Unlicensed and off-label uses of medicines: definitions and clarification of terminology.

The terms 'licensed', 'unlicensed', and 'off-label', often used in relation to marketing and prescribing medicinal products, may confuse UK prescribers. To market a medicinal product in the UK requires a Marketing Authorization ('product licence') for specified indications under specified conditions, regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The Marketing Authorization includes the product's agreed terms of use (the 'label'), described in the Summary of Product Characteristics (SmPC). Prescribing a licensed product outside those terms is called 'off-label' prescribing. Products for which no-one holds a UK Marketing Authorization are unlicensed. Prescribers can prescribe authorized products according to the conditions described in the SmPC ('on-label') or outside those conditions ('off-label'). They can also prescribe unauthorized products, even if they are unlicensed in the UK, if they are licensed elsewhere or if they have been manufactured in the UK by a licensed manufacturer as a 'special'. The complexities of this system can be understood by considering the status of the manufacturer of the product, the company that markets it (which may or may not be the same), the product itself, and its modes of use, and by emphasizing the word 'authorized'. If a Marketing Authorization is granted to the supplier of a product, it will specify the authorized modes of use; the product will be prescribable as authorized (i.e. 'on-label') or in other modes of use, which will all be off-label. Unlicensed products with no authorized modes of use can be regarded as 'unauthorized products'. All 'specials' can be regarded as authorized products lacking authorized modes of use.

Quality of drug information for healthcare professionals: the ARCA acronym / Calidad de la información sobre medicamentos para profesionales de la salud: el acrónimo ARCA

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Augmented Reality: Real-Time Information Concerning Medication Consumed by a Patient.

This paper describes a mobile prototype capable of recognizing characters from a photograph of a medication package. The prototype was built to work on the iOS platform and was developed using Objective-C and C programming languages. The prototype, capable of recognizing text out of an image, included image processing algorithms, text processing algorithms, and techniques to search and handle information from a database. This prototype is presented as an option for capturing reliable and validated information by using new technologies available to the general population.

Comparing Drug-Disease Associations in Clinical Practice Guideline Recommendations and Drug Product Label Indications.

Clinical practice guidelines (CPGs) and structured product labels (SPLs) are both intended to promote evidence-based medical practices and guide clinicians' prescribing decisions. However, it is unclear how well CPG recommendations about pharmacologic therapies for certain diseases match SPL indications for recommended drugs. In this study, we use publicly available data and text mining methods to examine drug-disease associations in CPG recommendations and SPL treatment indications for 15 common chronic conditions. Preliminary results suggest that there is a mismatch between guideline-recommended pharmacologic therapies and SPL indications. Conflicting or inconsistent recommendations and indications may complicate clinical decision making and implementation or measurement of best practices.

Searches for randomized controlled trials of drugs in MEDLINE and EMBASE using only generic drug names compared with searches applied in current practice in systematic reviews.

BACKGROUND: It is unclear which terms should be included in bibliographic searches for randomized controlled trials (RCTs) of drugs, and identifying relevant drug terms can be extremely laborious. The aim of our analysis was to determine whether a bibliographic search using only the generic drug name produces sufficient results for the generation of informative systematic reviews (SRs). METHODS: We conducted a retrospective analysis of relevant references included in SRs of drugs. We determined the proportion of references identified by a simplified technique consisting of a systematic search for RCTs in MEDLINE and EMBASE via the search interface Ovid and using only the truncated generic drug name in all search fields. We calculated aggregated sensitivity and also evaluated the unidentified references. RESULTS: Forty-eight SRs contained 873 primary publications, of which we found 829 in MEDLINE and 757 in EMBASE ("gold standard"). The simplified search identified 823 of the 829 MEDLINE references (sensitivity 99.3%) and 754 of the 757 EMBASE references (99.6%). Ultimately, only three references could not be found by additional searches. CONCLUSION: Our findings indicate that when searching for RCTs of drugs in MEDLINE and EMBASE, a search using the truncated generic drug name in all fields produces sufficient results.

