Agreement about Availability of Alternative Treatments for Innovative Drugs Assessed by the EMA and HTA Organizations.

The European Medicines Agency (EMA) and European national/regional health technology assessment (HTA) organizations consider the availability of existing treatments when evaluating a new drug. Since disagreement about the availability of alternative treatments may impact patient access to new drugs, this study aimed to investigate whether the EMA and HTA organizations agreed on the availability of alternative treatments and whether a lack of alternative treatments was associated with HTA organizations' added benefit assessment outcomes. For 97 innovative drugs authorized in 2019-2021 (excluding vaccines and diagnostic tools), assessments by the EMA and AEMPS (Spain), AIFA (Italy), HAS (France), IQWiG/G-BA (Germany), NICE (England and Wales), and ZIN (the Netherlands) were identified. Until 1 June 2022, 429 HTA drug-indication combinations were identified for these 97 drugs, of which 205 exactly matched the EMA's indication. For those, the overall agreement between the EMA and HTA organizations on whether alternative treatments were available was 87%. The agreement of HTA organizations with the EMA on whether available treatments were either pharmacological on-label, pharmacological off-label, or non-pharmacological was 87%, 21%, and 57%, respectively. For all 429 HTA drug-indication combinations, absence of alternative treatments as considered by HTA organizations was associated with a higher chance to provide added benefit: risk ratio 1.8 (95%-CI 1.4-2.3). In conclusion, although there was high overall agreement between the EMA and HTA organizations about whether alternative treatments exist, there were differences in the types of treatment considered. Parallel joint scientific consultations could inform drug developers about relevant alternative treatments to facilitate patient access to innovative drugs.

Off-label drug use in an adult intensive care unit of a Brazilian hospital

Abstract The objective of this study was to determine the prevalence and describe the factors associated with off-label drug use in an adult intensive care unit (ICU) of a Brazilian hospital. An analytical, cross-sectional, prospective study was conducted in the adult ICU population from March 2018 to May 2018. Off-label use of medication was classified by indication, dosage, route of administration, type and volume of diluent, and duration of administration. Most patients were female (57.89%), non-elderly (56.14%), and had a mean age of 54.44 ± 17.15 years. The prevalence of off-label drug use was 70.31%, but was not associated with the clinical severity of the patients. A statistically significant association was observed between label use of drugs and prescribing potentially inappropriate medicines (PIM). The most common reasons for off-label drug use were therapeutic indication (19.58%) and volume of diluent (23.30%). Drug administration by enteral tubes accounted for the largest number of off-label uses due to route of administration (90.85%). There was a higher prevalence of off-label use of systemic antimicrobials (14.44%) and norepinephrine (9.28%). Our study provided a broad characterization of off-label drug use in an adult ICU and showed why it is important for health professionals to evaluate the specific risks and benefits of this practice

Pharmacoepidemiology of testosterone: Impact of reimbursement policy on curbing off-label prescribing.

OBJECTIVES: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria. DESIGN: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria. MAIN OUTCOME MEASURES: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication and prescriber type. Total national testosterone prescriptions (private plus PBS) was verified from an independent data supplier (IQVIA). RESULTS: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and prescription for adult hypogonadism or pediatric/prepubertal indications were largely unaffected. CONCLUSIONS: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.

The French Cochlear Implant Registry (EPIIC): Cochlear implant candidacy assessment of off-label indications.

