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2.
AAPS PharmSciTech ; 20(5): 166, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30989447

RESUMO

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.


Assuntos
Contaminação de Medicamentos , Recall de Medicamento , Valsartana/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/análise , Bloqueadores do Receptor Tipo 1 de Angiotensina II/toxicidade , Dietilnitrosamina/análise , Dimetilnitrosamina/análise , Composição de Medicamentos , Indústria Farmacêutica , Humanos , Mutagênicos/análise , Mutagênicos/toxicidade , Segurança do Paciente , Estados Unidos , United States Food and Drug Administration
4.
BMJ Open ; 9(2): e026619, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30782947

RESUMO

OBJECTIVES: To introduce serialised medicines into an operational hospital dispensary and assess the technical effectiveness of digital medicine authentication (MA) technology under European Union Falsified Medicines Directive (EU FMD) conditions. DESIGN: Thirty medicine lines were serialised using 2D data matrix labels and introduced into an operational UK National Health Service (NHS) hospital dispensary. Staff were asked to check medicines for two-dimensional (2D) data matrices and scan those products, in addition to their usual medicine preparation and checking processes. Four per cent of the study medicines were labelled with a 2D barcode which generated a pop-up, identifying the medicine as either authenticated elsewhere (falsified), authenticated here, expired or recalled. SETTING: An NHS teaching hospital based in the UK, the same site as the Naughton et al 2016 study. PARTICIPANTS: General Pharmaceutical Council registered, accredited accuracy checking technicians and pharmacists. PRIMARY OUTCOME MEASURES: Average response times, offline issues, instances of incorrect quarantine and workarounds. The EU FMD maximum response time is 300 milliseconds (ms). RESULTS: During the checking stage of medicine preparation, the average response time for MA in this study was 131 ms. However, 4.67% of attempted authentications experienced offline issues, an increase of 4.23% from the previous study. An increase in offline instances existed alongside an increase in incorrect quarantine. CONCLUSIONS: Digital drug screening has the capability of operating with average response times which are below the maximum EU FMD limit of 300 ms. However, there was an increased incidence of offline errors and cases of incorrect quarantine. The practical and legal implications of supplying a substandard or falsified medicine during offline periods without prior authentication or withholding supply until online status resumes are not yet fully understood.


Assuntos
Medicamentos Falsificados , Recall de Medicamento , Erros de Medicação/prevenção & controle , Tecnologia Farmacêutica/normas , Hospitais de Ensino , Humanos , Reino Unido
5.
Fundam Clin Pharmacol ; 33(4): 471-478, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30687946

RESUMO

Atropinic drugs are known to potentially induce physical and/or mental impairments in the elderly. The aim of this study was to investigate trends of atropinic exposure in patients ≥65 years in France between 2006 and 2015. A repeated cross-sectional study was performed quarterly from January 1, 2006 to December 31, 2015, in the 'Echantillon Généraliste des Bénéficiaires (EGB)', a representative sample of the French population. Exposed patients were identified using the Anticholinergic Durán's list. Outcomes were rate of patients exposed to at least one atropinic drug (atropinic prevalence rate) and atropinic burden per patient (sum of atropinic burden scores). Interrupted time series were used to analyze the impact of market withdrawal of some drugs with atropinic properties during the period of the study. The number of patients ≥65 years registered in the EGB ranged from 75 611 in 2006 to 95 389 in 2015. Atropinic prevalence rate decreased significantly from 45.6% in 2006 to 33.2% in 2015 (-12.4%, slope significance P < 0.05). Subjects aged ≥85 years were the most exposed. Total atropinic burden decreased significantly between 2006 and 2015 (2.2 ± 1.7 in 2006; 2.0 ± 1.5 in 2015; slope significance P < 0.05), especially in patients ≥85 years. Market withdrawals for safety reasons of some atropinic drugs were significantly associated with a decrease in the atropinic prevalence rate (P < 0.05) and atropinic burden per patient (P < 0.05). In conclusion, atropinic drug exposure in the elderly significantly decreased in France between 2006 and 2015. This decrease can be partly explained by regulatory measures against some atropinic drugs.


