncertainties that could impact the feasiblity of using N-of-1 testing local drugs in Ethiopia. Therefore, a number of protocol amendments to address contextual threats and regulatory challenges, would be needed before progressing to conducting these tests.

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.

Background: To date there exist no internationally recognised Good Manufacturing Practices (GMP) that clearly outline universally accepted standards for manufacturing highly active or sensitising ingredients. The pharmaceutical industry is faced with a twofold problem: determining which drugs need dedicated production areas and identifying the different regulations required in different countries. The aim of this paper is to find, by comparing the current regulations of the various Regulatory Agencies, the differences between containment requirements for the production of highly active or sensitising ingredients., Methods: An analysis of the following Regulatory Agencies' GMPs was performed: Europe (EMA), China (CFDA), Mexico (COFEPRIS), United States (FDA), Canada (Health Canada) Brazil (ANVISA), India (CDSCO), PIC/S and WHO in order to examine the differences in terms of  containment requirements set by the different Regulatory Authorities for the manufacture of highly active or sensitising ingredients., Results: Our analysis found that the majority of Regulatory Agencies require that beta-lactams (sensitising materials) be produced in dedicated and segregated facilities. For "certain" highly active pharmaceutical ingredients (APIs), COFEPRIS, FDA, HC, EMA, PIC/S and WHO require that they be produced in facilities similar to those required for beta-lactams, while CDSCO, CFDA and ANVISA require that production takes place in segregated areas. Further differences between the Agencies  have emerged regarding classes of highly APIs that require dedicated production., Conclusion: A study of GMP adopted by Regulatory Agencies has uncovered significant differences, in particular concerning containment requirements for the production of APIs. For this reason, the harmonisation of GMP following  up-to-date quality standards based on cutting-edge science which are globally applicable is fundamental and will benefit companies and patients alike. Pharmaceutical companies would not be obliged to follow requirements enforced by the State in which they intend to manufacture a product, and patients would benefit from high-quality drugs regardless of their place of production.

Background: In 2006, artemether-lumefantrine (ALU), specifically Coartem ® (Novartis Pharma AG, Basel Switzerland), was approved as the first-line drug for treatment of uncomplicated malaria in Tanzania. Due to poor availability and affordability of the innovator's product, the government of Tanzania in 2013 prequalified the use of generic anti-malarial drugs, whereby Artefan ® (Ajanta, Pharma Ltd, India) was the first to be approved., Methods: This was an equivalence prospective study that aimed to determine the effectiveness of anti-malarial generic Artefan ® in comparison with innovator's product Coartem ® . Patients aged 6 to 59 months with uncomplicated malaria were recruited and randomized to either receive Artefan ® or Coartem ® as a control. Participants were required to revisit clinic five times as follow up to monitor treatment outcome as per World Health Organization recommendations. On each visit, thick and thin blood smears, dried blood spot (DBS), haemoglobin concentrations and auxiliary temperature were performed and documented., Results: Out of 230 recruited participants, 200 met inclusion criteria and were randomized equally to receive Artefan ® and Coartem ® . The overall PCR uncorrected cure rate were 80% for Artefan ® and 75% for Coartem ® (p = 0.44). Adequate clinical and parasitological response were 82.1% for Artefan ® and 74.7% for Coartem ® , and there was no early treatment failure (ETF) observed in both arms of treatment. Both drugs showed excellent early parasite clearance, whereby no participants had peripheral parasitaemia on day 3. Late clinical failures (LCF) were 3.6% for Artefan ® and 1.3% for Coartem ® (p = 0.31), and late parasitological failure (LPF) were 15.4% for Artefan ® and 22.7% for Coartem ® (p = 0.32). Mean haemoglobin (g/dl) concentrations observed on day 28 were higher compared to day 0 for both drugs, although not statistically significant. Only one (1.3%) participant on Artefan ® had temperature ≥ 37.5 °C on day 3., Conclusion: The findings of this study indicate that both Artefan ® and Coartem ® are equivalent and effective in the management of uncomplicated malaria amongst children in the Coast part of Tanzania.