OBJECTIVE: Evaluate in France the outcomes of cochlear implantation outside the selection criteria, off-label. MATERIAL AND METHODS: This is a prospective cohort study including adults and children having received a cochlear implant (CI) in an off-label indication, that is outside the criteria established by the "Haute Autorité de santé (HAS)" in 2012. The data was collected from the "EPIIC" registry on recipients who received CIs in France between 2011 and 2014. Speech audiometry was performed at 60dB preimplantation and after one year of CI use, as well as an evaluation of the scores of the quality of life with the APHAB questionnaire, the scores for CAP and the professional/academic status in pre- and post-implantation conditions. Major and minor complications at surgery have been recorded. RESULTS: In total, 590 patients (447 adults and 143 children) with an off-label indication for CIs were included in this study from the EPIIC registry (11.7% of the whole cohort of EPIIC). For adults, the median percentage of comprehension using monosyllabic word lists was 41% in preimplantation condition versus 53% after one year of CI use (P<0.001) and 60% versus 71% in dissyllabic word lists (P<0.001). The CAP scores were 5 versus 6 in pre- and post-implantation conditions respectively (P<0.001) and the APHAB scores were statistically lower after implantation (P<0.001). In the children cohort, the median percentage of comprehension using monosyllabic word lists was 51% in preimplantation condition and 65% after CI (P<0.001), and 48% versus 82% (P<0.001) for dissyllabic word lists. The CAP scores were 5 versus 7 respectively in pre- and post-CI conditions (P<0.001). Thirty-two minor complications (5.4%) and 17 major complications (2.8%) were reported in our panel of off-label indication patients. CONCLUSION: These results suggest that a revision of the cochlear implantation candidacy criteria is necessary to allow more patients with severe or asymmetric hearing loss to benefit from a CI when there is an impact on quality of life despite the use of an optimal hearing aid.

Impact of a health alert and its implementation on flutamide prescriptions for women: an interrupted time series analysis.

BACKGROUND: Off-label drug use among ambulatory patients is often based on little or no scientific support. This paper reports the impact of a health warning about the risks of off-label flutamide use by women and the actions subsequently implemented by the public health service targeting such use. METHOD: The study was undertaken in a region in north-west Spain. We designed a segmented regression model of an interrupted time series, in which the dependent variable was the monthly value of defined daily doses of flutamide per 1000 inhabitants/day (DDD/TID), both total and stratified by sex. The following two data sources were used: flutamide prescriptions billed to the Spanish National Health Service; and flutamide deliveries made by wholesale drug distributors to pharmacies. The intervention assessed consisted of the issue of an official health warning and the actions subsequently taken to implement it. RESULTS: There was an immediate reduction of 49.33% in DDD/TID billed to the Spanish National Health Service in respect of women; the mean value of the population percentage of DDD/TID of flutamide billed in respect of women fell from 34.4% pre-intervention to 23.72% post-intervention. There was an immediate reduction of 19.92% (95%CI: 6.68-33.15%) in total DDD/TID invoiced. There were no significant changes in DDD/TID billed in respect of men or in flutamide use in the private medical sector. CONCLUSIONS: Off-label drug misuse is a reality among ambulatory patients, even after actions are implemented following a toxicity warning issued by the competent Health Authority.

Off-label use of drugs by age in Brazilian children: a population study. / Uso off-label de medicamentos segundo a idade em crianças brasileiras: um estudo populacional.

OBJECTIVE: To estimate the prevalence of off-label drug use by age in children 12 years old and younger in Brazil. METHOD: Population-based cross-sectional study (National Survey on Access, Use and Promotion of Rational Use of Medicines - PNAUM), including 7,528 children aged 12 years or younger. Face-to-face interviews were used to collect the data in the domiciles. The age-related off-label classification was carried out using the electronic medication compendium of National Agency of Sanitary Surveillance (ANVISA). Sociodemographic characteristics, presence of chronic disease, use of health services and characteristics of the informant were collected. Data were expressed by relative frequencies and 95% confidence intervals. Pearson's chi-square test was used to evaluate the statistical significance of the differences between the groups, with a significance level of 5%. Main outcome measure was the prevalence of off-label use. RESULTS: The prevalence of off-label use by age was 18.7% (95%CI 16.4 - 21.3). Children younger than 2 years old presented the highest prevalence of off-label use. The most frequently used off-label drugs by age were amoxicillin, nimesulide and the combination of phenylephrine and brompheniramine. CONCLUSION: The off-label use of drugs by age is common in the Brazilian pediatric population, especially among children under two years old.

