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No. of bitstreams: 1 HalineTerezaMatiasDeLimaCosta_DISSERT.pdf: 2192045 bytes, checksum: fd4867171ed1080dec47c90260404de7 (MD5) Previous issue date: 2017-06-30 / INTRODU??O: Diversos estudos t?m mostrado que um n?mero significativo de medicamentos prescritos a pacientes pedi?tricos s?o off-label ou n?o licenciados, mas existe pouca informa??o sobre o uso destes medicamentos em unidades de terapia intensiva neonatal (UTIN), assim como estudos sobre fatores de risco para potenciais intera??es medicamento-medicamento (IMM). OBJETIVO: Identificar a prescri??o de medicamentos off-label e n?o licenciados utilizados em rec?m-nascidos (RN) hospitalizados em UTIN, al?m de avaliar frequ?ncia de IMM e seus fatores de risco. METODOLOGIA: Coorte prospectiva, no qual foram inclu?dos neonatos admitidos consecutivamente na UTIN da Maternidade Escola Janu?rio Cicco com pelo menos um medicamento prescrito e tempo de interna??o superior a 24 horas. Dados cl?nicos e farmacoterap?uticos dos neonatos foram coletados durante toda a interna??o, sendo a classifica??o dos medicamentos em off-label e n?o licenciados realizada de acordo com crit?rios da Food and Drug Administration atrav?s da base DrugDex-Micromedex?, a qual tamb?m foi utilizada na classifica??o das IMM, cujos fatores de risco foram identificados por regress?o log?stica. RESULTADOS: Entre agosto de 2015 e agosto de 2016 foram analisados 17421 itens medicamentosos em 3935 prescri??es de 220 neonatos, dos quais 96,4% foram expostos a medicamentos off-label e 66,8% a n?o licenciados. Mais de 70% dos prematuros e RN com menos de 2000g foram submetidos ? farmacoterapia com medicamentos off-label e mais de 50% aos n?o licenciados. Os anti-infecciosos para uso sist?mico foram o grupo farmacol?gico mais prescrito de forma off-label,sendo o fentanil (n=1358) e a gentamicina (n= 1197) os medicamentos com maior preval?ncia de uso off-label para RN. A cafe?na (n=1226) foi o medicamento n?o licenciado mais prescrito, seguido pelos agentes cardiovasculares (n=648) modificados pela enfermagem. Em 42,3% (n= 1665) das prescri??es foram detectadas IMM, cujos fatores de risco para IMM importantes foram o n?mero de medicamentos (OR 1,60, p<0,001), parto ces?reo (OR 2,68, p=0,06) e idade gestacional (OR 1,03, p= 0,002). CONCLUS?ES: RN em terapia intensiva ? submetido ? alta taxa de prescri??o e exposi??o a medicamentos off-label e n?o licenciados, sendo os mais frequentes os anti-infecciosos de uso sist?mico e os medicamentos atuantes no sistema nervoso, e tamb?m uma elevada incid?ncia de IMM, consistindo o n?mero de medicamentos prescritos, parto ces?reo e a idade gestacional os principais fatores de risco para IMM. / INTRODUCTION: Several studies have shown that a significant number of drugs prescribed to pediatric patients are off-label or unlicensed, but there is little information about the use of these drugs in neonatal intensive care units (NICUs), as well as studies about risk factors for drug-drug interactions (DDI). PURPOSE: To evaluate the use of off-label and unlicensed drugs in a Brazilian NICU of a teaching maternity hospital specialized in high risk pregnancy, and the frequency of DDI and associated risk factors. METHODS: A prospective cohort study was conducted between august 2015 and august 2016. All newborns admitted consecutively in the NICU of the Maternity School Janu?rio Cicco for over 24 hours and who had at least one medication prescribed were included. Demographic and clinical data were collected, as well as all medications prescribed during hospitalization. The classification of off-label and unlicensed drugs for the neonatal population according to the Food and Drug Administration criteria was done based on the DrugDex-Micromedex? database, which was also used for the classification of DDI. Logistic regression was used for the analysis of risk factors. RESULTS: A total of 17421 prescriptions items were analyzed in 3935 prescriptions of 220 newborns, of whom 96.4% were exposed to off-label medications and 66.8% to unlicensed drugs. More than 70% of premature and neonates with birth weight less than 2000g were submitted to off-label medicines and more than 50% to unlicensed. The anti-infectives for systemic use were the most prescribed off-label pharmacological group and the drugs most frequently classified as off-label for newborn were Fentanil (n= 1358) and gentamicin (n= 1197). Caffeine (n = 1226) was the most prescribed unlicensed drug, followed by cardiovascular agents (n= 648) modified by nursing. DDIs were found in 42,3% (n= 1665) of prescriptions , with number of drugs (OR 1.60, p<0,001), cesarean delivery (OR 2.68, p = 0,06) and gestational age (OR 1.03, p = 0,002) as risk factors for major DDI. CONCLUSION: Neonates in intensive care units have a high rate of prescriptions and exposure to off-label and unlicensed drugs, with antimicrobials for systemic use and drugs action on nervous system as the most frequently prescribed, as well as a high incidence of DDI, with number of medicines, cesarean delivery and gestational age being risk factors for major DDI.