Background: We demonstrated therapeutic nonequivalence of "bioequivalent" generics for meropenem, but there is no data with generics of other carbapenems., Methods: One generic product of imipenem-cilastatin was compared with the innovator in terms of in vitro susceptibility testing, pharmaceutical equivalence, pharmacokinetic (PK) and pharmacodynamic (PD) equivalence in the neutropenic mouse thigh, lung and brain infection models. Both pharmaceutical forms were then subjected to analytical chemistry assays (LC/MS)., Results and Conclusion: The generic product had 30% lower concentration of cilastatin compared with the innovator of imipenem-cilastatin. Regarding the active pharmaceutical ingredient (imipenem), we found no differences in MIC, MBC, concentration or potency or AUC, confirming equivalence in terms of in vitro activity. However, the generic failed therapeutic equivalence in all three animal models. Its Emax against S. aureus in the thigh model was consistently lower, killing from 0.1 to 7.3 million less microorganisms per gram in 24 hours than the innovator (P = 0.003). Against K. pneumoniae in the lung model, the generic exhibited a conspicuous Eagle effect fitting a Gaussian equation instead of the expected sigmoid curve of the Hill model. In the brain infection model with P. aeruginosa, the generic failed when bacterial growth was >4 log10 CFU/g in 24 hours, but not if it was less than 2.5 log10 CFU/g. These large differences in the PD profile cannot be explained by the lower concentration of cilastatin, and rather suggested a failure attributable to the imipenem constituent of the generic product. Analytical chemistry assays confirmed that, besides having 30% less cilastatin, the generic imipenem was more acidic, less stable, and exhibited four different degradation masses that were absent in the innovator., Competing Interests: MA and OV have no conflicts of interest. CAR has received honoraria for lectures from NovoNordisk, Allergan, Shire and Novartis. AFZ has received honoraria for lectures from Allergan, Amgen, Janssen, Lilly, Novartis, Novonordisk, Pfizer, Roche and Sanofi. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

There is a need of a relatively simple and inexpensive method for the determination of relative potency of various generic brands of antibiotics in comparison to original products. The current study describes an agar diffusion method which can be performed in any microbiology laboratory, is cheap (costs $2 per test) and its results can be available after overnight incubation. The results show that neither all generics are reliable nor are all generic antibiotics of poor quality., Competing Interests: None

Purpose: To determine differences in prescribing patterns of glaucoma drugs between ophthalmologists and optometrists in terms of (1) the proportions of generics prescribed when brand-name drugs were also available, (2) the relative proportions of drugs prescribed within a drug class, and (3) the relative frequency of all glaucoma drugs prescribed., Design: Cross-sectional study., Participants: All ophthalmologists and optometrists in the United States who prescribed any of the 36 drugs studied through Medicare Part D in 2015., Methods: Outcome measures were calculated using Excel 2016 (Microsoft, Redmond, WA) based on the 2015 Medicare Part D Prescriber data. The total number of drug claims for 36 glaucoma drugs by all ophthalmologists and optometrists through Medicare Part D in 2015 was determined. These data were then used to calculate, for each drug class, the relative proportions of each drug prescribed by ophthalmologists and optometrists in addition to the proportion of claims that were for the generic drug when at least 1 brand-name alternative was available for both professions., Results: The difference between ophthalmologists' and optometrists' proportions of claims that were for generics when at least 1 brand-name drug was available was generally less than 1%, with both professions' patients receiving primarily generic drugs. However, patients of both ophthalmologists and optometrists use relatively low proportions of generic betaxolol, brimonidine, travoprost, and bimatoprost (approximately 46%, 58%, 1%, and 0% of claims were for these generics, respectively, when compared with brand-name drugs for both ophthalmologists and optometrists). Within each drug class, ophthalmologists and optometrists generally chose the same drug. Overall, ophthalmologists prescribed a wider range of drugs, but both ophthalmologists and optometrists prescribed latanoprost most often., Conclusions: Ophthalmologists and optometrists exhibit similar clinical judgement when choosing a particular drug within a drug class. However, ophthalmologists tend to prescribe more drugs from a wider range of drug classes. Both ophthalmologists and optometrists could prescribe more generic betaxolol, brimonidine, travoprost, and bimatoprost, though generic bimatoprost only became available in 2015., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Antibiotics are not only used in morbidity but also help in prevention of infection. The irrational use of broad spectrum antibiotics is now increasing the resistance against pathogens. This present study has been carried out to evaluate the in-vitro antibacterial effect of levofloxacin against clinical isolates. According to Clinical and Laboratory Standards Institute (CLSI) guidelines, minimum inhibitory concentrations 90% (MIC 90 ) of the levofloxacin tested were evaluated by an agar dilution method. Total 63 clinical isolates Staphylococcus aureus (n=34) and Escherichia coli (n=29) were collected from different hospitals at Karachi and were evaluated MIC90 of eleven different brands of levofloxacin tablet (250 mg). Levofloxacin (Reference) was tested against E.coli standard (American Type Culture Collection) (ATCC=25922) with (MIC 90 ; 0.03μg/ml) and compared with different eleven brands of levofloxacin tablets 250mg (MIC90; 0.5μg/ml -16.0μg/ml). Levofloxacin (Reference) sensitivity against S. aureus standard (ATCC=25923) is (MIC90; 0.12μg/ml) and similarly when it was compared with same levofloxacin tablets (MIC 90 ; 0.5-16.0μg/ml). It has been concluded by the present study, a large number of strains of bacteria have shown better bactericidal action of different brands of levofloxacin and nearly all commercialized drugs were appropriate for therapeutic use.