Assuntos
Antagonistas Colinérgicos/administração & dosagem , Bases de Dados Factuais/estatística & dados numéricos , Recall de Medicamento/estatística & dados numéricos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , França , Humanos , Análise de Séries Temporais Interrompida , Masculino
9.
Curr Opin Anaesthesiol ; 31(4): 423-430, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29847365

RESUMO

PURPOSE OF REVIEW: The current review examines the success and failures of the development of new hypnotic compounds for the human market. One of the important aspects is that one of the key present agents, propofol, is considered by many anaesthesiologists as 'the ideal'. However, all drugs have adverse or side-effects. RECENT FINDINGS: The last 30 years since the introduction of propofol has seen many new compounds evaluated; but as at the present time, only three agents may achieve a pivotal position in the market - fospropofol (a sedative agent which may have a role in endoscopic surgery); remimazolam (a short-acting benzodiazepine) whose development is also being focused on the sedation rather than anaesthesia market; and the pregnane steroid, alfaxalone (an anaesthetic agent first introduced in 1972, but withdrawn in 1984 because of adverse allergic reactions to the solvent, Cremophor EL) now solvented in a cyclodextrin. SUMMARY: Studies of these three agents thus far have shown that none of them has any major adverse side-effects; all have properties which warrant further clinical evaluation.


Assuntos
Anestesia/métodos , Sedação Consciente/métodos , Hipnóticos e Sedativos/efeitos adversos , Anestesia/efeitos adversos , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Ensaios Clínicos como Assunto , Sedação Consciente/efeitos adversos , Recall de Medicamento , Humanos , Hipnóticos e Sedativos/administração & dosagem , Pregnanodionas/administração & dosagem , Pregnanodionas/efeitos adversos , Propofol/administração & dosagem , Propofol/efeitos adversos , Propofol/análogos & derivados
11.
Med Mycol ; 56(4): 389-394, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29420758

RESUMO

Recent (2012) grave but rare outbreaks of fungal meningitis and endophthalmitis associated with drugs contaminated with select environmental moulds (Exserohilum and Fusarium, respectively) have exacerbated mycology concerns for formulation, good laboratory practices (GLP), and use of the final drug product. Intensified investigations (2013-2015) by the Food and Drug Administration (FDA) that included added responsibilities for specialty compounding laboratories have prompted at least nine voluntary mould-related drug recalls during 2014-2015. Both primary manufactures (five recalls, two companies) and secondary-processing compound laboratories (at least eight recalls, six companies) and near 0.8 million units were involved. These constituted minor fractions of recalled drug products in an estimated 2500 recalls among other causes during this time period. Recalls of similar drugs in 2016 were indirectly related to fungi. None of the mould-related- drug-recall episodes during 2014-2016 have been identified with fungal disease outbreaks. The recalls included drugs in short supply worldwide such as injectable sodium chloride- and related saline solutions as well as ocular formulations. Insufficient environmental monitoring and GLP compliance, particularly for aseptic processing of non-preserved formulations, appeared to be underlying factors in the fungal contaminations. Observations of mould growth in drugs during their processing should be accurately recorded and investigated; cryptic listings under "particulate" designations should be avoided. Confirmed identifications for chronic contaminants are recommended. Heat-tolerant moulds with resistant morphotypes are prime concerns.


Assuntos
Contaminação de Medicamentos/estatística & dados numéricos , Indústria Farmacêutica/normas , Recall de Medicamento/estatística & dados numéricos , Fungos/isolamento & purificação , Preparações Farmacêuticas/provisão & distribução , Preparações Farmacêuticas/normas , Contaminação de Medicamentos/prevenção & controle , Indústria Farmacêutica/classificação , Monitoramento Ambiental/normas , Fungos/classificação , Humanos , Preparações Farmacêuticas/administração & dosagem , Retirada de Medicamento Baseada em Segurança/estatística & dados numéricos , Estados Unidos , United States Food and Drug Administration
14.
PDA J Pharm Sci Technol ; 72(1): 44-49, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29030530