Package leaflets of the most consumed medicines in Portugal: safety and regulatory compliance issues. A descriptive study / Bulas dos medicamentos mais consumidos em Portugal: aspectos de segurança e de adequação regulamentar. Um estudo descritivo

CONTEXT AND OBJECTIVES: Package leaflets are necessary for safe use of medicines. The aims of the present study were: 1) to assess the compliance between the content of the package leaflets and the specifications of the pharmaceutical regulations; and 2) to identify potential safety issues for patients. DESIGN AND SETTING: Qualitative descriptive study, involving all the package leaflets of branded medicines from the three most consumed therapeutic groups in Portugal, analyzed in the Department of Pharmacoepidemiology, School of Pharmacy, University of Lisbon. METHODS: A checklist validated through an expert consensus process was used to gather the data. The content of each package leaflet in the sample was classified as compliant or non-compliant with compulsory regulatory issues (i.e. stated dosage and descriptions of adverse reactions) and optional regulatory issues (i.e. adverse reaction frequency, symptoms and procedures in cases of overdose). RESULTS: A total of 651 package leaflets were identified. Overall, the package leaflets were found to be compliant with the compulsory regulatory issues. However, the optional regulatory issues were only addressed in around half of the sample of package leaflets, which made it possible to identify some situations of potentially compromised drug safety. CONCLUSION: Ideally, the methodologies for package leaflet approval should be reviewed and optimized as a way of ensuring the inclusion of the minimum essential information for safe use of medicines. .

CONTEXTO E OBJETIVO: As bulas dos medicamentos são necessárias para a sua utilização segura. Os objetivos do presente estudo foram: 1) avaliar a adequação entre o conteúdo das bulas e as especificações da regulação farmacêutica e 2) identificar os aspectos que potencialmente possam comprometer a utilização segura dos medicamentos pelos doentes. TIPO DE ESTUDO E LOCAL: Estudo descritivo qualitativo com a inclusão de todas as bulas dos medicamentos de marca dos três grupos terapêuticos mais consumidos em Portugal, analisados no Departamento de Farmacoepidemiologia da Faculdade de Farmácia da Universidade de Lisboa. MÉTODOS: Utilização de uma checklist para recolher os dados. A checklist foi validada por um processo de consenso entre peritos. O conteúdo de cada uma das bulas da amostra foi classificado em relação à adequação aos aspectos regulatórios obrigatórios, como a descrição das reações adversas, dose e frequência de administração, e à adequação dos aspectos regulatórios facultativos, como a frequência das reações adversas e sintomas e procedimentos em caso de sobredosagem. RESULTADOS: Foram identificadas 651 bulas. Em termos gerais, todas as bulas foram consideradas conformes em relação aos aspectos regulatórios obrigatórios. No entanto, os aspectos regulatórios opcionais foram descritos em apenas cerca de metade da amostra de bulas, o que permite a identificação de situações susceptíveis de comprometer a utilização segura dos medicamentos. CONCLUSÃO: Idealmente as metodologias de aprovação das bulas devem ser revistas e otimizadas de forma a assegurar um mínimo de informação essencial para a utilização segura dos medicamentos. .

Package leaflets of the most consumed medicines in Portugal: safety and regulatory compliance issues. A descriptive study.

CONTEXT AND OBJECTIVES: Package leaflets are necessary for safe use of medicines. The aims of the present study were: 1) to assess the compliance between the content of the package leaflets and the specifications of the pharmaceutical regulations; and 2) to identify potential safety issues for patients. DESIGN AND SETTING: Qualitative descriptive study, involving all the package leaflets of branded medicines from the three most consumed therapeutic groups in Portugal, analyzed in the Department of Pharmacoepidemiology, School of Pharmacy, University of Lisbon. METHODS: A checklist validated through an expert consensus process was used to gather the data. The content of each package leaflet in the sample was classified as compliant or non-compliant with compulsory regulatory issues (i.e. stated dosage and descriptions of adverse reactions) and optional regulatory issues (i.e. adverse reaction frequency, symptoms and procedures in cases of overdose). RESULTS: A total of 651 package leaflets were identified. Overall, the package leaflets were found to be compliant with the compulsory regulatory issues. However, the optional regulatory issues were only addressed in around half of the sample of package leaflets, which made it possible to identify some situations of potentially compromised drug safety. CONCLUSION: Ideally, the methodologies for package leaflet approval should be reviewed and optimized as a way of ensuring the inclusion of the minimum essential information for safe use of medicines.

[Original preparations versus generics--latanoprost: how similar is different?]. / Originalpräparat versus Generika--Latanoprost : Wie gleich ist unterschiedlich?