Aproximadamente apenas um terço dos medicamentos utilizados em crianças tem sido estudado de forma adequada e apresentam informações sobre eficácia e segurança do produto. Este fato se deve a dificuldade de realização de ensaios clínicos na população pediátrica tornando-a mais propensa a erros de medicação, predominantemente devido à necessidade de prescrições de apresentações farmacêuticas não aprovadas e não indicadas para uso pela indústria e agência de fiscalização sanitária. Dessa forma, uma ferramenta importante que pode ser utilizada para análise do uso de medicamentos nesta população compreende os estudos da utilização de medicamentos. O presente estudo analisou as prescrições medicamentosas realizadas para crianças hospitalizadas no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo, com a finalidade de estabelecer o perfil de utilização de medicamentos de acordo com os critérios de aprovação e indicação da Agencia Nacional de Vigilância Sanitária (ANVISA) e da Food and Drugs Administration (FDA). O estudo foi aprovado pelo Comitê de Ética em Pesquisa do respectivo hospital, e classificado como transversal, retrospectivo e observacional. Através do banco de dados informatizado, foram analisadas todas as prescrições medicamentosas a crianças menores de 12 anos no período compreendido entre 01/08/2008 a 31/07/2009. A população pediátrica foi dividida em subgrupos de acordo com os parâmetros fisiológicos do desenvolvimento estabelecidos pela Organização Mundial de Saúde. As apresentações farmacêuticas foram classificadas de acordo com o primeiro nível do sistema Anatomical Therapeutic Chemistry e, por conseguinte, foi realizada a classificação de uso das mesmas em: licenciado, não licenciado - registro, indicado, não indicado, não licenciado - dispersão e licenciado/indicado de acordo com a ANVISA e FDA. Durante o período analisado, foram identificados 6948 pacientes, 56,7% do sexo masculino, média de idade 3,1 (±3,5) anos, média de internação 17,5 (±29,8) dias, 1120 causas de internação e 79 unidades de atendimento. A causa de internação mais frequente esteve relacionada ao nascimento no hospital, sendo dessa forma, o centro obstétrico a unidade mais requisitada para hospitalização. Das 617 apresentações farmacêuticas identificadas, 17,6% foram referentes aos agentes infecciosos de uso sistêmico. A média de apresentações farmacêuticas por paciente foi de 6,1. Em relação ao uso não licenciado - registro 1,1% e 14,9% das apresentações farmacêuticas assim foram classificadas de acordo com a análise da ANVISA e FDA, respectivamente. O uso não indicado esteve presente em 36,5% e 37,3% de acordo com a ANVISA e FDA, respectivamente. Dessa forma, este trabalho ressalta a necessidade em se estabelecer um consenso sobre a classificação de uso dos medicamentos na população pediátrica entre os países, além de enfatizar a necessidade de aumentar a realização ensaios clínicos nesta população, uma vez que houve um elevado número de apresentações farmacêuticas com informações de uso apenas na população adulta sendo utilizadas em crianças / Approximately only one-third of the drugs used in children has been studied adequately and presents information about its effectiveness and safety. This fact is due to the difficulty of conducting clinical trials in the pediatric population making them more prone to medication errors, mainly due to the need for pharmaceutical dosage forms unapproved and off-label for use by industry and regulatory agency. Thus, an important tool that can be used to analyze the use of drugs in this population comprises studies of drug utilization. This study analyzed drug prescriptions for children hospitalized at the Clinical Hospital of the Faculty of Medicine of Ribeirão Preto - University of São Paulo, in order to establish the profile of drug utilization in accordance to the criteria for approval and indication of the Brazilian Regulatory Agency (ANVISA) and the Food and Drugs Administration (FDA). The study was approved by the Research Ethics Committee of the respective hospital, being classified as cross-sectional, retrospective, observational study. Through the computerized database, all drug prescriptions to children under the age of 12 were analyzed in the period of August 1st, 2008 to July 31st, 2009. The pediatric population was divided into subgroups according to the physiological parameters of development established by the World Health Organization. The pharmaceutical dosage forms were classified according to the first level of the Anatomical Therapeutic Chemistry system. Thereafter, the use of pharmaceutical dosage forms was classified as follows: licensed, unlicensed - registered, label, off-label, unlicensed - dispersion and licensed/label according to FDA and ANVISA. During the study period, 6948 patients were identified, being 56.7% male, mean age 3.1 (± 3.5) years, mean length of hospitalization 17.5 (± 29.8) days, 1120 causes of hospitalization and 79 service units. The most prevalent cause of hospital stays was related to birth at the hospital, being the obstetric center the most required unit for hospitalization. Of the 617 pharmaceutical dosage forms identified, 17.6% were related to infectious agents for systemic use. The average pharmaceutical dosage forms per patient were 6.1. Regarding the unlicensed use, 1.1% and 14.9% of the pharmaceutical dosage forms were classified according to the analysis from ANVISA and FDA, respectively. The off-label use was present in 36.5% and 37.3% according to ANVISA and FDA, respectively. This work emphasizes the need to establish a consensus on the classification of the use of drugs in the pediatric population among countries, and underline the necessity of increase the number of clinical trials performed in this population, since there were a high number of pharmaceutical dosage forms with use information only for adult populations being used in children.