The use of off-label medications in substance abuse treatment programs.

Background: Substance use disorder (SUD) treatment centers serve a population of clients who have diverse needs, and may desire or require access to varied treatments while seeking care for their SUDs. While pharmacotherapies have increased in popularity for the treatment of SUDs, adoption rates do remain quite low. But a wider array of pharmacotherapies has become available in recent years which may shift the trend. This article helps shed light on how variations in SUD treatment centers develop and persist with regard to the adoption and delivery of off-label medications. Methods: We use a nationally representative and longitudinal sample of SUD treatment centers in the US (N = 196). We use a logistic regression to analyze the relationship between organizational characteristics and offering any medications, off-label. We also use a negative binomial regression to analyze the relationship between organizational characteristics and the number of medications that were used off-label. Results: Our findings reveal that older centers, accredited centers, and centers that offer mental health screenings are all positively associated with the provision of off-label medication in SUD treatment. We also find a positive relationship between private funding and offering a greater number of off-label medications. Conclusions: Our results suggest that SUD clients who seek treatment from centers that offer medications off-label, may have access to a greater number of medication-assisted treatment options.

Prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among university students / Prevalência e fatores associados ao uso de metilfenidato para neuroaprimoramento farmacológico entre estudantes universitários

ABSTRACT Objective To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. Methods Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. Results Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. Conclusion The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.

RESUMO Objetivo Estimar a prevalência e os fatores associados ao uso de metilfenidato para neuroaprimoramento entre estudantes universitários. Métodos Amostra aleatória simples de discentes da Universidade Federal de Minas Gerais (n=438), convidados a responder um questionário online sobre o consumo de metilfenidato. A coleta ocorreu de setembro de 2014 a janeiro de 2015. A amostra foi descrita em termos de proporções, médias e desvio padrão. A análise multivariada foi realizada utilizando o algoritmo Classification and Regression Tree para classificação dos casos de uso do metilfenidato para neuroaprimoramento em grupos, com base nas variáveis de exposição. Resultados Dos 378 alunos incluídos, 5,8% (n=22) declararam ter feito uso de metilfenidato para neuroaprimoramento, sendo 41% (9/22) nas 4 semanas anteriores à pesquisa. A situação da moradia foi a variável mais associada ao uso de metilfenidato para neuroaprimoramento. Relataram o uso do metilfenidato para neuroaprimoramento e outros fins nas 4 semanas anteriores à pesquisa 11 estudantes, sendo que 27% não apresentaram prescrição médica para adquiri-lo. Conclusão O uso de metilfenidato para neuroaprimoramento ocorre no meio acadêmico brasileiro e deve ser considerado sério problema de saúde pública, principalmente diante dos riscos de danos e efeitos adversos associados ao seu uso.

Uso off-label de medicamentos segundo a idade em crianças brasileiras: um estudo populacional / Off-label use of drugs by age in Brazilian children: a population study

RESUMO: Objetivo: Estimar a prevalência de uso off-label de medicamentos segundo a idade em crianças de 0 a 12 anos no Brasil. Métodos: Estudo transversal de base populacional (Pesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos - PNAUM), incluindo 7.528 crianças de 0 a 12 anos de idade. Entrevistas individuais face a face foram utilizadas para coletar os dados nos domicílios. A classificação off-label segundo a idade foi realizada por meio de consulta ao compêndio eletrônico da Agência Nacional de Vigilância Sanitária (ANVISA). Características sociodemográficas, presença de doença crônica, uso de serviços de saúde e características do informante foram coletadas. Os dados foram expressos por frequências relativas e intervalos de confiança de 95% (IC95%). O teste do χ2 de Pearson foi usado para avaliar a significância estatística das diferenças entre os grupos, com um nível de significância de 5%. A principal medida de desfecho foi a prevalência de uso off-label segundo a idade. Resultados: A prevalência de uso off label por idade foi de 18,7% (IC95% 16,4 - 21,3). Crianças com menos de 2 anos apresentaram maior prevalência desse uso em relação às mais velhas. Os medicamentos com maior frequência de uso off-label segundo a idade foram amoxicilina, nimesulida e a combinação de fenilefrina com bronfeniramina. Conclusão: O uso off-label de medicamentos segundo a idade é comum na população pediátrica brasileira, especialmente nas crianças menores de 2 anos de idade.