Sevelamer carbonate is a cross-linked polymeric amine; it is the active ingredient in Renvela ® tablets. US FDA provides recommendation for demonstrating bioequivalence for the development of a generic product of sevelamer carbonte using in-vitro equilibrium binding study. A simple UV-vis spectrophotometry method was developed and validated for quantification of free phosphate to determine the binding parameter constant of sevelamer. The method validation demonstrated the specificity, limit of quantification, accuracy and precision of measurements. The validated method has been successfully used to analyze samples in in-vitro equilibrium binding study for demonstrating bioequivalence., Competing Interests: Authors have declared that no competing interests exist., (© Georg Thieme Verlag KG Stuttgart · New York.)

In a 2×2 crossover trial for establishing average bioequivalence (ABE) of a generic agent and a currently marketed drug, the recommended approach to hypothesis testing is the two one-sided test (TOST) procedure, which depends, among other things, on the estimated within-subject variability. The power of this procedure, and therefore the sample size required to achieve a minimum power, depends on having a good estimate of this variability. When there is uncertainty, it is advisable to plan the design in two stages, with an interim sample size reestimation after the first stage, using an interim estimate of the within-subject variability. One method and 3 variations of doing this were proposed by Potvin et al. Using simulation, the operating characteristics, including the empirical type I error rate, of the 4 variations (called Methods A, B, C, and D) were assessed by Potvin et al and Methods B and C were recommended. However, none of these 4 variations formally controls the type I error rate of falsely claiming ABE, even though the amount of inflation produced by Method C was considered acceptable. A major disadvantage of assessing type I error rate inflation using simulation is that unless all possible scenarios for the intended design and analysis are investigated, it is impossible to be sure that the type I error rate is controlled. Here, we propose an alternative, principled method of sample size reestimation that is guaranteed to control the type I error rate at any given significance level. This method uses a new version of the inverse-normal combination of p-values test, in conjunction with standard group sequential techniques, that is more robust to large deviations in initial assumptions regarding the variability of the pharmacokinetic endpoints. The sample size reestimation step is based on significance levels and power requirements that are conditional on the first-stage results. This necessitates a discussion and exploitation of the peculiar properties of the power curve of the TOST testing procedure. We illustrate our approach with an example based on a real ABE study and compare the operating characteristics of our proposed method with those of Method B of Povin et al., (Copyright © 2018 John Wiley & Sons, Ltd.)