Background: FDA black box warning, Risk Evaluation and Mitigation Strategies (REMS), and CMS national coverage determination (NCD) aim to reduce inappropriate use of erythropoiesis-stimulating agents (ESAs) that are widely used in anemic patients. Previous studies have not linked specific safety interventions to changes in ESA utilization patterns in the inpatient settings nor assessed such interventions on off-label use of the drugs. Ineffectiveness of the intervention and lag time between such interventions and the observed change in clinical practice could lead to serious clinical outcomes. In addition, such interventions may unintentionally reduce on-label and some off-label use of ESAs considered “appropriate” in patients who could otherwise benefit. Objectives: The primary aim of the study is to quantify the impacts of the (1) addition of black box warning, (2) implementation of NCD, and (3) institution of REMS on ESA on-label and off-label utilization patterns of adult inpatients. Demographic, clinical condition, physician, and hospital characteristics of ESAs users by their use category are also described in detail. Methods: Electronic health records in Cerner Database from January 1, 2005 to June 30, 2011 were used. The use of the two erythropoietic drugs: epoetin alfa and darbepoetin alfa were categorized into three groups using ICD-9-CM diagnoses and procedures codes and patients’ medication information. The three categories were (1) on-label use (approved by the FDA); (2) off-label use supported (use for the indications not approved by the FDA, but there is strong clinical evidence to support its use); and (3) off-label use unsupported (use for the indications not approved by the FDA and lacking clinical evidence). The immediate and trend impacts of the interventions on the proportion of ESAs prescribed for each usage category between 2005 and 2011 were assessed using an interrupted time series technique. The likelihood of receiving ESAs among patients with on-label, off-label supported, off-label unsupported indications was assessed using a generalized estimating equation approach with binary logistic regression technique, clustering for hospitals and controlling for potential confounders such as patient characteristics, patient clinical conditions, physician specialty, and hospital characteristics. Results: During the study period, there were 111,363 encounters of ESA use. These encounters represented 86,763 patients admitted to Cerner health system between January 1, 2005 and June 30, 2011. Of these patients, 66,121 were prescribed epoetin alfa only (76.2%); 20,088 darbepoetin alfa only (23.2%); and 554 were prescribed both epoetin alfa and darbepoetin alfa (0.6%). Forty-nine percent of the patients used ESAs for the on-label indications, 8.6% for off-label supported indications, and 42.7% for the off-label unsupported indications. The main uses of ESAs in our sample were for CKD (ONS, 41.1%) and chronic anemia (OFU, 31.8%). From 2005 to 2010, the proportion of visits with ESA ONS and OFS use decreased 53.2% and 81.9%, while ESA OFU increased 112.6%. Results from binary logistic regression using GEE model showed overall decreasing trends in ESA use for the on-label and off-label supported indications, but not off-label unsupported indications. REMS had no impact on the odds of receiving ESAs among patients with on-label and off-label conditions. Black box warning reduced the odds of being prescribed with epoetin alfa in patients with off-label unsupported conditions by 40%. It was also associated with 4% and 15% per month reduction in the odds of using darbepoetin alfa in patients with off-label supported and unsupported conditions. Lastly, there was a significant decline in all categories of ESA use the month after Medicare national coverage determination was implemented. The impact of NCD ranged from a 20% reduction in the odds of off-label supported use to a 37% reduction in on-label use. Age, gender, race, source of payment, admission type, clinical complexity, discharge disposition, and hospital size were significant associated with ESA use on-label and off-label. Conclusion: This study was the first to determine the impact of safety interventions on ESA on-label and off-label utilization patterns in the inpatient settings using the Cerner database. We demonstrated lag between the interventions and observed change in clinical practice, and the relative impacts of three types of safety interventions on on-label and off-label ESA use in the hospital settings. The indirect impact of the reimbursement change was the potential unintended consequence of reducing the likelihood of receiving ESAs for a patient with indicated conditions who could have otherwise benefited from the drugs.