Abstract: Objective: To estimate the prevalence of off-label drug use by age in children 12 years old and younger in Brazil. Method: Population-based cross-sectional study (National Survey on Access, Use and Promotion of Rational Use of Medicines - PNAUM), including 7,528 children aged 12 years or younger. Face-to-face interviews were used to collect the data in the domiciles. The age-related off-label classification was carried out using the electronic medication compendium of National Agency of Sanitary Surveillance (ANVISA). Sociodemographic characteristics, presence of chronic disease, use of health services and characteristics of the informant were collected. Data were expressed by relative frequencies and 95% confidence intervals. Pearson's chi-square test was used to evaluate the statistical significance of the differences between the groups, with a significance level of 5%. Main outcome measure was the prevalence of off-label use. Results: The prevalence of off-label use by age was 18.7% (95%CI 16.4 - 21.3). Children younger than 2 years old presented the highest prevalence of off-label use. The most frequently used off-label drugs by age were amoxicillin, nimesulide and the combination of phenylephrine and brompheniramine. Conclusion: The off-label use of drugs by age is common in the Brazilian pediatric population, especially among children under two years old.

Prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among university students.

OBJECTIVE: To estimate the prevalence of and factors associated with the use of methylphenidate for cognitive enhancement among undergraduate students. METHODS: Simple random sample of students of the Universidade Federal de Minas Gerais (n=438), invited to answer an online questionnaire about the use of methylphenidate. Data collection occurred from September 2014 to January 2015. The sample was described by means of proportions, means and standard deviations. A multivariate analysis was performed using the Classification and Regression Tree algorithm to classify the cases of use of methylphenidate for cognitive enhancement in groups, based on the exposure variables. RESULTS: Out of 378 students included, 5.8% (n=22) reported using methylphenidate for cognitive enhancement; in that, 41% (9/22) in the 4 weeks prior to the survey. The housing situation was the variable most often associated with the use of methylphenidate for cognitive enhancement. Eleven students reported using methylphenidate for cognitive enhancement and other purposes 4 weeks prior to the survey, 27% of whom had no medical prescription to purchase it. CONCLUSION: The use of methylphenidate for cognitive enhancement is frequent among Brazilian undergraduate students and should be considered a serious public health problem, especially due to risks of harm and adverse effects associated with its use.

Identification of potential drug name confusion errors in the Sentinel System.

PURPOSE: In July 2015, the US Food and Drug Administration (FDA) published a drug safety communication regarding errors in prescribing and dispensing of the antidepressant Brintellix (vortioxetine) and the antiplatelet Brilinta (ticagrelor) that arose due to proprietary drug name confusion. Brintellix is indicated for major depressive disorder; Brilinta is indicated to reduce cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or history of myocardial infarction. Brintellix was renamed to Trintellix in May 2016. Using Brilinta and Brintellix as a proof-of-concept feasibility use case, we assessed whether drug name confusion errors between the pair could be identified in electronic health care data via the combination of a claims-based algorithm and limited manual claims data review. METHODS: Using data from the Sentinel System, we defined potential errors as Brintellix users without an on- or off-label indication for Brintellix, without a dispensing for a drug with the same indications as Brintellix, and with an on- or off-label indication for Brilinta between -365 and +30 days after index Brintellix dispensing; the reverse was done for Brilinta. We manually reviewed claims profiles of potential cases. RESULTS: We identified 27 (0.1%) potential errors among 21 208 Brintellix users; 16 appeared to be likely errors based on claims profile review. Fifty-one (0.3%) of the 16 779 Brilinta users were identified as potential errors, and four appeared to be likely errors. CONCLUSIONS: A claims-based algorithm combined with manual review of claims profiles could identify potential drug name confusion errors, and narrow down likely errors that warrant further investigation.