The case of generic imatinib demonstrates several potential barriers to effective generic price competition for specialty prescription drugs, including fewer market entrants, smaller-than-expected price reductions, shifts in prescribing toward more expensive brand-name treatments, and limited uptake of the generic product.

Generic drugs are important components of measures introduced by healthcare regulatory authorities to reduce treatment costs. In most patients and conditions the switch from a branded drug to its generic counterpart is performed with no major complications. However, evidence from complex diseases suggests that generic substitution requires careful evaluation in some settings and that current bioequivalence criteria may not always be adequate for establishing the interchangeability of branded and generic products. Rare diseases, also called orphan diseases, are a group of heterogeneous diseases that share important characteristics: in addition to their scarcity, most are severe, chronic, highly debilitating, and often present in early childhood. Finding a treatment for a rare disease is challenging. Thanks to incentives that encourage research and development programs in rare diseases, several orphan drugs are currently available. The elevated cost of orphan drugs is a highly debated issue and a cause of limited access to treatment for many patients. As patent protection and the exclusivity period of several orphan drugs will expire soon, generic versions of orphan drugs should reach the market shortly, with great expectations about their impact on the economic burden of rare diseases. However, consistent with other complex diseases, generic substitution may require thoughtful considerations and may be even contraindicated in some rare conditions. This article provides an overview of rare disease characteristics, reviews reports of problematic generic substitution, and discusses why generic substitution of orphan drugs may be challenging and should be undertaken carefully in rare disease patients.

The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and of two bioequivalent generic products, by evaluating: (a) fentanyl release; (b) fentanyl permeation across porcine skin and (c) fentanyl ease of extraction. Additional characteristics studied are the effect of temperature and skin integrity, applied individually or combined, to check a possible synergism. The two generic patches resulted equivalent to the originator according to the new Guideline. Nevertheless, the same data reported in a different way, i.e. considering the total amount of drug permeated from the whole patch over the application time, highlight differences among the patches. The additional tests performed showed that skin integrity does not represent a barrier for fentanyl permeation across the skin, regardless of the type and complexity of the patch. The effect of temperature resulted critical for two out of three patches, probably due to the different composition and to the different structure. The combination of skin damage and elevated temperature did not produce a synergistic effect. Fentanyl extraction was different for the different products and variable according to the conditions used. The results reported in the present work underline the influence of patch composition and complexity on fentanyl extraction, release and skin permeation, in particular in conditions that can be critical, such as elevated temperature. In particular, the effect of critical variables, such as skin integrity and temperature, should be addressed to in the development of a new or new generic patch and new discriminant tests should be developed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood-brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development.

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA., (© 2017 New York Academy of Sciences.)

The treatment of hepatitis C virus in monoinfected and HIV-coinfected patients has greatly changed over recent years as a result of the introduction of direct-acting antiviral agents (DAAs), which have revolutionized clinical outcomes and led to sustained virological response rates above 90-95%. The discovery of new molecules and the subsequent competition between pharmaceutical companies, together with the negotiated price policies pursued by many national health systems, have led to a gradual reduction in the cost of DAAs, and expand their use to an increasing number of patients, including those with mild liver damage. However, the cost of branded DAAs is still too high for many developing countries, and many patients are still left without therapy. In this context, the availability of generic DAAs certainly provides a major opportunity for further cost savings in industrialized countries and will ensure broader access to treatment elsewhere. However, their more widespread use must not lead to a reduction in pharmaceutical quality because this could result in serious clinical consequences, including high rat failures, and selection of drug resistance. It is therefore essential that all generic formulations of DAAs are pre-qualified by the World Health Organization, and that real-life studies are carried out to verify their pharmacokinetic bioequivalence (ideally in patients, and not just in healthy volunteers) and clinical effectiveness. In this regard, lessons from expanding access programs in the HIV field would be very helpful.

