Original Moxonidine and Generics: Where is the Edge of Difference?

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.

Antimicrobial activity and pathogen mutation prevention of originator and generics of cefepime, linezolid and piperacillin/tazobactam against clinical isolates of Staphylococcus aureus.

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.

Effect of compromised skin barrier on delivery of diclofenac sodium from brand and generic formulations via microneedles and iontophoresis.

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.

Towards a generic prototyping approach for therapeutically-relevant peptides and proteins in a cell-free translation system.

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.

Comparative Effectiveness of Generic vs Brand-Name Levothyroxine in Achieving Normal Thyrotropin Levels.

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.

Report from the 2018 consensus conference on immunomodulating agents in thoracic transplantation: Access, formulations, generics, therapeutic drug monitoring, and special populations.

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation.

Knowledge, attitude, and practice of pharmacy professionals on generic medicines in Eastern Ethiopia: A cross-sectional study.

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.

Evaluation of Generic versus Original Prostaglandin Analogues in the Treatment of Glaucoma: A Systematic Review and Meta-Analysis.

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.

Brand-Name Antidepressants Outperform Their Generic Counterparts in Preventing Hospitalization for Depression: The Real-World Evidence from Taiwan.

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.

Comparison of In Vivo Pharmacokinetics and Pharmacodynamics of Vancomycin Products Available in Korea.

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 (Cmax) 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 (Emax) 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.

Bioequivalence and pharmacodynamics of a generic dabigatran etexilate capsule in healthy Chinese subjects under fasting and fed conditions.

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 Cmax , AUC0-t , and AUC0-∞ 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.

In vitro equivalence of generic and branded amoxicillin tablet by microbiological assay method.

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.

Acceptability and barriers to implementation of N-of-1 tests in Ethiopia - a qualitative study.

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.

Relative potency of different generic brands of meropenem, colistin and fosfomycin: Implications for antimicrobial therapy and antimicrobial formulary.

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.

The requirements for manufacturing highly active or sensitising drugs comparing Good Manufacturing Practices.

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.

The effect of rebranding generic medicines on drug efficacy and side effects.

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 ß-blockers (actually placebos) for pre-examination anxiety. In Study 1, participants received either a generic ß-blocker with enhanced packaging, a plainly packaged generic or a branded ß-blocker. Study 2 compared an enhanced packaging generic to a plainly packaged generic ß-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.

Did Generic Clopidogrel Commercialization Affect Trends of ER Consultations and Hospitalizations in the Population Treated with Clopidogrel?

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.

Comparison of malaria treatment outcome of generic and innovator's anti-malarial drugs containing artemether-lumefantrine combination in the management of uncomplicated malaria amongst Tanzanian children.

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.

Nontherapeutic equivalence of a generic product of imipenem-cilastatin is caused more by chemical instability of the active pharmaceutical ingredient (imipenem) than by its substandard amount of cilastatin.

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.