Use of non-formulary high-cost medicines in an Australian public hospital.

Background Clinicians prescribe high-cost medicines for rare diseases and nonapproved indications when conventional therapies have failed. Objective To examine the use of non-formulary high-cost medicines at an Australian public hospital. Methods Retrospective audit of individual patient use applications for nonformulary medicines costing more than $5000 AUD per year at a large tertiary referral hospital in Adelaide, South Australia over a 12-month study period from January 2015 to December 2015. Main outcome measures Total cost of non-formulary high-cost medicines, medication class, indications for use, level of supporting evidence and proposed monitoring outcomes. Results Eighty-seven individual patient use applications were examined. All except one were approved, at a total cost of $1,339,203 AUD. The most common drug classes were anti-CD20 (n = 33, 38%), combined antiretrovirals (n = 10, 11%) and TNF-alpha antagonists (n = 10, 11%). There were 56 indications for these medicines with the majority being inflammatory conditions (n = 52, 60%), followed by infections (n = 14, 16%) and malignancies (n = 14, 16%). Of the first-time individual patient use applications (n = 63), there were 25 applications (40%) that provided a case series as supporting evidence. Approximately half of new individual patient use applications (n = 32) proposed an objective monitoring outcome, but few (n = 13, 21%) contained sufficient information to allow a third party to determine efficacy of the medication. Conclusions Non-formulary high-cost medicines are being used for a broad range of indications based largely on low levels of evidence. Prospective definition of an adequate response to treatment and reporting of these outcomes is required to improve the evidence-base and to aid decision-making for subsequent treatment courses.

Assessment of the FDA Risk Evaluation and Mitigation Strategy for Transmucosal Immediate-Release Fentanyl Products.

IMPORTANCE: Transmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately. OBJECTIVES: To evaluate knowledge assessments of pharmacists, prescribers, and patients regarding appropriate TIRF use; to describe sponsor assessments, based on claims data, of whether the REMS program was meeting its goals; and to characterize how the FDA responded to REMS assessments. DESIGN, SETTING, AND PARTICIPANTS: Qualitative analysis of 4877 pages of FDA documents obtained through a Freedom of Information Act request, including 6 annual REMS assessment reports (2012-2017), FDA evaluations of these reports, and FDA-sponsor correspondence about safety issues. EXPOSURE: A REMS program to reduce the risk of adverse outcomes, including misuse, abuse, addiction, and overdose, arising from use of TIRFs. MAIN OUTCOMES AND MEASURES: (1) Knowledge assessments of pharmacists, prescribers, and patients; (2) survey and claims-based prescribing assessments; (3) FDA and TIRF sponsor communications; (4) modifications to the REMS program; and (5) disenrollment of noncompliant prescribers. RESULTS: Twelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing. CONCLUSIONS AND RELEVANCE: In this review of FDA documents pertaining to the TIRF REMS, surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge regarding proper TIRF prescribing, yet some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program.

Cross-sectional survey of off-label and unlicensed prescribing for inpatients at a paediatric teaching hospital in Western Australia.

