Age-related off-label drug prescribing in pediatric patients in South Korea and consistency of labeling compared to the United States, Europe, and Japan.

Insufficient labeling information regarding the appropriate age for prescribing drugs to the pediatric population is challenging. This study aimed to analyze the off-label prescription of age-related drugs for pediatric patients using claims data from South Korea and to assess the consistency of the approved age in South Korea, the United States, Europe, and Japan. In 2020, 1004 unique drugs were prescribed to the pediatric population in South Korea. We found that 641 drugs (63.8%, p < 0.0001) were related to off-label prescriptions for age-related use at least once, and the total number of off-label prescriptions was 2,236,669 (62.2%, p < 0.0001). Chlorpheniramine (28%) was the most frequently prescribed drug for pediatric patients with an age-related off-label, followed by budesonide (9%) and epinephrine (9%). The degree of agreement in the approved age range for 641 off-label drugs across countries was assessed using the overall kappa coefficient. We observed slight agreement in labeling across all countries (κ: 0.16, 95% confidence interval [CI]: 0.14-0.18). The highest degree of agreement was observed between the United States and Europe (0.41, 0.37-0.45) due to pediatric-population-specific legislation. South Korea showed the lowest degree of agreement with the United States and Europe (0.10, 0.06-0.14). The United States, Europe, and Japan showed fair agreement (0.23, 0.21-0.26). However, the degree of agreement between South Korea, the United States, and Japan (0.09, 0.06-0.11) and South Korea, Europe, and Japan (0.08, 0.05-0.10) was low. This study highlights the need for South Korean regulatory agencies to consider introducing pediatric legislation to prescribe evidence-based drugs for safe and effective use.

Comparative analysis of PIM criteria and drug labels in the elderly.

PURPOSE: By discussing the corresponding situation of PIM criteria and labels, it provides a reference for the formulation and update of the criteria and the content of the section of "medications for the elderly" in the labels, so as to realize rational drug use for the elderly. METHODS: Extract the four indicators of Beers criteria, STOPP criteria, and the EU(7)-PIM list that involve dosage, duration, age, and mortality, and compare them with the latest labels for drugs marketed in the USA and the EU. RESULTS: There are 148 drugs involving four indicators in the criteria, and 85.14% of the drugs are found in at least one region. In terms of dose, there are 28 drugs with inconsistent descriptions in the labels of the two regions, accounting for 47.46% of the 59 drugs found in both regions. A total of 42.37% of the drugs are consistent in both regions with the criteria (25/59), 28.81% of the drugs are inconsistent in both regions with the criteria (17/59), and 28.81% of the drugs are inconsistent in only one region with the criteria (17/59). The doses of 50 drugs found in F/D labels are consistent with the criteria, accounting for 54.35% of the 92 drugs found in F/D labels, and of 41 drugs found in E/H SmPC are consistent with the criteria, accounting for 60.29% of the 68 drugs found in E/H SmPC. Only the duration of omeprazole in the labels in both regions is consistent with the criteria, and only the age of prasugrel in both regions is consistent with the criteria. Five drugs whose labels mentioned increased mortality, accounting for 38.46% of the 13 drugs found in both regions. CONCLUSION: There are certain differences between PIM criteria and PIM criteria, labels and labels, and PIM criteria and labels, which will affect the use of drugs in the elderly. Therefore, the unity between the criteria and labels should be strengthened to provide more instructive guidance for the elderly, so as to jointly realize rational drug use in the elderly.

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective, multicentre cross-sectional study of prevalence, nature and anaesthetists' approach to management.