BACKGROUND: To test the interchangeability of the commercially available (in Germany) latanoprost drugs and their generics respectively, the concentration of the active substance was tested. Guidelines of the European Medicines Agency postulate a sufficient bioequivalence, if the range of the agent is within 80-125% of the original drug. METHODS: All compounds of latanoprost were procured registered. The concentration of latanoprost and benzalkoniumchloride was measured by high-performance liquid chromatography (HPLC) in a validated reference labroratory for 23 generics. In addition, the mean volume of drops and the pH of the formulation were measured. The packaging label and the readability of the enclosed information leaflet were checked. RESULTS: All products contained less than 50 µg/ml latanoprost. The deviating reduction of the active substance (mean: - 7.39%, ± 2.8%) was accompanied by fluctions of the eyedrops' mass (mean: 0.03 g, ± 0.002 g). The concentration of benzalkonium chloride was mostly increased (median: 5.45%, min: - 2.5%, max: 11.5%). The pH of the original drug and the generics (median 6.78, min: 6.62, max: 6.81) was similar to the original drug, but was significantly different from an unpreserved formulation (pH 7.18). Due to type size, the packaging leaflet was illegible for humans with impaired vision. CONCLUSIONS: Before prescribing generics in ophthalmology, different factors have to be considered, which might influence the amount of IOP lowering in effect. In the absence of healthcare research it is still unclear, how different bottle forms of eyedrops--such as appearance (e.g. Cyrillic characters) or pressure point (administration)--reduce the adherence of glaucoma patients.

Medication extraction and guessing in Swedish, French and English.

Extraction of information related to the medication is an important task within the biomedical area. Our method is applied to different types of documents in three languages. The results indicate that our approach can efficiently update and enrich the existing drug vocabularies.

Children's misunderstandings of hazard warning signs in the new globally harmonized system for classification and labeling.

Accidental chemical poisoning causes more than 35 000 child deaths every year across the world, and it leads to disease, disability, and suffering for many more children. Children's ignorance of dangers and their failure to interpret hazard warning signs as intended contribute significantly to this problem. A new Globally Harmonized System for Classification and Labeling is being implemented internationally with a view to unifying the current multiple and disparate national systems. This study was designed to establish a productive, effective means of teaching the new GHS warning signs to primary school children (aged 7-11 years). A pre-test, post-test, follow-up test design was employed, with a teaching intervention informed by a Delphi survey of expert opinion. Children from one school formed the experimental group (n = 49) and a second school provided a control group (n = 23). Both groups showed a gain in knowledge from pre-test to post-test, the experimental group with a larger gain but which was not statistically significant. However, longer-term retention of knowledge, as shown by the follow-up test, was statistically significantly greater in the experimental group (p = 0.001). The employment of teaching to match children's preferred learning styles, and the use of active learning were found to be related to improved retention of knowledge. Part of the study involved eliciting children's interpretation of standard hazard warning symbols, and this provoked considerable concern over the potential for dangerous misinterpretation with disastrous consequences. This article focuses on the reasons for such misconception and the action required to address this successfully in testing the intervention.

Responsabilidad por daños producidos por medicamentos / Responsability due to damages produces by drugs

Un medicamento, desde la fase de ensayos clínicos, hasta que es administrado a un paciente, pasa por diferentes situaciones de riesgo que conviene conocerlas para evitarlas en lo posible, y poderlas controlar. En la fase de ensayos clínicos, el riesgo es claro, los conocimientos del fármaco son muy limitados, por ello la normativa obliga a contratar una importante póliza de responsabilidad por posibles daños. En la fase de fabricación, son frecuentes los lotes defectuosos que escapan al control y suponen un riesgo. En la fase de comercialización (dispensación y administración) es donde se dan el mayor número de daños, puesto que al prescribir el medicamento ante la generalidad de pacientes (distinto del ensayo clínico donde el enfermo es elegido cuidadosamente), es cuando aparecen reacciones adversas desconocidas, etc. que generan responsabilidad para el laboratorio fabricante o comercializador. La ficha técnica de nuevos productos, que deben recibirla todos los sanitarios prescriptores, es la mejor guía para hacer un buen uso del medicamento, puesto que aparece la frecuencia y gravedad de reacciones adversas, las interacciones y cualquier acción que deba tenerse en cuenta. Finalmente, debemos tener en cuenta la farmacovigilancia, o sea, que el prescriptor, en el caso de cualquier sospecha de una reacción adversa o cualquier circunstancia, tiene la obligación de comunicarla a la Consejería, por cualquier medio, del posible evento será tenida en cuenta en el seguimiento del producto (AU)