OBJECTIVES: To evaluate the prevalence of off-label and unlicensed prescribing in inpatients at a major paediatric teaching hospital in Western Australia and to identify which drugs are commonly prescribed off-label or unlicensed, including factors influencing such prescribing. METHODS: A retrospective cross-sectional study was conducted in June, 2013. Patient and prescribing data were collected from 190 inpatient medication chart records which had been randomly selected from all admissions during the second week of February 2013. Drugs were categorised as licensed, off-label or unlicensed, according to their approved Australian registration product information (PI). All drugs were classified according to the Anatomical Therapeutic Chemical (ATC) code. RESULTS: There were 120 male and 70 female inpatients. The average age was 6.0 years (± 4.7). The study included 1160 prescribed drugs suitable for analysis. The number of drugs prescribed per patient ranged from 1 to 25 with an average of 6.1 (± 4.3). More than half (54%) were prescribed off-label. Oxycodone, clonidine, parecoxib and midazolam were always prescribed off-label. The most common off-label drugs were ondansetron (18.5%), fentanyl (12.9%), oxycodone (8.8%) and paracetamol (6.1%). Many ATC classifications included high off-label proportions especially the genitourinary system and sex hormones, respiratory system drugs, systemic hormonal preparations and alimentary tract and metabolism drugs. CONCLUSIONS: This study highlights that prescribing of paediatric drugs needs to be better supported by existing and new evidence. Incentives should be established to foster the conduct of evidence-based studies in the paediatric population. The current level of off-label prescribing raises issues of unexpected toxicity and adverse drug effects in children that are in some cases severely ill.

Evaluation of Clinical Compendia Used for Medicare Part D Coverage Determinations for Off-label Prescribing in Dermatology.

Importance: When making coverage determinations for off-label prescribing, Medicare Part D recognizes 2 compendia: the American Hospital Formulary Service (AHFS) Drug Information and the DRUGDEX Information System. Deficiencies in the accuracy and completeness of these compendia could result in coverage denials for necessary, effective, evidence-based treatments. Objective: To evaluate these compendia for dermatologic conditions, with a focus on less common conditions that often require systemic treatment. Design, Setting, and Participants: This cross-sectional study was conducted from July 1, 2018, through September 30, 2018. To identify diseases for which dermatologists may often need access to off-label systemic treatments, a list of 22 chronic, noninfectious, nonneoplastic diseases with at least 4 systemic therapies (including 1 in the first-line therapies and less than 25% approved by the US Food and Drug Administration) were selected for evaluation. With use of Treatment of Skin Disease, 5th Edition, a list of first-, second-, and third-line medications was created, including the level of evidence for each disease. A search of AHFS and DRUGDEX compendia was performed to evaluate for inclusion of the evidence-based therapies. In addition, the references cited in the compendia to justify inclusion of the therapy were examined qualitatively. Main Outcomes and Measures: Percentage of treatment options included in each compendium, stratified by level of evidence and position on the therapeutic ladder. Concordance between the 2 compendia was assessed using Cohen κ. Results: Overall, 73 of 238 treatments (30.7%) evaluated were included in either compendium. Among individual diseases, 10 of 22 (45%) had 1 or fewer treatments included in the DRUGDEX compendium and 15 of 22 (68%) had 1 or fewer treatments included in the AHFS compendium. Discrepancies in which a medication was included in one compendium but not in the other compendium occurred for 53 of the 238 medications (22.3%) evaluated. Literature use did not follow a discernible pattern and was often based on decades-old sources. Conclusions and Relevance: The findings suggest that treatment options listed in these compendia are incomplete, outdated, idiosyncratic, and unpredictable. To ensure that patients can access treatments for their disease, it appears that policies to reduce the reliance on these compendia for coverage determinations should be developed.

Off-label use of antipsychotics and associated factors in community living older adults.