BACKGROUND: We sought to define the prevalence and nature of patient-reported drug allergies, determine their impact on prescribing, and explore drug allergy knowledge and attitudes amongst anaesthetists. METHODS: We performed a prospective cross-sectional study in 213 UK hospitals in 2018. Elective surgical patients were interviewed, with a detailed allergy history taken in those self-reporting drug allergy. Anaesthetists completed a questionnaire concerning perioperative drug allergy. RESULTS: Of 21 219 patients included, 6214 (29.3 %) (95% confidence interval [CI]: 28.7-29.9) reported drug allergy. Antibiotics, NSAIDs, and opioids were the most frequently implicated agents. Of a total of 8755 reactions, 2462 (28.1%) (95% CI: 29.2-31.1) were categorised as high risk for representing genuine allergy after risk stratification. A history suggestive of chronic spontaneous urticaria significantly increased the risk of reporting drug allergy (odds ratio 2.68; 95% CI: 2.4-3; P<0.01). Of 4756 anaesthetists completing the questionnaire, 1473 (31%) (95% CI: 29.7-32.3) routinely discuss perioperative allergy risk with patients. Prescribing habits in the presence of drug allergy labels differ depending on the implicated agent. Most anaesthetists (4678/4697; 99.6%) (95% CI: 99.4-99.8) prescribe opioids when reactions are consistent with side-effects, although 2269/4697 (48%) (95% CI: 46.9-49.7) would avoid the specific opioid reported. CONCLUSIONS: Almost 30% of UK elective surgical patients report a history of drug allergies, but the majority of reported reactions are likely to be non-allergic reactions. Allergy labels can impact on perioperative prescribing through avoidance of important drugs and use of less effective alternatives. We highlight important knowledge gaps about drug allergy amongst anaesthetists, and the need for improved education around allergy.

ADR databases for on-site clinical use: Potentials of summary of products characteristics.

Adverse drug reactions (ADRs) for all drugs in Europe are described in the legally approved Summary of Product Characteristics (SmPC). An overview of all ADRs of the patients' drug list can support healthcare staff to link patient symptoms to possible ADRs. We review the possibilities and challenges to extract ADR information from SmPCs or American Structured Product Labels and present the development of our semi-automated procedure for extraction of ADRs from the tabulated section in the SmPCs to create a database, named Bikt, which is regularly updated and used at point of care in Sweden. The existence of five major table formats for ADRs used in the SmPCs required the development of different parsing scripts. Manual checks for correctness for all content have to be performed. The quality of extraction was investigated for all SmPCs by measuring precision, recall and F1 scores and compared with other methods published. We conclude that it is possible to semi-automatically extract ADR information from SmPCs. However, clear technical and content guidelines and standards for ADR tables and terms from drug registration authorities would lead to improved extraction and usability of ADR information at point of care.

Why are certain age bands used for children in paediatric studies of medicines?

Rational prescribing of medicines requires evidence from clinical trials on efficacy, safety and the dose to be prescribed, based on clinical trials. Regulatory authorities assess these data and information is included in the approved summary of product characteristics. Regulatory guidelines on clinical investigation of medicinal products in the paediatric population generally propose that studies are done in defined age groups but advise that any classification of the paediatric population into age categories is to some extent arbitrary or that the age groups are intended only as a guide. The pharmaceutical companies tend to plan their studies using age groups the regulatory guidelines suggest, to avoid problems when applying for marketing authorisation. These age bands end up in the paediatric label, and consequently into national paediatric formularies. The age bands of the most commonly used age-subsets: neonates, infant/toddlers, children and adolescents, are more historical than based on physiology or normal development of children. Particularly problematic are the age bands for neonates and adolescents. The age of 12 years separating children from adolescents, and the upper limit of the adolescents set by the definition of paediatric age in healthcare, which varies according to the region, are particularly questionable. Modern pharmacometric methods (modelling and simulation) are being increasingly used in paediatric drug development and may allow assessment of growth and/or development as continuous covariables. Maybe time has come to reconsider the rational of the currently used age bands.

What should patients do if they miss a dose? A systematic review of patient information leaflets and summaries of product characteristics.