A drug, from the phase of its clinical trial until the administration to a patient, goes through different situations of risk that we should know in order to avoid and control. In the clinical trial phase, the risk is clear, the familiarity with the drug is limited. This is why the rules oblige to hire a liability policy for possible future damages. In the manufacturing phase, there exists defective batches that escape from the control and involve a risk. In the marketing phase (dispensation and administration) is where there exists the highest number of damages, because when the drug is administred to different kind of patients (different from the clinical trial where the patient is chosen) is when there appears unknown adverse reactions, etc... that generate responsibility for the manufacturer or the marketer laboratory. The technical data sheet of the new product, that must be received by all the medical prescribers is the best guide in order to make a good use of the drug, because it shows the frequency and seriousness of the adverse reactions, the interactions and any other action that should be taken into account. Finally, we should take into account the pharmaco-surveillance, that is to say, the prescriber, under any question of an adverse reaction or any circumstance, has the obligation to inform to the Ministry, of any way, about the possible fact that is going to be taken into account (AU)

[Hazard for human health and life by unintentional use of synthetic sibutramine, which was sold as Chinese herbal product "meizitanc"]. / Zagroienie dla zdrowia i zycia ludzkiego przez nieswiadome zastosowanie syntetycznej sibutraminy, sprzedawanej jako chinski preparat ziolowy "meizitanc".

UNLABELLED: Problem of adulteration of herbal medicines with synthetic drugs is getting a common and dangerous phenomenon in Poland. The purpose of this study was the qualitative estimation of content of the Chinese herbal medicine for slimming "Meizitanc" as well as the estimation of hazard for human health and life. Twenty herbal packages which were secured by police in the 2006 year were investigated. The main ingredient of herbal medicine "Meizitanc" was sibutramine. The average mass of sibutramine hydrochloride in the "Meizitanc" capsule was about 10 mg. Additionally the trace amount of xylene and a starch were detected in the capsules. The presence of mentioned above substances were confirmed by different analytical methods like: gas chromatography with mass spectrometry GC/MS, thin layer chromatography TLC, high-pressure liquid chromatography HPLC/UV-DAD and infrared spectrometry IR. There were not determined any herbal-originated substances, which were mentioned on the packages. It was not found any pharmacologically active substance in one of the twenty examined packages. CONCLUSIONS: The medicine containing sibutramine should be used under the strict medical control. For safety of the patients all herbal products should be buy from authorized her

[Side effects after the usage of Chinese dieting product Meizitanc]. / Dzialania niepozadane spowodowane stosowaniem chinskiego srodka odchudzajacego Meizitanc.

UNLABELLED: Side effects of self-treatment of eight obese women aged between 28 and 45 (average 36.5) with the body mass index (BMI) between 28 and 32 (average 30) kg/m2 have been described. All these women, without any medical consultation and upon their own will had been using Meizitanc as the only remedy for slimming. They started with a dosage of 1 capsule per day, gradually increasing the Meizitanc dose to 3 capsules a day. The patients had used the drug from 2.5 to 6 (average 3.2) months. There were many side effects observed in all women like palpitation, headache and vertigo, warm feeling, nervousness, and tremor of the hands which was observed in four patients. All these effects appeared during the last few weeks and thus forced them to get the consultation in the Poison Information Centre in the Medical University of Gdansk. All capsules were examined with the use of gas chromatography and mass spectrophotometer GC/MS. It was found that each capsule contained 10 mg of sibutramine. There was no information about the presence of sibutramine in the composition of Meizitanc on the package and leaflet. After discontinuation of Meizitanc all side effects disappeared. CONCLUSIONS: Special caution is advised during the Meizitanc treatment. In case of any side effects like palpitation, headache and vertigo, nervousness or tremor which take place during the Meizitanc treatment the medical consultation is needed.

Drug related problems and off-label drug treatment in children as seen at a drug information centre.