Biosimilar therapeutic proteins in oncology offer the potential to decrease costs while providing safety and efficacy profiles consistent with their respective reference or originator products. Biosimilars have a number of important differences from generic small-molecule drugs, including manufacturing processes that are unique from their reference products. These differences may affect biosimilars through posttranslational modifications that can occur in specific cellular production lines, and these modifications have potential effects on protein structure, function, clinical pharmacology, and immunogenicity. Regulatory agencies expect these differences to be identified, analyzed, and minimized through iterative processes and extensive preclinical efforts. Generic naming of biosimilars reflects the nonproprietary reference product name along with a meaningless four-letter suffix to ensure that each product can be uniquely identified for prescribing and pharmacovigilance purposes. Labeling information for biosimilars reflects a greater detail of comparisons to reference products than conventional generic drugs, which ensures that prescribers can understand the source of information and have a complete understanding of the therapeutic profile of each biosimilar agent. Postmarketing surveillance programs will be required to evolve and ensure optimal pharmacovigilance reporting, because the potential for unexpected adverse events with biosimilars is higher than with conventional generic agents as a result of different manufacturing processes and different clinical trial designs and durations. The existing filgrastim biosimilars are likely to be joined soon by therapeutic monoclonal antibodies, including rituximab, trastuzumab, and bevacizumab, on the basis of patent expiration dates and clinical trial results.

Recent studies have shown that the pharmacodynamic (PD) index driving the efficacy of β-lactam/β-lactamase inhibitor combinations such as ceftazidime/avibactam and ceftolozane/tazobactam is the percentage of time the free inhibitor concentration is above a threshold (fT >threshold ). However, data with piperacillin/tazobactam (TZP) are scarce. Here we aimed to assess the relationship between fT >threshold and TZP antibacterial efficacy by a population pharmacokinetic study in mice and dose-effect experiments in a neutropenic murine thigh infection model with two isogenic strains of Escherichia coli differentially expressing TEM-1 β-lactamase. We also explored the dynamics of resistance selection with the innovator and a non-equivalent generic, extrapolated the results to the clinic by Monte Carlo simulation of standard TZP doses, and estimated the economic impact of generic-selected resistance. The fT >threshold index described well the efficacy of TZP versus E. coli, with threshold values from 0.5 mg/L to 2 mg/L and mean exposures of 42% for stasis and 56% for 1 log 10 kill. The non-equivalent generic required a longer exposure (fT >threshold 33%) to suppress resistance compared with the innovator (fT >threshold 22%), leading to a higher frequency of resistance selection in the clinical simulation (16% of patients with the generic vs. 1% with the innovator). Finally, we estimated that use of TZP generics in a scenario of 25% therapeutic non-equivalence would result in extra expenses approaching US$1 billion per year in the USA owing to selection of resistant micro-organisms, greatly offsetting the savings gained from generic substitution and further emphasising the need for demonstrated and not assumed therapeutic equivalence., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

This study aimed to evaluate the long-term efficacy and safety of a generic tacrolimus (Tacrobell [TCB]) compared to the original tacrolimus (Prograf [PGF]) in kidney transplant recipients. In this retrospective observational study, we analyzed the data from 444 patients who took TCB as a first-line immunosuppressive drug and 245 patients who took PGF. The 5-year graft survival rate was 92% for patients in the PGF group and 97% for patients in the TCB group, respectively. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval [CI] limit of the hazard ratio [HR]<1.2) for TCB compared to PGF (HR: 0.58; 95% CI: 0-1.14). The 5-year patient survival rate was 96% for patients in the PGF group and 97% for patients in the TCB group. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval limit of the HR<2.0) for TCB compared to PGF (HR: 0.83; 95% CI: 0-1.95). The 5-year acute rejection-free graft survival rate was not significantly different between the groups (TCB 67%, PGF 68.8%; P =0.6286). The incidence of adverse events including adverse cardiovascular or cerebrovascular events, malignancies, new-onset diabetes after transplantation, and infection events did not differ significantly between the two groups. We conclude that TCB is a comparable alternative to the original tacrolimus as a first-line immunosuppressive drug. Producers of generics should support further study of their products after approval to assure physicians of their efficacy and safety., Competing Interests: The authors report no conflicts of interest in this work.