PURPOSE: Medicines regulatory authorities advise that patient information leaflets (PILs) should provide specific advice on what actions to take if one or more doses are missed. We aimed to assess the content in this regard, of PILs and Summaries of Product Characteristics (SmPCs) of prescription only medicines (POMs) marketed in the UK. METHODS: PILs and SmPCs were accessed via the electronic Medicines Compendium. The following terms were used in the advanced search facility: miss(ed), omit(ted), adhere(d), delay(ed), forgot, forget, lapse. Identified documents were screened for instructions on missed doses which were categorised according to level of specificity, and cross-referenced to the National Patient Safety Agency (NPSA) grading of risk of harm from omitted and delayed medicines. Any supporting clinical or pharmacological evidence was identified from SmPCs. RESULTS: Two thousand two hundred eighty-four documents were identified from 7248 PILs and SmPCs relating to 1501 POMs. Seven hundred eighty-three (52%) POMs had SmPCs or PILs with no instructions on missed doses; 487 POMs (32%) included non-specific advice (e.g. "take as soon as possible"); 138 (9%) provided specific instructions; and 93 (6%) referred patients to seek medical advice. SmPCs for only 13/138 (9%) of those which included specific instructions provided any supporting clinical or pharmacological evidence. Instructions were absent for several medicines where the NPSA assessed that dose omissions may result in significant risk of harm. CONCLUSIONS: Advice on missed doses is generally inadequate. Pharmaceutical companies and regulatory authorities should produce clear and concise instructions on what patients should do if they miss doses, with supporting evidence where necessary.

Current Challenges in Labelling for Generic Medicinal Products: Company Core Data Sheet (CCDS) Development and Maintenance.

Labelling of pharmaceutical products plays a vital role in the safe and effective use of approved medicinal products. This information may be provided to end-users including patients and/or prescribers, and it needs to be made available in multiple formats including printed forms (patient information leaflets, pack inserts, etc.) or web portals of the product, based on national authority guidelines. The Company Core Data Sheet (CCDS) serves as a key document representing the pharmaceutical company's position on the product and is used as a reference document for national labels. Content from national labels may differ from the CCDS for different reasons including implementation of national authority requirements in the serving market and findings from local markets. In the current article, we discuss the process, challenges and key concepts in creating and maintaining CCDS documents for generic products. We highlight key parameters that are worthy of process improvement in generic products' CCDS updates. In addition, we argue that labelling harmonisation across multiple regions, especially safety section-related information, plays a key role in promoting end-user safety and would help communicate risks. We also strongly believe that the topic is worthy of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) consideration, and propose that this is the key area that requires standardisation and harmonisation.

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective multicentre cross-sectional study of incidence, risks, and attitudes in penicillin de-labelling strategies.

BACKGROUND: Penicillin allergy is associated with a range of poor health outcomes. Allergy testing can be made simpler by using a direct drug provocation test in patients at low risk of genuine allergy. This approach could allow population-level 'de-labelling'. We sought to determine the incidence and nature of penicillin allergy labels in UK surgical patients and define patient and anaesthetist attitudes towards penicillin allergy testing. METHODS: A prospective cross-sectional questionnaire study was performed in 213 UK hospitals. 'Penicillin allergic' patients were interviewed and risk-stratified. Knowledge and attitudes around penicillin allergy were defined in patients and anaesthetists. RESULTS: Of 21 219 patients, 12% (n=2626) self-reported penicillin allergy; 27% reported low-risk histories potentially suitable for a direct drug provocation test; an additional 40% reported symptoms potentially suitable for a direct drug provocation test after more detailed assessment. Of 4798 anaesthetists, 40% claimed to administer penicillin routinely when they judged the label low risk. Only 47% of anaesthetists would be happy to administer penicillin to a patient previously de-labelled by an allergy specialist using a direct drug provocation test; perceived lack of support was the most common reason for not doing so. CONCLUSIONS: At least 27% of patients with a penicillin allergy label may be suitable for a direct drug provocation test. Anaesthetists demonstrated potentially unsafe prescribing in patients with penicillin allergy labels. More than half of anaesthetists lack confidence in the results of a direct drug provocation tests undertaken by a specialist. Our findings highlight significant barriers to the effective implementation of widespread de-labelling in surgical patients.

FDA postmarketing safety labeling changes: What have we learned since 2010 about impacts on prescribing rates, drug utilization, and treatment outcomes.

PURPOSE: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. METHODS: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study. RESULTS: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. CONCLUSIONS: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications.

A descriptive analysis of medicines safety advisories issued by national medicines regulators in Australia, Canada, the United Kingdom and the United States - 2007 to 2016.

PURPOSE: To determine the frequency and characteristics of safety advisories issued by medicines regulatory agencies in Australia, Canada, United Kingdom (UK) and the United States (US). METHODS: This retrospective analysis examines medicines safety warnings issued by the US Food and Drug Administration (FDA), Health Canada (HC), the Australian Therapeutic Goods Administration (TGA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) from January 1, 2007 until December 31, 2016. A database of warnings obtained from regulators' websites was developed and warnings were classified by communication type, drug, or therapeutic class focus, and the risk discussed. Advisories identifying the same drug or therapeutic class and risk were combined into groups termed "drug-risk issues" for comparisons between regulators. RESULTS: Over this 10-year period, 1441 advisories were identified, with the MHRA issuing the most advisories (MHRA = 469, FDA = 382, HC = 370 TGA = 220). Seventy two percent focussed on single drugs (1034/1441) and 58.7% were alerts (846/1441) posted on the regulators' websites. Diabetes drugs, smoking cessation drugs and immunomodulatory agents were the individual drug types most often subject to safety advisories, while antidepressants, antipsychotics, and proton-pump inhibitors were the top three therapeutic classes. Of 680 identified drug-risk issues, 3.8% (26/680) described a risk of death. By body system, cardiac effects were the most frequent: 10.4% (71/680). CONCLUSION: We found considerable differences in the use of advisories including frequency, communication type, and focus. Disparities in communication about emergent evidence on risks may mean that clinicians and patients in some countries are less well informed about medicine safety concerns than others.

Postmarketing Safety of Vaccines Approved by the U.S. Food and Drug Administration : A Cohort Study.

BACKGROUND: Vaccines are one of the greatest achievements in public health. Prevalence and clinical significance of emerging postapproval, vaccine-related safety issues have not been systematically studied. OBJECTIVE: To explore postmarketing safety modifications in U.S. Food and Drug Administration (FDA)-approved vaccine labels. DESIGN: Retrospective cohort study. SETTING: United States. PARTICIPANTS: Initial and subsequent labels of all vaccines that were FDA-approved between 1 January 1996 and 31 December 2015. MEASUREMENTS: The primary aim was a descriptive analysis of the prevalence and characteristics of postapproval, safety-related label changes. The secondary aim was to describe the distribution of data sources triggering these modifications. RESULTS: The study cohort comprised 57 FDA-approved vaccines. Initial approval for 53 (93%) of the vaccines was supported by randomized controlled trials, with a median cohort size of 4161 participants (interquartile range, 2204 to 8634 participants). There were 58 postapproval, safety-related label modifications associated with 25 vaccines (49 warnings and precautions, 8 contraindications, and 1 safety-related withdrawal). The initial approval trial characteristics were similar in vaccines with and without postmarketing, safety-related label modifications. The most common safety issue triggering label modifications was expansion of population restrictions (n = 21 [36%]), followed by allergies (n = 13 [22%]). The most common source of safety data was postmarketing surveillance (n = 28 of 58 [48%]). LIMITATION: The data source of the initial signal triggering safety-related label changes may not necessarily represent all safety data received and processed by the FDA. CONCLUSION: Over a 20-year period, vaccines were found to be remarkably safe. A large proportion of safety issues were identified through existing postmarketing surveillance programs and were of limited clinical significance. These findings confirm the robustness of the vaccine approval system and postmarketing surveillance. PRIMARY FUNDING SOURCE: None.

Pediatric Orphan Drug Indications: 2010-2018.