The aim of this work was to analyse the characteristics of Questions and Answers (Q&As) at a drug information centre (DIC) regarding drug related problems and off-label drug treatment in children. All questions concerning children 15 years or younger at a DIC in Stockholm, Sweden during the years 1995-2004 were analysed with respect to the main drug related problem, drug/s and drug group/s, whether the drugs were licensed or not, pediatric labelling of the drug/s and age and sex of the patient. Q&As were classified as whether or not they included evaluated literature information, adding to the labelling of the drugs. We identified 249 Q&As concerning pediatric drug treatment. Each question addressed an average of 1.5 drugs. More than two-thirds of the Q&As concerned adverse drug reactions and pediatric drug choice or dosing. Every second question was classified as off-label, psychotropic drugs being the most common. In half of all off-label Q&As, pediatric documentation on drug efficacy and safety outside the Swedish catalogue of medical products was found. Most Q&As concerned newborns and infants. However, the off-label proportion among questions was highest in adolescence as well as the evaluated literature information, adding to the labelling of the drugs. It was thus found that off-label drug treatment is common among pediatric questions at a DIC. This service can provide additional literature based information contributing to a safer use of drugs in children. There is still, however, a substantial need for clinical documentation of drug use in children.

Evaluación de la calidad de la identificación de las muestras para investigación clínica tras la aplicación de la normativa europea / Quality identification evaluation on investigational drugs after European regulatory requirements application

Objetivo: Evaluar la calidad de la identificación de las muestras para investigación clínica tras la aplicación de la normativa vigente. Método: Estudio retrospectivo. Fuentes de recogida de datos: registros de los controles de recepción realizados por el Servicio de Farmacia. Resultados: Se evaluaron 339 controles de recepción correspondientes a 76 muestras diferentes de 52 ensayos clínicos. El 71,1% de las muestras (n=54) correspondieron a ensayos en los que el promotor fue un laboratorio farmacéutico, para un 23,7% (n=18) fue una sociedad científica y en un 5,2% (n=4) un grupo de investigadores. La identificación fue correcta para el 21,1% (n=16) de las muestras. El cumplimiento medio en función de la entidad promotora fue del 93,7% para los laboratorios farmacéuticos, 91,1% para las sociedades científicas y 88,5% para los grupos de investigadores. Conclusiones: 1. El grado de adecuación del etiquetado a la normativa vigente es bajo (21,1% de las muestras). 2. Cuando el promotor es un laboratorio farmacéutico se alcanza el mayor porcentaje de cumplimiento (93,7% de los ítem)

Aim: To evaluate the quality on identification of investigational drugs, by analysing their adaptation to the regulatory requirements. Method: Retrospective study. Data sources: registries of reception control made by Pharmacy Service. Results: 339 reception controls were evaluated corresponding 76 differents investigational drugs and 52 clinical trials. 71,1% (n=54) investigational drugs were belonging to clinical trials sponsored by pharmaceutical laboratory, 23,7% (n=18) by scientific society and 5,2% (n=4) by a group of investigators. Identification was corrected in 21,1% (n=16) of investigational drugs. The average fulfillment based on promotional organization was 93,7% for pharmaceutical laboratories, 91,1% for scientific societies and 88,5% for group of investigators. Conclusion: 1. Identification adjustment to the regulatory requirements was low (21,1% of investigational drugs). 2. When sponsor was a pharmaceutical laboratory the greater percentage of fulfillment (93,7% of item) was reached

Antidiarrheal drug products for over-the-counter human use; amendment of final monograph. Final rule.

The Food and Drug Administration (FDA) is issuing a final rule amending the final monograph (FM) for over-the-counter (OTC) antidiarrheal drug products to include relief of travelers' diarrhea as an indication for products containing bismuth subsalicylate. Travelers' diarrhea occurs in travelers and is most commonly caused by an infectious agent. This final rule is part of FDA's ongoing review of OTC drug products.

Unlicensed and off-label drug use in children: implications for safety.

Throughout the world, many drugs prescribed for children are used in an off-label or unlicensed manner. The incidence of unlicensed and off-label drug prescriptions appears to be greatest in critically ill neonates and children and lowest in the general population. The risk associated with unlicensed and off-label drug use appears to be greater than for prescribing in accordance with the product licence. Health professionals, however, usually have no alternative but to use unlicensed and off-label medicines. More clinical trials for medicines in children are required to provide the evidence base for safe and effective drug prescribing.