Memantine is the first clinically available glutamate antagonist, with an antagonist action at the N-methyl-D-aspartate receptors in the brain, for correction of cognitive and behavioral functions in neurodegenerative disorders. Glutamate mediated excitotoxic neuronal damage has been implicated in Alzheimer's disease (AD) and other parkinsonism-related dementias and, therefore, memantine represents a novel mode of action to counteract the glutamate-mediated excitotoxicity. In moderate to severe AD, 20 mg of memantine shows a positive effect on cognition, mood, behavior and the ability to perform activities of daily living. Long-term studies show good tolerability of memantine with an acceptable side-effect profile. In recent years, there have been a proliferation of a number of companies producing generic memantine with different trade names. In Russia, the first memantine generic drug noojerone was approved in 2010 and its use has since been supported by a growing evidence base of efficacy in real-life clinical practice. Postmarketing studies show that noojerone provides long-term and effective therapy in patients with moderate and severe Alzheimer's dementia. This observation is supported by the clinically significant therapeutic effect of noojerone on cognitive and daily functioning, behavioral and psychotic symptoms of dementia and a reduction of the burden on caregivers. This generic version of memantine is affordable and, therefore, reduces financial burden on patients and improves compliance with treatment.

Objectives: In this study, peripheral blood lymphocytes were compared between a brand-name and a generic tacrolimus group in stable liver transplant recipients., Subjects and Methods: Sixteen patients who underwent ABO-compatible living donor liver transplants between 2012 and 2013 and had stable graft function were included in this study. Ten patients received brand-name tacrolimus and 6 patients received generic tacrolimus. CD3, CD4, CD8, γδ, CD4+FoxP3+, and CD3-CD56+ T cells were analyzed in peripheral blood obtained preoperatively and 4, 8, 12, and 24 weeks after liver transplantation. Categorical variables were compared using a χ2 test or Fisher exact test, and continuous variables were compared using the Mann-Whitney U test., Results: Regarding the baseline and perioperative characteristics, there were no statistically significant differences between the 2 groups. Immunosuppression also was not different. Subtype analysis of T-cell populations carried out in parallel showed similar levels of CD3, CD4, CD8, and γδT cells with brand-name tacrolimus and generic tacrolimus in stable liver transplant recipients. However, the levels of CD4+Foxp3+ and CD3-CD56+ T cells were higher in the brand-name tacrolimus group than in the generic tacrolimus group 8 weeks after transplantation (p < 0.05)., Conclusions: The level of CD4+Foxp3+ T cells was higher in the brand-name tacrolimus group than in the generic tacrolimus group after transplantation. This finding showed that brand-name tacrolimus could have more potential immunosuppressive activity than generic tacrolimus regarding the contribution of CD4+Foxp3+ T cells to graft tolerance in liver transplant recipients., (© 2017 S. Karger AG, Basel.)

Objective . The marketing authorization of generic and similar pharmaceutical drug products involves the analysis of proposing company's administrative aspects as well as drug product technical description and scientific evaluations. This study evaluated the main reasons for registration refusal of generic and similar pharmaceutical drug products in Brazil. The aim is to help future applicants to better organize the proposal. Methods . A retrospective search of drug products registration processes was performed on the Brazilian Government Official Gazette from January 1, 2015, and December 31, 2015. Results . Drug product quality control, drug product stability study, deadline accomplishment, API quality control made by drug manufacturer, active pharmaceutical ingredient (API), and production report were the main reasons for marketing authorization application refusal of generic and similar pharmaceutical drug products in 2015. Conclusion . Disclosure of the reasons behind failed applications is a step forward on regulatory transparency. Sharing of experiences is essential to international regulatory authorities and organizations to improve legislation requirements for the marketing authorization of generic and similar pharmaceutical drug products., Competing Interests: Ana Cerúlia Moraes do Carmo, Stefânia Schimaneski Piras, and Nayrton Flávio Moura Rocha are employees of the Brazilian Health Regulatory Agency (ANVISA). The remaining authors declare no conflict of interests.