BACKGROUND: Orphan drug development is crucial for children, who are disproportionately affected by rare diseases. Data are lacking on the number, nature, and benefit of recently approved pediatric orphan indications. METHODS: We classified the 402 orphan indications the US Food and Drug Administration approved between 2010 and 2018 as "pediatric" if they were approved for children only or targeted pediatric diseases. We determined the number of unique diseases targeted by pediatric orphan indications and calculated the proportion that were for (1) novel drugs, (2) non-novel drugs approved to treat ≥1 common disease, and (3) non-novel drugs approved only to treat rare diseases. Among pediatric orphan indications eligible for US Food and Drug Administration breakthrough designation (granted to drugs potentially representing major therapeutic advances), we calculated the proportion receiving this designation. RESULTS: Of the 402 orphan indications, 136 (33.8%) were pediatric. These 136 indications targeted 87 unique diseases; 21 diseases were targeted by ≥1 indication. Of the 136 pediatric orphan indications, 60 (44.1%) were for novel drugs, 45 (33.1%) were for non-novel drugs approved to treat ≥1 common disease, and 31 (22.8%) were for non-novel drugs approved only to treat rare diseases. Among 97 indications eligible for breakthrough designation, 20 (20.6%) received this designation. CONCLUSIONS: Recent orphan drug development has increased the availability of treatments for pediatric rare diseases. Most pediatric orphan indications expanded use of existing drugs, and many targeted the same disease. Some indications may represent breakthroughs, but substantial unmet need for treatments remains for most pediatric rare diseases.

Development and exploratory analysis of software to detect look-alike, sound-alike medicine names.

BACKGROUND: 'Look-alike, sound-alike' (LASA) medicines may be confused by prescribers, pharmacists, nurses and patients, with serious consequences for patient safety. The current research aimed to develop and trial software to proactively identify LASA medicines by computing medicine name similarity scores. METHODS: Literature review identified open-source software from the United States Food and Drug Administration for screening of proposed medicine names. We adapted and refined this software to compute similarity scores (0.0000-1.0000) for all possible pairs of medicines registered in Australia. Two-fold exploratory analysis compared: RESULTS: Screening of the Australian medicines register identified 7,750 medicine pairs with at least moderate (arbitrarily ≥0.6600) name similarity, including many oncology, immunomodulating and neuromuscular-blocking medicines. Computed similarity scores and resulting risk categories demonstrated a modest correlation with the manually-calculated similarity scores (r = 0.324, p < 0.002, 95 % CI 0.119-0.529). However, agreement between the resulting risk categories was not significant (Cohen's kappa = -0.162, standard error = 0.063). CONCLUSIONS: The software (LASA v2) has potential to identify pairs of confusable medicines. It is recommended to supplement incident reports in risk-management programs, and to facilitate pre-screening of medicine names prior to brand/trade name approval and inclusion of medicines in formularies.

[Usefulness of the summary of product characteristics as a tool to improve prescription in elderly patients]. / Utilidad de la ficha técnica de los medicamentos como herramienta para mejorar la prescripción en pacientes mayores.

BACKGROUND AND OBJECTIVE: The Drug Technical Data Sheet should contribute to a safe and effective use of medications in the elderly, providing accurate information on the prescription, on the possible benefits or risks of the medications, or failing that, communicating the lack of information on their use in this group. The aim of this article was to quantify the specific information for people over 65 years of age included in the data sheets of the drugs available in Spain, and enables an adequate prescription in this population. MATERIALS AND METHODS: A multidisciplinary group reviewed all the Technical Data Sheets of drugs approved by the Spanish Agency for Medicines and Health Devices (AEMPS). The quality of the information was classified into 4 categories: information specifically referring to the population over 65 years old; information specifically referring to the population over 80 years old; recommendations not specific to the elderly; and specific information for the elderly. RESULTS: A total of 1,462 Technical Sheets were reviewed, of which 48% had information regarding prescription in the elderly. Information on the use in patients over 80 years old was present in 1.23% of the sheets. Only 6.83% of all the sheets reviewed included specific recommendations for the elderly. CONCLUSIONS: There is little specific information regarding prescription in the elderly in the technical data sheets of drugs prescribed/sold in Spain. To improve knowledge in this field, data must be provided in the sheets that are based on the scientific literature, clinical trials for the elderly, or pharmacovigilance studies focused on this population.