BACKGROUND: Given the common off-label use of antipsychotics (AP), we aimed to assess the factors associated with this use in community living older adults. METHODS: The study sample consisted of a large representative sample of older adults (n = 4108), covered under a public drug insurance plan in Canada. Off-label use of antipsychotics was defined by the absence of an approved indication for this use, according to Health Canada's drug product database. Multinomial logistic regression was used to assess the factors associated with off-label use. RESULTS: The prevalence of antipsychotics use was 2.5%, of which 78% was off-label. Compared to non-use, off-label antipsychotics use was negatively associated with advanced age (≥75 vs. 65-74 years old) (OR: 0.46; 95%CI: 0.27-0.78); and positively associated with higher education level (OR: 2.68; 95% CI: 1.64-4.40), higher number of outpatient visits (≥6) (OR: 2.39; 95%CI: 1.34-4.25), antidepressant or benzodiazepine use (OR: 5.81; 95%CI: 3.31-10.21), and the presence of an organic brain syndrome & Alzheimer's (OR: 5.73; 95%CI: 1.74-18.89). Compared to labeled use, off-label use was less likely in those with major depression (OR: 0.02; 95%CI: <0.01-0.11) and with insomnia (OR: 0.13; 95%CI: 0.02-0.91). CONCLUSIONS: The majority of antipsychotics prescribed to community living older adults were off-label. This off-label use was more likely in complex clinical cases with multiple outpatient visits and other psychotropic drugs use. Further research should focus on the long-term effects associated with off-label use of antipsychotics.

Patterns and predictors of off-label prescription of psychiatric drugs.

Off-label prescribing of psychiatric drugs is common, despite lacking strong scientific evidence of efficacy and potentially increasing risk for adverse events. The goal of this study was to characterize prevalence of off-label prescriptions of psychiatric drugs and examine patient and clinician predictors of off-label use. This manuscript presents a retrospective, cross-sectional study using data from the 2012 and 2013 National Ambulatory Medical Care Surveys (NAMCS). The study examined all adult outpatient visits to psychiatric practices for chronic care management with a single listed visit diagnosis in which at least one psychiatric drug was prescribed. The main outcome measure was off-label prescribing of at least one psychiatric drug, defined as prescription for a condition for which it has not been approved for use by the FDA. Among our sample representative of 1.85 billion outpatient visits, 18.5 million (1.3%) visits were to psychiatrists for chronic care management in which at least one psychiatric drug was prescribed. Overall, the rate of off-label use was 12.9% (95% CI: 12.2-15.7). The most common off-label uses were for manic-depressive psychosis treated with citalopram and primary insomnia treated with trazodone. Several patient and clinician characteristics were positively associated with off-label prescribing, including seeing a psychiatrist (OR: 1.06, 95% CI, 1.01-1.12; p = 0.03) instead of another type of clinician, the office visit taking place in the Western region of the country (OR: 1.09, 95% CI, 1.01-1.17; p = 0.02), and the patient having 3 or more chronic conditions (OR: 1.12, 95% CI, 1.02-1.14; p = 0.003). In contrast, having Medicare coverage (OR: 0.93, 95% CI, 0.84-0.97; p = 0.04) and receiving payment assistance from a medical charity (OR: 0.91, 95% CI, 0.88-0.96; p = 0.03) instead of private insurance were negatively associated with off-label prescribing. These results suggest that certain classes of psychiatric medications are being commonly prescribed to treat conditions for which they have not been determined by the FDA to be clinically efficacious and/or safe.

Trends and Patterns of Antidepressant Use in French Children and Adolescents From 2009 to 2016: A Population-Based Study in the French Health Insurance Database.

PURPOSE/BACKGROUND: Over the last decade, the use of antidepressants (ATDs) in children and adolescents has markedly increased in several occidental countries, but recent data in French children are missing. This study aimed to assess trends of ATD use in French children (6-11 years) and adolescents (12-17 years) and to characterize changes in ATD prescribing patterns from 2009 to 2016. METHODS: Using data from the French Health Insurance Database, annual prevalence and incidence of ATD use and changes in ATD prescribing patterns were analyzed. RESULTS: Overall ATD prevalence of use rose slightly from 0.51% in 2009 to 0.53% in 2016 (+3.9%), with a decrease in children (0.18%-0.11%; -38.9%) and an increase in adolescents (0.86%-0.98%; +14.0%) and an overall female preponderance (56.7% in 2009; 58.7% in 2016). Serotonin reuptake inhibitor prevalence of use increased from 0.24% to 0.34%, whereas tricyclic ATD use decreased (from 0.20% to 0.16%). Similar trends were obtained with overall incidence of use, from 0.39% in 2009 to 0.36% in 2016 (-7.7%). Sertraline was the most frequently prescribed in adolescents (2009: 22.2% of all ATD prescriptions; 2016: 32.9%), whereas amitriptyline was the most prescribed in children (2009: 42.7% and 2016: 41.2%). Off-label use decreased in adolescents (from 48.4% to 34.8%) but increased in children (from 10.0% to 26.5%). IMPLICATIONS/CONCLUSIONS: Antidepressant level of use in French children and adolescents was stable in recent years and lower than that observed in other European countries and the United States.