Generic medicines were developed to increase population access to health treatment, to reduce costs and to allow drugs with the same outcomes to be purchased at lower prices. They are therapeutically equivalent to their brand-name counterparts and are interchangeable with them. However, the acceptance of generic medicines by physicians and general consumers is often affected by distrust related to quality and efficacy. In this study three different brands of generic amoxicillin were tested. The results showed that two of them were indistinguishable from the innovator in terms of microbiological potency; however, generic B was unable to reach the Brazilian Pharmacopoeia specifications for potency limits. In contrast, generic B was bioequivalent to the innovator amoxicillin in pharmacokinetic assessment and, surprisingly, generic A, which was approved in the microbiological potency assay, lacked pharmacokinetic equivalence compared with the innovator. Both tests, when used singly, may not be effective at detecting quality deviations in antimicrobial medicines, which indicates that pharmacokinetic tests in rats in association with microbiological potency assays are a valuable tool for post-marketing surveillance of generic antibiotics., (Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Treatment effectiveness between equivalent doses of non-OROS (osmotic controlled release oral delivery system) methylphenidate ER and OROS methylphenidate ER (brand name Concerta) was examined in a clinical case series of children and adolescents followed for treatment of attention-deficit/hyperactivity disorder (ADHD). The Conners-Third Edition: Parent Rating Scale was used to compare ADHD symptoms when patients were taking non-OROS versus OROS at follow-up visits. A repeated-measures mixed-model approach was used to compare treatment effectiveness. The entire sample (N = 14) demonstrated a reduction in the mean score on the Inattention Scale from clinically significant (T-score > 65) to not clinically significant (T-score < 65) when patients were changed from non-OROS to OROS at the same dosage (mean T-score reduction = 23, p < .0001). The reduction in mean T-score after changing from non-OROS to OROS at the same dosage is indicative of improvement in symptoms of ADHD. Results provide empirical support for US Food and Drug Administration concerns regarding the therapeutic equivalence of non-OROS versus OROS for the treatment of ADHD., (© The Author(s) 2015.)

Background: Generic anticancer drugs represent an opportunity in terms of cost savings but there are some concerns about their tolerability. The safety profiles of generic versus branded oxaliplatin formulations have never been studied in detail., Patients and Methods: We tested in vitro concentrations, stability and efficacy of branded versus generic oxaliplatin formulations, then we retrospectively collected data about hypersensitivity reactions (HSR) of 427 colorectal cancer patients treated with oxaliplatin-based regimens., Results: No significant difference in oxaliplatin concentration or time-dependent antiproliferative activity between branded and generic oxaliplatin was detected. The incidence of HSR was 12.1% (33/273 patients) in those treated with branded and 9.8% (15/154 patients) in those treated with generic oxaliplatin (p=0.46). The occurrence of grade III-IV HSRs and severe HSRs leading to oxaliplatin discontinuation were comparable., Conclusion: No difference between generic and branded formulations of oxaliplatin were demonstrated in preclinical nor in clinical settings. Generic oxaliplatin can be considered a safe alternative to branded formulation., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Context: Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy., Objective: To compare the anti-tumor efficacy of different PPIs in vitro and in vivo., Materials and Methods: In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice., Results: Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation., Discussion: These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole., Conclusion: The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

