Zugl.: Mannheim, Univ., Diss., 2008

對於藥品之管理，主管機關往往僅著重於新藥的核准，對於藥品上市後之監督即第四階段往往付之闕如，因此許多藥商利用上市後對於藥品之反應，往往變相做為另外新適應症的適用研究，對於主管機關而言，藥品標示外使用原則上是已核准藥品之運用，因此，若非有重大不良反應之回報，否則基本上是漠視。 藥害救濟基金會在西元1999年至西元2015年2月第1～217次審議會之統計資料顯示，其中有1030件申請案，審議會審定結果是不予救濟，進一步分析其不予救濟之理由，名列第二名的原因為「未依藥品許可證所載之適應症或效能而為藥品之使用」，占整體不予救濟給付案件的23%，突顯現行的藥害救濟制度下藥害政策與實際臨床用藥的落差。 本文認為醫療行為之目的，乃在救治病人生命及恢復病人之健康，其過程本就充滿不確定性與高度危險性，醫療行為之歸責，應以可合理期待之安全性為考量。然根據衛生署(民國102年7月改制成衛生福利部)於民國91年之函釋說明藥品標示外使用原則為「應據實告知病人」與「不得違反藥品使用當時，已知的、具公信力的醫學文獻」等。因此，雖藥品標示外使用為醫師治療方式之選項之一，但法令上對於藥品標示外使用，卻未有明確之規範，因此產生許多醫學倫理與法律責任之爭議。 本文主題內容鎖定在藥品標示外使用與醫療過失之探討，且從刑法理論觀點，探討藥品標示外使用之法律性質，其在我國刑法規範體系中之定位，並加以闡釋注意義務，告知後同意，醫療過失，醫師說明義務等概念，並以實際發生的實際案例為例，進行說明。 其中，藥品標示外使用是否成為醫師應說明義務之內容?又其說明義務之基礎如何架構，說明內容又為何? 除此之外，文中將分析醫師注意義務與說明義務在藥品標示外使用時所應該達成的程度為何，結合國內的實務現狀與看法提供立法意見。 / After marketing approval, the labels of on drug packages should outline the indications for use, dosage, administrative directions, and safety information. The use of drug could expand over time. Off-label use, which means prescribing an approved drug for a use that is not claimed in the product information, is common in medical practice, especially for some serious or rare diseases. Since there is no regulation for off-label use , a number of clinical , legal and ethical issues arise. According to Taiwan Drug Relief Foundation for Drug Hazards’ statistics regarding the rejected reasons by foundation from 1030 application cases 1999 to 2015. The 2nd reason for unapproved cases is off-label use which is around 23% of total unapproved cases. This shows current criteria for drug relief is quite not fit in real world practice. Medicine is intended to save patients’ lives and to help patients reach renewed health. During the process of treatment, the risk versus benefit profile beyond the original product approval should first be taken into consideration. In Taiwan, the department of health provides an guidance regarding off-label use, ex: The necessity of informed consent before prescribing off-label products. Do physicians need to follow the duty of informed consent whiling prescribing a drug which is off-label use? There should be a guidance to follow in this regard. This study has established the principles and flow chart of off-label use. We suggest that some amendments to the laws are necessary, including setting up the scope of the duty of disclosure.

Zugl.: Göttingen, Univ., Diss., 2007

Masters of Science / Problem and significance: Off-label use of medicines is not illegal; however, it can be risky and harmful, or beneficial and innovative. The main problem of this practice is the lack of systems for monitoring adverse drug reactions, since the drugs are used in a manner that is not approved by regulatory agencies. For this reason public health protection is not guaranteed. Purpose: To identify the various systems employed in different regions to monitor/manage the risks and benefits of off-label use; and to ascertain their extent of implementation. Method/search strategy: Electronic and manual literature search was done. Articles referring to off-label medicine use were reviewed. The literature included journal articles, national MRA guidelines, international guidelines, etc. The articles were sourced from databases such as Pubmed and Google Scholar. Data was collected from both developed and emerging markets. There was no limit to publication date. Findings: Pharmacovigilance systems for off-label use do exist although the degree of commitment and advancement differs per country. Explicit off-label laws are present in the developed countries but not in the developing ones. Implications of findings: Stakeholder involvement is very important in monitoring off-label use. Reporting of ADRs can be improved by asserting the role of off-label PV in drug repositioning. The regulator is under pressure to maintain public trust through efficient control of off-label use.