More medicines for children: impact of the EU paediatric regulation.

INTRODUCTION: This paper focuses on the authorisation of new medicines, new indications and new pharmaceutical forms or strengths for use in children and also on the availability of paediatric information in the product information of centrally authorised medicinal products following the enforcement of the Paediatric Regulation on 26 January 2007. OBJECTIVES: To investigate whether the Paediatric Regulation has led to more medicines available for children in the European Union (EU) and if more information on paediatric use is now available in the product information of medicines authorised via the centralised procedure. MATERIALS AND METHODS: We retrospectively analysed the centrally authorised medicinal products in the EU that had an approval for an initial marketing authorisation, a type II variation, or a line extension during the years 2004-2006 and 2012-2014. Medicinal products not subjected to the obligations of the Paediatric Regulation were excluded. RESULTS: In 2004-2006, 20 new medicines and 10 new indications were centrally authorised for paediatric use compared with 26 new medicines and 37 new indications in 2012-2014. The number of medicines with a new pharmaceutical form or strength for use in children was eight in 2004-2006 and seven in 2012-2014. There was a huge increase in the number of products with changes of paediatric relevance in the summary of product characteristics in 2012-2014 compared with 2004-2006. CONCLUSIONS: The entry into force of the Paediatric Regulation has had a positive impact on paediatric drug development with more medicines available for children in the EU and substantially more information available for clinicians on paediatric use in the product information.

The Impact of a State Medicaid Peer-Review Authorization Program on Pediatric Use of Antipsychotic Medications.

OBJECTIVE: This cross-sectional study assessed the impact of a peer-review program on the prevalence of pediatric antipsychotic use among Medicaid-insured youths in a Mid-Atlantic state. METHODS: Medicaid claims (2010-2014) were assessed among continuously enrolled youths in the 12 months before and after implementation of peer review. The study identified children ages zero to four preimplementation (N=118,815) and postimplementation (N=121,431), ages five to nine preimplementation (N=98,681) and postimplementation (N=107,872), and ages 10 to 17 preimplementation (N=154,696) and postimplementation (N=161,370). (Age ranges are inclusive of the final number). In each age group, multivariable logistic regression models with generalized estimating equations assessed the change in annual prevalence of antipsychotic use pre- to postimplementation. Use of other leading psychotropic classes and antipsychotic prescribing by medical specialty were also examined. RESULTS: The annual pre- to postimplementation prevalence of antipsychotic use decreased significantly, from .07% to .03% (adjusted odds ratio [AOR]=.41) among children ages zero to four, from 1.57% to .86% (AOR=.54) among those ages five to nine, and from 3.28% to 2.40% (AOR=.72) among those ages 10 to 17. With the exception of alpha-agonist use, which increased postimplementation (AOR=1.30) among those ages zero to four, no clinically significant pre-post change was noted in other leading psychotropic classes among children ages zero to four and 10 to 17. By contrast, postimplementation use of other psychotropic medications decreased among those ages five to nine (AOR=.73). CONCLUSIONS: A state Medicaid peer-review program resulted in decreased antipsychotic use across all age groups, particularly among children younger than ten. No notable substitution of other psychotropic classes for antipsychotics was observed.