A Perspective on Evaluating Life Stage Differences in Drug Dosages for Drug Labeling and Instructions.

Drug labeling and instructions provide essential information for patients regarding the usage of drugs. Instructions for the dosage of drug usage are critical for the effectiveness of the drug and the safety of patients. The dosage of many drugs varies depending on the patient's age. However, as our understanding of human biology deepens, we believe that these instructions need to be modified to incorporate different life stages. This is because human biology and metabolism differ significantly among different life stages, and their responses to drugs also vary. Additionally, the same age of different persons may fall into different life stages. Therefore, our group from multiple institutes and countries proposes a reexamination of whether incorporating life stages in all or any drug instructions will greatly enhance drug efficiency and patients' health.

Assessment of knowledge of the new pregnancy and lactation labeling rule among pharmacists and physicians in Saudi Arabia.

Researchers in Saudi Arabia conducted this study to determine the level of familiarity that pharmacists and physicians possess with the pregnancy and lactation labeling rules established by the Food and Drug Administration. The present study included a cross-sectional survey conducted among pharmacists and physicians working in Saudi Arabia. The sample size was determined using the Rao sample size calculator. We utilized the Statistical Package for the Social Sciences (SPSS) version 25 for our analysis. A total of 122 respondents completed the study. Among them, 72.9% were aged between 25 and 44 years, and approximately 63.9% were male. About 64% of the respondents indicated familiarity with the A, B, C, D, and X letter system of pregnancy category labeling. Over 37% stated that the new pregnancy and lactation labeling rule would continue to use the lettering system. Additionally, 83% believed that the A, B, C, D, and X risk category labeling system is a useful resource, and 82% believed that working with this risk category labeling improves patient care. The study revealed that pharmacists and physicians exhibited good knowledge of the old rule but a low level of knowledge regarding the new rule. Despite significant flaws in the old system, most preferred it. Enhancing knowledge in this area is crucial for improving risk communication and the quality of care for women of reproductive age.

Removing the FDA's Boxed Hepatotoxicity Warning and Liver Function Testing Requirement for Ambrisentan.

Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1 000 000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10 261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11 159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.

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.

The continuing challenge of drug recalls: Insights from a ten-year FDA data analysis.

In this study we analyzed drug recall data from the U.S. Food and Drug Administration (FDA) over the period 2012-2023. We identified trends in the number of recalls initiated annually and their underlying causes. On average, 330 drug recalls are initiated each year, showing an overall increasing trend. The average duration of a recall, from initiation to termination date, was 1.3 years and each recall involved on average 400 000 product units, implying considerable resource demands and consequences for all stakeholders. The most frequent cause of these recalls was found to be impurities and contaminants (37 %), followed by control (28 %) and labeling/packaging (19 %) issues. Recalls of medicines causing serious health problems or death (class I), accounted for 14 % of the recall events. Continuous evaluation of recalls is expected to reduce their number, mitigate their impact on the healthcare system and improve drug safety.

Label Accuracy of Legal Oral Cannabis Oil Products in Ontario, Canada.

This case series compares amounts of tetrahydrocannabinol and cannabidiol reported on product labels vs levels found in laboratory testing in legal oral cannabis oil products in Ontario, Canada.

Overdosage Section in US and EU Labeling.

The Prescribing Information (PI) in the United States (US) and the Summary of Product Characteristics (SmPC) in the European Union (EU) are approved by the US Food & Drug Administration (FDA), and the European Medicines Agency (EMA), respectively. The inclusion of overdosage information in these documents is a regulatory requirement in both regions. This research evaluates the content of the overdosage section of US and EU labeling. The overdosage sections of labels for drugs approved in the US in three time periods were analyzed: 2000-2001, 2010-2011, and 2020-2021. EU labels for these same products were also reviewed if registered through the Centralized Procedure. Data collection and analyses were performed using a predefined questionnaire, focusing on adherence to regulatory requirements and identifying areas where additional regulatory guidance may be beneficial. The findings indicate that the content of the overdosage sections largely comply with the regulatory requirements of their respective regions. Fewer than half of the labels included information on supratherapeutic doses observed from clinical studies, risk factors for overdose or population specific data associated with overdose. Inconsistencies were noted concerning the incorporation of animal data when human data were available, in addition to the referencing of Poison Centers. The overall utility of non-specific treatment recommendations, in addition to gastric lavage is discussed. While the content of the overdosage section generally aligns with regulatory expectations, additional regulatory guidance could enhance consistency in how this section of labeling is presented and clarify expectations to improve its usefulness for health care professionals (HCPs).