Der Weg von der Entwicklung bis zur Zulassung neuer Virostatika ist bis heute mit hohen Kosten und einem großen Zeitaufwand verbunden. Sollten jedoch bereits zugelassene antivirale Medikamente eine Wirkung auf andere virale Infektionen zeigen, könnte dieser Prozess stark verkürzt werden. Daher war es Ziel dieser Arbeit, den Effekt von zugelassenen Medikamenten, gegen HSV-1, mCMV, hCMV, RSV, Parainfluenzavirus-3, DENV-2, CHIKV, Poliovirus, Masernvirus und HIV-1 zu evaluieren. Getestet wurden die Polymeraseinhibitoren ACV, GCV, CDV, sowie das neuere Medikament T-705 und die reversen Transkriptase-Inhibitoren TDF, 3TC, AZT und ABC. Außerdem die Proteaseinhibitoren SMV, GRV, DCV, LDV, ELB, VEL, SOF und DSV. TDF senkte in einer Konzentration von 10 µM die Infektiosität von HSV-1 und mCMV bis zu 1 Größenordnung. Auch ABC senkte die Infektiosität von HSV-1 und mCMV in einer Konzentration von 30 µM um 0,4 bzw. 0,6 Größenordnungen. AZT und ELB senkten die Infektiosität bei Infektionen mit HSV-1 in einer Konzentration von 30 µM um 0,4 Größenordnungen. VEL senkte die Infektiosität von mCMV bis zu einer Konzentration von 2 µM um 0,7 Größenordnungen. Durch die Substanzen ELB und LDV konnte die Replikation von DENV-2 bei einer Konzentration von 10 µM um 0,6 bzw. 0,8 Größenordnungen gesenkt werden. Die Substanzen zeigten jedoch keinen Effekt auf Infektionen mit CHIKV und Poliovirus, sodass für beide Substanzen ein virusspezifischer Effekt anzunehmen ist. Es wurde keine Wirkung der Substanzen gegen Infektionen mit Masernvirus, RSV oder Parainfluenzavirus-3 in den Versuchen beobachtet. Es wurde gezeigt, dass die verwendeten Methoden eine schnelle und effektive Möglichkeit darstellen, neue direkt-antivirale Medikamente zu etablieren. Zudem stellen die gefundenen Wirkstoffe eine gute Grundlage als Leitsubstanzen zur Entwicklung neuer Wirkstoffe dar. Weitere Versuche mit Kombinationen der wirksamen Substanzen sollten zur weiteren Therapiefindung durchgeführt werden. Damit hat die vorgelegte Arbeit eine hohe Relevanz für die weitere Forschung. / To this day, the process from development to approval of new antivirals is associated with high costs and a great deal of time. This process could be greatly shortened, if an effect of approved antiviral drugs on other viral infections could be shown. Therefore, the aim of this study was to evaluate the effect of approved drugs against infections with HSV-1, mCMV, hCMV, RSV, parainfluenza virus-3, DENV-2, CHIKV, poliovirus, measles virus and HIV-1. The polymerase inhibitors ACV, GCV, CDV, as well as the newer drug T-705 and the reverse transcriptase inhibitors TDF, 3TC, AZT and ABC were tested. In addition, the protease inhibitors SMV, GRV, DCV, LDV, ELB, VEL, SOF and DSV were included. TDF reduced the infectivity of HSV-1 and mCMV by up to 1 order of magnitude at a concentration of 10 μM. ABC also reduced the infectivity of HSV-1 and mCMV by 0.4 and 0.6 orders of magnitude, respectively, at a concentration of 30 μM. AZT and ELB reduced infectivity by 0.4 orders of magnitude in HSV-1 infections at a concentration of 30 μM. VEL reduced the infectivity of mCMV by 0.7 orders of magnitude up to a concentration of 2 μM. The substances ELB and LDV reduced the replication of DENV-2 by 0.6 and 0.8 orders of magnitude, respectively, at a concentration of 10 μM. However, the substances had no effect on CHIKV and poliovirus infections, and it was assumed that both substances had a virus-specific effect. No effect of the substances against infections with measles virus, RSV or parainfluenza virus-3 was observed in the trials. The methods used proved to be a fast and effective way to establish new direct antiviral drugs. In addition, the used drugs provide a good basis as lead substances for the development of new antiviral drugs. Further experiments with combinations of the active substances should be carried out in order to find further antiviral therapies. Thus, the submitted work has a high relevance for further research.