Update on Therapeutic Protein-Drug Interaction: Information in Labeling.

This review evaluated the significance of therapeutic protein (TP)-drug interactions and the current practices for assessing the interaction potential. We reviewed US FDA labels of approved TPs with drug-drug interaction (DDI) assessment. TP-drug interactions have been evaluated from in vitro studies, animal studies, and/or clinical settings. Of the 150 FDA-approved TPs as of May 2019, 49 TP labels contained pharmacokinetic (PK)-related DDI information derived from at least one study method. Our review found that more than half of the clinical PK DDI evaluations showed no interaction, and no dose adjustment has been recommended for any of the rest TPs. The results and trends observed in this review may further enhance and inform risk-based approaches to evaluating the potential for TP-drug interactions.

Trends in antidepressant use among children and adolescents: a Scandinavian drug utilization study.

OBJECTIVE: To compare antidepressant utilization in individuals aged 5-19 years from the Scandinavian countries. METHODS: A population-based drug utilization study using publicly available data of antidepressant use from Denmark, Norway, and Sweden. RESULTS: In the study period from 2007 to 2017, the proportion of antidepressant users increased markedly in Sweden (9.3-18.0/1000) compared to Norway (5.1-7.6/1000) and Denmark (9.3-7.5/1000). In 2017, the cumulated defined daily doses (DDD) of selective serotonin reuptake inhibitors were 5611/1000 inhabitants in Sweden, 2709/1000 in Denmark, and 1848/1000 in Norway. The use of 'other antidepressants' (ATC code N06AX) also increased in Sweden with a higher DDD in 2017 (497/1000) compared to Denmark (225/1000) and Norway (170/1000). The use of tricyclic antidepressants was generally low in 2017 with DDDs ranging between 30-42 per 1000. The proportion of antidepressant users was highest among 15- to 19-year-old individuals. Girls were more likely to receive treatment than boys, and the treated female/male ratios per 1000 were similar in Sweden (2.39), Denmark (2.44), and Norway (2.63). CONCLUSION: Even in highly comparable healthcare systems like the Scandinavian countries', variation in antidepressant use is considerable. Swedish children and adolescents have a markedly higher and still increasing use of antidepressants compared to Danish and Norwegian peers.

Labelling and quality of antimicrobial products used in chicken flocks in the Mekong Delta of Vietnam.

BACKGROUND: The Mekong Delta of Vietnam is a hotspot of antimicrobial use (AMU), but there is no information on the quality of the labelling and strength of antimicrobial products used in poultry production. METHODS: Based on a large random sample of farms, we identified the 20 most used antimicrobial products in the area, and investigated their antimicrobial active ingredient (AAI) content by UPLC-MS/MS (91 analytical tests). RESULTS: Only 17/59 (28.8%) batches contained all AAIs within 10% of the declared strength. Worryingly, 65.0% products provided in their label preparation guidelines for both therapeutic and prophylactic use. Withdrawal times for both meat and eggs were stated in 8/20 (40%) products. CONCLUSION: Results highlight deficiencies in quality and labelling contents that undermine authorities' efforts to discourage inappropriate use of antimicrobials.

Evaluation of color-coded drug labeling to identify endovenous medicines.

OBJECTIVE: To analyze the opinion of nursing professionals on the design, practicality of use and the usefulness of color-coded drug labeling in a pediatric intensive care unit. METHODS: A cross-sectional study with 42 nursing professionals. A structured questionnaire was used based on a five-level Likert scale. To assess the proportions, a binomial test was used. RESULTS: Concordance ratio >0.8 for all propositions related to design, practicality and most of the propositions related to error prevention. CONCLUSION: According to the opinion of the nursing team, the implemented technology has an adequate design, as well as being practical and useful in the prevention of medication errors in the population at the ICU.