“Off-label use” is defined as the use of medicine for indications other than recommended or registered for, e.g. the prescribing of a particular active substance for a patient younger than the substance is recommended or indicated for, or different formulations or dosages of a substance (Ekins-Daukes et al., 2004:349; Stedman’s medical dictionary, 2006). Off-label prescribing is common, and fluctuates by physician, patient and drug (Eguale et al., 2012:781). Drug classes most commonly prescribed off-label include anti-asthmatic, cardiovascular drugs and antidepressants. Lee et al. (2012:140) found that 9 out of 10 antidepressants prescribed were associated with unapproved usage of antidepressants. An antidepressant can be defined as a substance that prevents or relieves depression or depressive episodes (Mosby, 2009:115). There is paucity of information on the off-label prescribing practices of antidepressants in the South African private health sector. According to Eguale et al. (2012:781), the paucity of information on off-label prescribing practices may be, in part, ascribed to the difficulty in the establishment of reasons for treatment. The objective of this study was to determine the prescribing patterns of antidepressants as well as to identify off-label prescribing of antidepressants among adults in a section of the private health sector of South Africa by using a medicine claims database. A quantitative and observational, descriptive cross-sectional design was followed in this study. Data for a period of a year, from January to December 2010 were obtained for analysis. The data set consisted of medicine claims for a total number of 1 220 289 patients, containing a total of 8 515 428 prescriptions and 20 527 777 medicine items. The study population (patients receiving antidepressants 18 years and older) accounted for 14.8% (n = 1 220 289) of the total data set. The average age of patients receiving antidepressants was 56.1 ± 16.6 (median = 56.2) (Inter quartile range = 43.3–68.1). Results of the study showed that antidepressant prescriptions accounted for 8.3% (n = 8 515 428) of all prescriptions claimed during 2010. A total 3.5 % (n = 20 527 777) of antidepressants were claimed during the study period. Using the DU90% method it was established that the majority of antidepressant medicine items were prescribed by general practitioners (i.e. 75.7%, n = 702 285) and psychiatrists (14.9%, n = 702 285). Almost 72% (n = 702 885) of antidepressant medicine items claimed for the study population were for women. The most prescribed antidepressants (based on the DU90%) were amitriptyline (20.6%, n = 702 885), citalopram (19.2%), escitalopram (14.6%), fluoxetine (11.7%), venlafaxine (5.7%), paroxetine (5.2%), duloxetine (4.4%), sertraline (3.8%), bupropion (3.1%) and mirtazapine (2.6%). Amitriptyline accounted for 82.4% of off-label prescriptions (n = 2 635), whereas escitalopram and fluoxetine accounted for 4.2% and 3.8%, respectively. The tricyclic antidepressants (TCAs) were mostly prescribed off-label for migraine, headache and sleep disorders. The off-label prescribing of selective serotonin re-uptake inhibitors (SSRIs) included menopause, schizophrenia and headache. The off-label indicated prescriptions of the serotonin and noradrenaline re-uptake inhibitors (SNRIs) were mostly for schizophrenia and other anxiety disorders. Mirtazapine, a serotonin modulator/tetracyclic antidepressant, was mostly prescribed off-label for anxiety disorders. Off-label prescriptions for bupropion, a noradrenaline and dopamine re-uptake inhibitor mainly included other anxiety disorders and attention deficit hyperactivity disorder (ADHD). Furthermore, the prescribed daily dose (PDD) of each active antidepressant for all off-label indications was determined. In conclusion: This study investigated the off-label prescribing patterns of antidepressants among adults a section of the private health sector of a South Africa, using a large medicine claims database. Recommendations for future research were made. / MPham (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

La prescription de médicament hors AMM est légitime quand elle s’appuie sur les connaissances médicales acquises ou validées au moment de la proposition de soins, lors du colloque singulier patient-médecin. L’AMM d’un médicament ne représente qu’un sous-ensemble de connaissances médicales, sans cesse changeantes, qui ne peut être regardée comme le référentiel idoine de la prescription d’un médicament, à la fois sur un plan médical et sur un plan juridique. La démocratie sanitaire est particulièrement inachevée dans la gestion européenne ou nationale de l’AMM d’un médicament. / The off-label drug prescribing is legitimate when it is based on accepted or validated medical knowledge at the time of the proposal care during the patient-physician singular interview. The marketing authorization of a drug represents only a fraction of medical knowledge, constantly changing, which can not be considered as a suitable reference document of drug prescribing, both from a medical and legal aspect. Health democracy is particularly incomplete in the European or national management of the drug marketing authorization.