The American Medical Association (AMA) has estimated that as many as 40 percent of all prescriptions are issued for off-label use. Off-label prescribing is considered to be clinically beneficial and rational in certain life-threatening situations. However, off-label use can pose risks to patients in terms of adverse drug events as well as contribute to rising pharmaceutical costs. The anti-anemic drugs erythropoietin and darbepoetin are costly, and there are significant off-label uses for these drugs some of which are not supported with clinical evidence, hence were selected as study drugs. Our study goals included quantification of the prevalence rate and appropriateness of off-label use of erythropoietin and darbepoetin across U.S. hospitals, and identification of possible predictors of off-label use from the domains of patient characteristics, physician specialty, hospital characteristics and drug characteristics. To address the research questions we performed a retrospective review of 464,834 discharged patients across 515 hospitals who have received erythropoietin and darbepoetin from the time periods between 2001and 2004. The data was supplied by Solucient®. The uses of the two drugs have been categorized using an evidence-based medicine framework that classifies them into: a) on-label use (approved by the FDA), b) off-label use supported (use not approved by FDA but there is strong clinical evidence supporting off-label use), and c) off-label use unsupported (lack of clinical evidence). A multinomial logistic regression model clustered by hospitals was conducted to determine predictors of off-label use. The results of this study revealed that more than half of the utilization of the two erythropoietic drugs is for off-label purposes, the majority of which is supported with evidence. Among the covariates, physician specialty, patient age group, race, drug coverage and length of hospital stay were significant (0.05 level) predictors of off-label use (supported and unsupported) relative to on-label. It is useful to understand the extent and appropriateness of off-label utilization in order to ensure safe and cost-effective use in patients. The availability of empirically derived knowledge on the national level could precipitate the promulgation of more meaningful post-marketing surveillance measures.

Objective To describe off-label utilization of erythropoietic agents in ICU patients.Methods A retrospective, observational study design was used to describe off-label utilization of erythropoietin alfa and darbepoetin alfa by 91,357 patients in the ICU during January 2002- June 2004 at 433 U.S. hospitals. Results Approximately 62% of patients received erythropoietic agents off-label in the ICU compared to 49% in the non-ICU population. Off-label use in the ICU was more likely in teaching hospitals, in larger sized hospitals, in females, for certain physician specialties, and in different regions of the U.S., The longer the hospital stay, the less likely off-label prescribing occurred. ConclusionsOff-label use of erythropoietic agents was common in the ICU. Multiple factors affected off-label use in the ICU although no single one was dominant.