RESUMO

INFARMED, the Portuguese national health authority, alerts the general public and health care professionals about quality or safety issues detected in health products. The present study analyses recalls of substandard medicines in Portugal between 2005 and 2015. All 338 alerts for medicine recalls were analysed, which represents a total of 378 drugs withdrawn. Despite the fact that the total number of medicine alerts has increased during the past decade, the number of actual medicine recalls remained relatively constant. The number of batches affected in each recall varies from only one to several batches. In addition, 294 of the alerts are related to voluntary recalls, that is, those initiated by the marketing authorisation holder, whereas only 40 were mandatory recalls. There are marketing authorisation holders that have had several medicine recalls over the period studied. The main cause of product recall was the pharmaceutical dosage form, followed by packaging problems. Forty-two percent of the withdrawn medicines are from solid oral forms, a value slightly higher than that obtained for the injectables group. Finally, substandard medicines have been accessible in the Portuguese market for a period that varied between one month and over four years. The data seem to show that the number of substandard medicines in Portugal has not been increasing. However, this may be due to a variety of causes, that is, better performance of the industry, non-detection of these cases, and so on.LAY ABSTRACT: INFARMED, the Portuguese national health authority, alerts the general public and health care professionals about quality or safety issues detected in health products. The present study analyses market recalls of substandard medicines in Portugal between 2005 and 2015. All 338 alerts for medicine recalls were analysed, which represents a total of 378 drugs withdrawn. Despite the fact that the total number of medicine alerts has increased during the past decade, the number of actual medicine recalls has remained relatively constant. In addition, 294 of the alerts are related to voluntary recalls, that is, initiated by the marketing authorisation holder, whereas only 40 were mandatory recalls. There are marketing authorisation holders that have had several medicine recalls over the period studied. It was also found that substandard medicines have been accessible in the Portuguese market for a period that varied between 1 month and over 4 years. The data seem to show that the number of substandard medicines in Portugal has not been increasing. However, this may be due to a variety of causes, that is, better performance of the industry, non-detection of these cases, and so on.


Assuntos
Recall de Medicamento/estatística & dados numéricos , Preparações Farmacêuticas/normas , Confiabilidade dos Dados , Indústria Farmacêutica , Humanos , Programas Nacionais de Saúde , Portugal , Controle de Qualidade , Estudos Retrospectivos
15.
Eur Urol Focus ; 3(4-5): 395-402, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29174614

RESUMO

CONTEXT: Testosterone replacement therapy (TRT) is currently approved by the Food and Drug Administration only for classic hypogonadism, although off-label indications have resulted in a dramatic expansion in prescriptions in the USA. Marketing may significantly affect prescriber behavior. OBJECTIVE: To systematically review all available evidence on marketing and TRT in the USA. EVIDENCE ACQUISITION: PubMed, Embase, and Scopus were searched up to July 2017 for all relevant publications reporting on assessments of the TRT market size, economic costs associated with hypogonadism, trends in TRT prescriptions, drug discontinuation rates, and advertising and sales efforts in the USA. EVIDENCE SYNTHESIS: Twenty retrospective studies were included in the final analysis. The market size for hypogonadism constitutes 5.6-76.8% of men in the USA, with the lower end of the range representing the strictest criteria for diagnosis. Men with a diagnosis of hypogonadism consume $14 118 in direct and indirect costs to the payer. Over the last 2 decades, TRT prescriptions have increased between 1.8- and 4-fold. After 1 yr, 80-85% of men discontinue TRT. There is an association between direct-to-consumer advertising and testosterone testing, TRT prescriptions, and TRT without testosterone testing. There is a high prevalence of misinformation on Internet advertising. CONCLUSIONS: Off-label indications have driven the dramatic expansion of TRT prescriptions over the last 2 decades. Direct-to-consumer advertising poses a unique challenge in the USA. Overtreatment can be avoided by applying strict diagnostic criteria for hypogonadism, which limits the addressable market for TRT. PATIENT SUMMARY: In this report, we reviewed the relationship between marketing and testosterone therapy in the USA. We found that many patients are prescribed testosterone without an appropriate diagnosis of hypogonadism, which may be related to the marketing efforts for off-label prescribing.