Generic agents play a crucial role in reducing the cost of medical care in many countries. However, the therapeutic equivalence remains a great concern. Our study aims to assess the in vitro antimicrobial activity and bioequivalence between generic and brand-name levofloxacin. Enantiomeric purity test, dissolution test, and in vitro antimicrobial susceptibility against seven clinically important pathogens by the agar dilution method were employed to assess the similarity between four generic products and brand-name levofloxacin (Daiichi Sankyo). All the generic and brand-name levofloxacin passed enantiomeric purity test. The results of dissolution tests were not similar among the generic products and the brand-name levofloxacin. Compared with the generic products, the brand-name levofloxacin had the smallest mean variations (-25% to 13%) with reference standard (United States Pharmacopeia levofloxacin Reference Standards). Variations were observed particularly in dissolution profiles and in vitro activity between generic products and brand-name levofloxacin., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: This study was designed to characterize the pharmacokinetic profile and to assess bioequivalence of the sponsor's test formulation (imatinib mesylate 400 mg tablets) with an innovator product (Gleevec 400 mg tablets, Novartis Pharmaceuticals) under fed conditions, in adult patients of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) stabilized on imatinib mesylate 400 mg. In addition, the aim of this study was to monitor the safety profile of investigational medicinal products (IMPs)., Materials and Methods: A multicenter, randomized, open label, two-period, crossover, single dose bioequivalence study was designed for conduct under fed conditions in 42 adult Ph+ CML patients already stabilized on imatinib 400 mg tablets. Pharmacokinetic parameters Tmax, Cmax, and AUC0-24 were calculated using a non-compartmental model on validated WinNonlin software. Validated SAS software was used for statistical evaluation of data. The safety profile of investigational products was monitored during the course of study by applying a clinical process for recording observed untoward effects postadministration of investigational products., Results: The 90% confidence intervals for the test/reference mean ratios of the ln-transformed PK variables Cmax (99.0%) and AUC0-24 (99.2%) were within an acceptable range of 80%-125%, as per bioequivalence assumptions. Both formulations were well tolerated after oral administration of IMPs., Conclusion: The test product was found to be bioequivalent and safe, and thus can be used interchangeably in clinical practice.

Both proprietary and nonproprietary medicines are expected to undergo rigorous preapproval testing and both should meet stringent health authority regulatory requirements related to quality to obtain approval. Nonproprietary (also known as copy, or generic) medicines, which base their authorization and use on the proprietary documentation and label, are often viewed as a means to help lower the cost and, thus, increase patient access. If these medicines fail to meet quality standards, such as good manufacturing practice and bioequivalence (in humans), they are then defined as substandard copies and can pose serious risks to patients in terms of safety and efficacy. Potentially noncontrolled or different manufacturing process and excipients in nonproprietary medicines may result in poor batch-to-batch reproducibility (accurate and consistent quantity of each ingredient in each capsule/tablet) and lower quality. Substandard, nonproprietary copies of medicines that are immunomodulatory or immunosuppressive are of concern to patients due to their possible untoward safety and lack of efficacy events. This article reviews the potential risks associated with nonproprietary medicines that do not meet the regulatory requirements of the United States Food and Drug Administration, the European Medicines Agency, or the World Health Organization. The clinical implications for patients are described. This article focuses on nonproprietary medicines for multiple sclerosis, particularly fingolimod, that are not identical to proprietary versions and could thus fail to meet efficacy expectations or have different impact on the safety of patients with multiple sclerosis.

Background: Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy., Methods: The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777., Findings: Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98-103, Cmax 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study., Interpretation: Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate., Funding: American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In order to test if two chemically or pharmaceutically equivalent products have the same efficacy and/or toxicity, a bioequivalence (BE) study is conducted. The 80%/125% rule is the most commonly used criteria for BE and states that BE cannot be claimed unless the 90% CIs for the ratio of selected pharmacokinetics (PK) parameters of the tested to the reference drug are within 0.8 to 1.25. Considering that estimates of these PK parameters are derived from the concentration-versus-time curves, a direct comparison between these curves motivates an alternative and more flexible approach to test BE. Here, we propose to frame the BE test in terms of an equivalence of concentration-versus-time curves which are constructed using local polynomial smoother (LPS). A metric is presented to quantify the distance between the curves and its 90% CIs are calculated via bootstrapping. Then, we applied the proposed procedures to data from an animal study and found that BE between a generic drug and its brand name cannot be concluded, which was consistent with the results by applying the 80%/125% rule. However, the proposed procedure has the advantage of testing only on a single metric, instead of all PK parameters., Competing Interests: The authors declare that they have no competing interests.

Statines are first choice medications for hypercholesterolemia and combined hyperlipidemia of varying severity in wide population of patients. Atorvastatine is one of the most effective statines. In Russia, Atorvastatine is represented by nearly twenty drugs most of which are generics. The article covers data on efficiency, safety and good tolerance of Liptonorm--a generic Atorvastatine.