Introdução: O uso de formas farmacêuticas inadequadas à pediatria, também conhecido como uso off-label, pode levar a uma terapia medicamentosa insegura. No ambiente hospitalar, em especial nas Unidades de Terapia Intensiva Pediátrica, há alta prevalência de prescrições com medicamentos não apropriados para crianças, entre eles os antimicrobianos, devido à gravidade das infecções, o estado crítico dos pacientes internados, a maior realização de procedimentos invasivos e uma maior incidência de bactérias resistentes. Em geral, o uso de antimicrobianos em crianças, bem como dos demais grupos farmacológicos, tem sido baseado principalmente em extrapolações e adaptações do uso em adultos, informações obtidas de raros estudos observacionais e consensos de especialistas na área. Devido ao estado crítico dos pacientes, as complexas terapias envolvendo antimicrobianos nem sempre são feitas de forma adequada, podendo trazer prejuízos à saúde dos pacientes e contribuir, ainda, para a resistência bacteriana. Objetivo: Avaliar a incidência do uso de antimicrobianos em pacientes internados em Unidade de Terapia Intensiva Pediátrica. Método: Estudo do tipo transversal realizado na Unidade de Terapia Intensiva Pediátrica do município de Rio Branco, Acre, no período de agosto de 2014 a julho de 2015. A amostra foi composta por 246 crianças de zero a onze anos de idade, internadas com quaisquer patologias. Foram analisadas as prescrições das primeiras 24 horas. Pesquisou-se o uso off label de antimicrobianos e potenciais interações medicamentosas com esses medicamentos. Resultados: Duzentas e trinta e uma crianças (93,9 por cento ) receberam a prescrição de pelo menos um antimicrobiano. O antimicrobiano mais prescrito foi a ceftriaxona. Em média, cada paciente recebeu dois antimicrobianos. Em 66,8 por cento dos casos, houve uso off-label, sendo a dose prescrita superior ao recomendado em 41 por cento , dos casos. Em 56 por cento das prescrições havia pelo menos uma potencial interação medicamentosa envolvendo antimicrobianos. Ampicilina e gentamicina foram os antibióticos que mais se envolveram em interações. Conclusões: a alta frequência do uso off-label e interações medicamentosas potenciais envolvendo antimicrobianos foi confirmada neste estudo. Tratar crianças como adultos pequenos pode expor esses pacientes a eventos adversos a medicamentos que comprometem a segurança desse grupo específico de pacientes. Isso aponta para a necessidade de equipes multidisciplinares trabalharem em conjunto e serem estimuladas a realizar mais estudos que garantam a segurança do uso de medicamentos na pediatria. / Introduction: The use of inadequate dosage forms for pediatrics, also known as off-label use, may lead to unsafe drug therapy. In the hospital environment, especially in Pediatric Intensive Care Units, there is a high prevalence of prescriptions with drugs not suitable for children, among them antimicrobial agents, due to the severity of the infections, the critical state of the hospitalized patients, more accomplishment of invasive procedures and a higher incidence of resistant bacteria. In general, the use of antimicrobials in children, as well as other pharmacological groups, has been based mainly on extrapolations and adaptations of the use in adults. This information was obtained from rare observational studies and consensus of specialists in the area. Due to the critical condition of patients, the complex therapies involving antimicrobial agents are not always adequately done, which may cause harm to the patients\' health and also contribute to bacterial resistance. Objective: To evaluate the incidence of antimicrobial use in patients hospitalized in a Pediatric Intensive Care Unit. Method: A cross-sectional study conducted at the Pediatric Intensive Care Unit of the municipality of Rio Branco, Acre, from August 2014 to July 2015. The sample consisted of 246 children from zero to eleven years old and hospitalized with any pathologies. The prescriptions of the first 24 hours were analyzed. The use of off-label antimicrobials and potential drug interactions with these drugs was investigated. Results: Two hundred and thirty-one children (93.9 per cent ) received the prescription of at least one antimicrobial. The most commonly prescribed antimicrobial agent was ceftriaxone. On average, each patient received two antimicrobials. In 66.8 per cent of cases, there was an off-label use, with the prescribed dose being higher than recommended in 41 per cent of the cases. In 56 per cent of prescriptions there was at least one potential drug interaction involving antimicrobials. Ampicillin and gentamicin were the antibiotics most involved in interactions. Conclusions: the high frequency of off-label use and potential drug interactions involving antimicrobials was confirmed in this study. Treating children as young adults may expose these patients to adverse drug events that compromise the safety of this particular group of patients. That points to the need for multidisciplinary teams to work together and be encouraged to carry out more studies that ensure the safety of use of medication in pediatrics.

Introdução: O uso de formas farmacêuticas inadequadas à pediatria, também conhecido como uso off-label, pode levar a uma terapia medicamentosa insegura. No ambiente hospitalar, em especial nas Unidades de Terapia Intensiva Pediátrica, há alta prevalência de prescrições com medicamentos não apropriados para crianças, entre eles os antimicrobianos, devido à gravidade das infecções, o estado crítico dos pacientes internados, a maior realização de procedimentos invasivos e uma maior incidência de bactérias resistentes. Em geral, o uso de antimicrobianos em crianças, bem como dos demais grupos farmacológicos, tem sido baseado principalmente em extrapolações e adaptações do uso em adultos, informações obtidas de raros estudos observacionais e consensos de especialistas na área. Devido ao estado crítico dos pacientes, as complexas terapias envolvendo antimicrobianos nem sempre são feitas de forma adequada, podendo trazer prejuízos à saúde dos pacientes e contribuir, ainda, para a resistência bacteriana. Objetivo: Avaliar a incidência do uso de antimicrobianos em pacientes internados em Unidade de Terapia Intensiva Pediátrica. Método: Estudo do tipo transversal realizado na Unidade de Terapia Intensiva Pediátrica do município de Rio Branco, Acre, no período de agosto de 2014 a julho de 2015. A amostra foi composta por 246 crianças de zero a onze anos de idade, internadas com quaisquer patologias. Foram analisadas as prescrições das primeiras 24 horas. Pesquisou-se o uso off label de antimicrobianos e potenciais interações medicamentosas com esses medicamentos. Resultados: Duzentas e trinta e uma crianças (93,9 por cento ) receberam a prescrição de pelo menos um antimicrobiano. O antimicrobiano mais prescrito foi a ceftriaxona. Em média, cada paciente recebeu dois antimicrobianos. Em 66,8 por cento dos casos, houve uso off-label, sendo a dose prescrita superior ao recomendado em 41 por cento , dos casos. Em 56 por cento das prescrições havia pelo menos uma potencial interação medicamentosa envolvendo antimicrobianos. Ampicilina e gentamicina foram os antibióticos que mais se envolveram em interações. Conclusões: a alta frequência do uso off-label e interações medicamentosas potenciais envolvendo antimicrobianos foi confirmada neste estudo. Tratar crianças como adultos pequenos pode expor esses pacientes a eventos adversos a medicamentos que comprometem a segurança desse grupo específico de pacientes. Isso aponta para a necessidade de equipes multidisciplinares trabalharem em conjunto e serem estimuladas a realizar mais estudos que garantam a segurança do uso de medicamentos na pediatria. / Introduction: The use of inadequate dosage forms for pediatrics, also known as off-label use, may lead to unsafe drug therapy. In the hospital environment, especially in Pediatric Intensive Care Units, there is a high prevalence of prescriptions with drugs not suitable for children, among them antimicrobial agents, due to the severity of the infections, the critical state of the hospitalized patients, more accomplishment of invasive procedures and a higher incidence of resistant bacteria. In general, the use of antimicrobials in children, as well as other pharmacological groups, has been based mainly on extrapolations and adaptations of the use in adults. This information was obtained from rare observational studies and consensus of specialists in the area. Due to the critical condition of patients, the complex therapies involving antimicrobial agents are not always adequately done, which may cause harm to the patients\' health and also contribute to bacterial resistance. Objective: To evaluate the incidence of antimicrobial use in patients hospitalized in a Pediatric Intensive Care Unit. Method: A cross-sectional study conducted at the Pediatric Intensive Care Unit of the municipality of Rio Branco, Acre, from August 2014 to July 2015. The sample consisted of 246 children from zero to eleven years old and hospitalized with any pathologies. The prescriptions of the first 24 hours were analyzed. The use of off-label antimicrobials and potential drug interactions with these drugs was investigated. Results: Two hundred and thirty-one children (93.9 per cent ) received the prescription of at least one antimicrobial. The most commonly prescribed antimicrobial agent was ceftriaxone. On average, each patient received two antimicrobials. In 66.8 per cent of cases, there was an off-label use, with the prescribed dose being higher than recommended in 41 per cent of the cases. In 56 per cent of prescriptions there was at least one potential drug interaction involving antimicrobials. Ampicillin and gentamicin were the antibiotics most involved in interactions. Conclusions: the high frequency of off-label use and potential drug interactions involving antimicrobials was confirmed in this study. Treating children as young adults may expose these patients to adverse drug events that compromise the safety of this particular group of patients. That points to the need for multidisciplinary teams to work together and be encouraged to carry out more studies that ensure the safety of use of medication in pediatrics.

Universiẗat, Diss., 2007--Düsseldorf.