Assuntos
Recall de Medicamento/estatística & dados numéricos , Hipogonadismo/tratamento farmacológico , Marketing/métodos , Testosterona/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Androgênios/economia , Androgênios/uso terapêutico , Publicidade Direta ao Consumidor/tendências , Humanos , Hipogonadismo/economia , Hipogonadismo/epidemiologia , Masculino , Marketing/normas , Sobremedicalização/prevenção & controle , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Testosterona/economia , Estados Unidos/epidemiologia
19.
BMJ Open ; 7(5): e013838, 2017 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-28478398

RESUMO

OBJECTIVES: This study aims to establish expert opinion and potential improvements for the Falsified Medicines Directive mandated medicines authentication technology. DESIGN AND INTERVENTION: A two-round Delphi method study using an online questionnaire. SETTING: Large National Health Service (NHS) foundation trust teaching hospital. PARTICIPANTS: Secondary care pharmacists and accredited checking technicians. PRIMARY OUTCOME MEASURES: Seven-point rating scale answers which reached a consensus of 70-80% with a standard deviation (SD) of <1.0. Likert scale questions which reached a consensus of 70-80%, a SD of <1.0 and classified as important according to study criteria. RESULTS: Consensus expert opinion has described database cross-checking technology as quick and user friendly and suggested the inclusion of an audio signal to further support the detection of counterfeit medicines in secondary care (70% consensus, 0.9 SD); other important consensus with a SD of <1.0 included reviewing the colour and information in warning pop up screens to ensure they were not mistaken for the 'already dispensed here' pop up, encouraging the dispenser/checker to act on the warnings and making it mandatory to complete an 'action taken' documentation process to improve the quarantine of potentially counterfeit, expired or recalled medicines. CONCLUSIONS: This paper informs key opinion leaders and decision makers as to the positives and negatives of medicines authentication technology from an operator's perspective and suggests the adjustments which may be required to improve operator compliance and the detection of counterfeit medicines in the secondary care sector.


Assuntos
Medicamentos Falsificados/análise , Técnica Delfos , Prova Pericial , Preparações Farmacêuticas/normas , Atenção Secundária à Saúde/métodos , Tecnologia Farmacêutica/métodos , Consenso , Recall de Medicamento/métodos , Pesquisas sobre Serviços de Saúde , Humanos , Pesquisa Qualitativa , Tecnologia Farmacêutica/normas , Reino Unido
20.
BMJ Open ; 6(12): e013837, 2016 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-27940634

RESUMO

OBJECTIVES: To identify the authentication and detection rate of serialised medicines using medicines authentication technology. DESIGN AND INTERVENTION: 4192 serialised medicines were entered into a hospital dispensary over two separate 8-week stages in 2015. Medicines were authenticated using secure external database cross-checking, triggered by the scanning of a two-dimensional data matrix with a unit specific 12-digit serial code. 4% of medicines included were preprogrammed with a message to identify the product as either expired, pack recalled, product recalled or counterfeit. SETTING: A site within a large UK National Health Service teaching hospital trust. PARTICIPANTS: Accredited checking staff, pharmacists and dispensers in a pharmacy department. PRIMARY OUTCOME MEASURES: Authentication and detection rate of counterfeit expired and recalled medicines. RESULTS: The operational detection rate of counterfeit, recalled and expired medicines scanned as a combined group was 81.4% (stage 1 (S1)) and 87% (stage 2 (S2)). The technology's technical detection rate (TDR) was 100%; however, not all medicines were scanned and of those that were scanned not all that generated a warning message were quarantined. Owing to an operational authentication rate (OAR) of 66.3% (over both stages), only 31.8% of counterfeit medicines, 58% of recalled drugs and 64% of expired medicines were detected as a proportion of those entered into the study. Response times (RTs) of 152 ms (S1) and 165 ms (S2) were recorded, meeting the falsified medicines directive-mandated 300 ms limit. CONCLUSIONS: TDRs and RTs were not a limiting factor in this study. The suboptimal OAR poses significant quality and safety issues with this detection approach. Authentication at the checking stage, however, demonstrated higher OARs. There is a need for further qualitative research to establish the reasons for less than absolute authentication and detection rates in the hospital environment to improve this technology in preparation for the incumbent European Union regulative deadline.


Assuntos
Medicamentos Falsificados , Recall de Medicamento , Erros de Medicação/prevenção & controle , Preparações Farmacêuticas/normas , Tecnologia Farmacêutica/métodos , Humanos , Pesquisa Qualitativa , Atenção Secundária à Saúde/métodos
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