Fosamax Fractures-Justice Has Not Been Served.

This Viewpoint discusses the ongoing lawsuit between plaintiffs who had been affected by atypical femoral fractures while receiving alendronate and the drug manufacturer.

Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

A framework enabling LLMs into regulatory environment for transparency and trustworthiness and its application to drug labeling document.

Regulatory agencies consistently deal with extensive document reviews, ranging from product submissions to both internal and external communications. Large Language Models (LLMs) like ChatGPT can be invaluable tools for these tasks, however present several challenges, particularly the proprietary information, combining customized function with specific review needs, and transparency and explainability of the model's output. Hence, a localized and customized solution is imperative. To tackle these challenges, we formulated a framework named askFDALabel on FDA drug labeling documents that is a crucial resource in the FDA drug review process. AskFDALabel operates within a secure IT environment and comprises two key modules: a semantic search and a Q&A/text-generation module. The Module S built on word embeddings to enable comprehensive semantic queries within labeling documents. The Module T utilizes a tuned LLM to generate responses based on references from Module S. As the result, our framework enabled small LLMs to perform comparably to ChatGPT with as a computationally inexpensive solution for regulatory application. To conclude, through AskFDALabel, we have showcased a pathway that harnesses LLMs to support agency operations within a secure environment, offering tailored functions for the needs of regulatory research.

FDA Issues Warning About 'Gas Station Heroin'.

The highly addictive dietary supplement mimics opioid effects.

Patient information leaflets and package inserts of ibuprofen provided in the UK and Thailand: a comparative assessment.

OBJECTIVES: Written medicine information (WMI) is important for ensuring patients understand and use their medicines optimally, but relatively little research has assessed the quality of available WMI. This study assessed the quality of WMI using a sample of leaflets for ibuprofen in the UK and Thailand. METHODS: Leaflets were obtained by purchasing a product from retail outlets or community pharmacies, 18 from each country. In the UK, these were patient information leaflets (PILs); in Thailand, they were package inserts PIs not specifically designed for patients. Leaflets were assessed for content, layout, and readability using standard methods and compared to relevant guidelines. KEY FINDINGS: The UK PILs were uniform and conformed to EU regulatory requirements for content, whereas Thai PIs varied considerably, many failing to include important information required by Thai regulations. Several forms of Thai PIs were found, including some very short leaflets, containing minimal information. The readability of both was rated as poor, all used small font size and had less than desirable white space. Fewer Thai PIs than UK PILs met the Keystone Criteria for ibuprofen. CONCLUSIONS: The extent of variation in format and content of Thai WMI could potentially cause confusion and reduce willingness to read it. PILs, conforming to Thai regulatory guidelines, should be provided with medicines instead. Leaflets in both countries would benefit from improved readability and layout.

Accuracy of Labeling of Galantamine Generic Drugs and Dietary Supplements.

This study examines the accuracy of labeling for galantamine products formulated as both generic drugs and dietary supplements, as well as tests for contamination with microorganisms.

Statin Drug-Drug Interactions: Pharmacokinetic Basis of FDA Labeling Recommendations and Comparison Across Common Tertiary Clinical Resources.