“Off-label use” is defined as the use of medicine for indications other than recommended or registered for, e.g. the prescribing of a particular active substance for a patient younger than the substance is recommended or indicated for, or different formulations or dosages of a substance (Ekins-Daukes et al., 2004:349; Stedman’s medical dictionary, 2006). Off-label prescribing is common, and fluctuates by physician, patient and drug (Eguale et al., 2012:781). Drug classes most commonly prescribed off-label include anti-asthmatic, cardiovascular drugs and antidepressants. Lee et al. (2012:140) found that 9 out of 10 antidepressants prescribed were associated with unapproved usage of antidepressants. An antidepressant can be defined as a substance that prevents or relieves depression or depressive episodes (Mosby, 2009:115). There is paucity of information on the off-label prescribing practices of antidepressants in the South African private health sector. According to Eguale et al. (2012:781), the paucity of information on off-label prescribing practices may be, in part, ascribed to the difficulty in the establishment of reasons for treatment. The objective of this study was to determine the prescribing patterns of antidepressants as well as to identify off-label prescribing of antidepressants among adults in a section of the private health sector of South Africa by using a medicine claims database. A quantitative and observational, descriptive cross-sectional design was followed in this study. Data for a period of a year, from January to December 2010 were obtained for analysis. The data set consisted of medicine claims for a total number of 1 220 289 patients, containing a total of 8 515 428 prescriptions and 20 527 777 medicine items. The study population (patients receiving antidepressants 18 years and older) accounted for 14.8% (n = 1 220 289) of the total data set. The average age of patients receiving antidepressants was 56.1 ± 16.6 (median = 56.2) (Inter quartile range = 43.3–68.1). Results of the study showed that antidepressant prescriptions accounted for 8.3% (n = 8 515 428) of all prescriptions claimed during 2010. A total 3.5 % (n = 20 527 777) of antidepressants were claimed during the study period. Using the DU90% method it was established that the majority of antidepressant medicine items were prescribed by general practitioners (i.e. 75.7%, n = 702 285) and psychiatrists (14.9%, n = 702 285). Almost 72% (n = 702 885) of antidepressant medicine items claimed for the study population were for women. The most prescribed antidepressants (based on the DU90%) were amitriptyline (20.6%, n = 702 885), citalopram (19.2%), escitalopram (14.6%), fluoxetine (11.7%), venlafaxine (5.7%), paroxetine (5.2%), duloxetine (4.4%), sertraline (3.8%), bupropion (3.1%) and mirtazapine (2.6%). Amitriptyline accounted for 82.4% of off-label prescriptions (n = 2 635), whereas escitalopram and fluoxetine accounted for 4.2% and 3.8%, respectively. The tricyclic antidepressants (TCAs) were mostly prescribed off-label for migraine, headache and sleep disorders. The off-label prescribing of selective serotonin re-uptake inhibitors (SSRIs) included menopause, schizophrenia and headache. The off-label indicated prescriptions of the serotonin and noradrenaline re-uptake inhibitors (SNRIs) were mostly for schizophrenia and other anxiety disorders. Mirtazapine, a serotonin modulator/tetracyclic antidepressant, was mostly prescribed off-label for anxiety disorders. Off-label prescriptions for bupropion, a noradrenaline and dopamine re-uptake inhibitor mainly included other anxiety disorders and attention deficit hyperactivity disorder (ADHD). Furthermore, the prescribed daily dose (PDD) of each active antidepressant for all off-label indications was determined. In conclusion: This study investigated the off-label prescribing patterns of antidepressants among adults a section of the private health sector of a South Africa, using a large medicine claims database. Recommendations for future research were made. / MPham (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014