Statins are widely prescribed and highly susceptible to pharmacokinetic (PK)-based drug-drug interactions (DDIs). To date, there has not been a comprehensive analysis of the basis upon which statin DDI recommendations in US Food and Drug Administration (FDA) prescribing information (PI) are derived. We have conducted such an analysis. We also assessed the degree of concordance of statin DDI recommendations in FDA PI and those provided in common tertiary clinical resources. We catalogued statin DDI information, including PK data and management recommendations, for statin precipitant drugs approved from 2010 to 2021, available from FDA PI and tertiary clinical resource databases. Recommendations were categorized and mapped with associated PK data to assess consistency in the PK basis for labeling recommendations. From the 80 precipitant drugs evaluated, 180 statin DDIs were identified in FDA PI. Dedicated clinical DDI studies were conducted for 54% (n = 97) of these DDIs and 34% (n = 61) of DDI recommendations were extrapolated from clinical data with other statins. Overall, we found that PK-based statin recommendations were consistent across PI. These findings highlight regulatory precedence for translating information across statins without conducting dedicated clinical DDI studies, which may support future efforts toward streamlining the approach to investigation and labeling of statin DDIs. In addition, with the exception of some notable discrepancies, general concordance was observed between FDA and tertiary resources regarding "Dose Adjustment" and "Avoid Coadministration" recommendations. However, further analyses are warranted across other DDI pairs to determine whether discordance can routinely lead to different clinical recommendations depending on the drug information resource.

Investigating Variations in Medicine Approvals for Attention-Deficit/Hyperactivity Disorder: A Cross-Country Document Analysis Comparing Drug Labeling.

OBJECTIVE: This study aimed to compare the approval of medicines for attention deficit/hyperactivity disorder (ADHD) for pediatric patients across five countries. METHOD: A document analysis was completed, using the drug labeling for ADHD medicines from five countries; United Kingdom, Australia, New Zealand, Canada and United States (US). Comparisons of available formulations and approval information for ADHD medicine use in pediatric patients were made. RESULTS: The US had the highest number of approved medicines and medicine forms across the studied countries (29 medicine forms for 10 approved medicines). Approved age and dosage variations across countries and missing dosage information were identified in several drug labeling. CONCLUSIONS: The discrepancies in approval information in ADHD medicine drug labeling and differing availability of medicine formulations across countries suggest variations in the management of ADHD across countries. The update of drug labeling and further research into reasons for variability and impact on practice are needed.

Warning Labels as a Public Health Intervention: Effects and Challenges for Tobacco, Cannabis, and Opioid Medications.

Warning labels help consumers understand product risks, enabling informed decisions. Since the 1966 introduction of cigarette warning labels in the United States, research has determined the most effective message content (health effects information) and format (brand-free packaging with pictures). However, new challenges have emerged. This article reviews the current state of tobacco warning labels in the United States, where legal battles have stalled pictorial cigarette warnings and new products such as electronic cigarettes and synthetic nicotine products pose unknown health risks. This article describes the emerging research on cannabis warnings; as more places legalize recreational cannabis, they are adopting lessons from tobacco warnings. However, its uncertain legal status and widespread underestimation of harms impede strict warning standards. The article also reviews opioid medication warning labels, suggesting that lessons from tobacco could help in the development of effective and culturally appropriate FDA-compliant opioid warning labels that promote safe medication use and increased co-dispensing of naloxone.

Inconsistencies of absolute drug-drug contraindication reports: Analysis of Summaries of Product Characteristics of commonly prescribed drugs.

AIMS: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug-drug contraindications (DDCI) in the section 'contraindications' and references to sections 'special warnings and precautions for use' (here as 'warnings') and 'interaction with other medicinal products and other forms of interaction' (here as 'interactions'). METHODS: SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in 'contraindications' sections. References to sections on 'warnings' and 'interactions' were evaluated to characterize information provided about DDCI. RESULTS: Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on 'warnings' or 'interactions', 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on 'interactions' and 'warnings' in 41 (87.2%) and 9 (19.1%) SmPCs, respectively. CONCLUSIONS: Information regarding absolute DDCI was found not only in sections on 'contraindications' but also in sections on 'warnings' and 'interactions'. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables.