Drug Package Inserts Research Articles

Insufficient correctness of package inserts for psychotropic drugs in Germany

AbstractPackage inserts often cause displeasure among patients as they are perceived as misleading and confusing. The aim of this study was to find out how comprehensible, complete, and truthful package inserts are formulated in Germany. 311 package inserts for antipsychotics (mGPCR antagonists) and antidepressants (NE/5-HT enhancers) from different manufacturers and dosages were analysed. The analysis criteria included the description of the effect, the warning of increased suicide risk, the explanation of interactions with co-medication, food and stimulants, as well as alcohol and the warning of impaired roadworthiness. In addition, the timeliness of the information regarding pregnancy and breastfeeding was checked and the symptoms mentioned under the topic of discontinuation symptoms and adverse drug reactions were compared. For most parameters, inconsistencies among various products, deficiencies and incorrect information were noted. This was particularly true for the items pregnancy and breastfeeding. Thus, package inserts for mGPCR antagonists and NE/5-HT enhancers need to be updated and standardised urgently. Such measures will reduce confusion among patients and increase drug adherence.

Adverse Event Profiles of Adalimumab in Children: A Disproportionality Analysis.

Adalimumab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult rheumatoid arthritis (RA), and subsequently approved for pediatric treatment of various autoimmune diseases in children of different ages. Due to genetic differences between children and adults in terms of physiology and immunity, there is a need to explore the safety of adalimumab in children in the real world. The aim of this study is to identify potential adverse event (AE) signals associated with the use of adalimumab in pediatric patients (<18 years old) using data from the FDA Adverse Event Reporting System (FAERS). AEs associated with adalimumab in pediatric patients reported in the FAERS database from the first quarter (Q1) of 2017 to the third quarter (Q3) of 2022 were systematically gathered. Reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the empirical Bayes geometric mean (EBGM) were used to assess the relationship between adalimumab and AEs in children. Out of 8,363,304 reports collected from the FAERS database during the study period, 3819 reports on children on adalimumab were identified. Adalimumab-related AEs reports were concentrated on 10 toxicity areas and a total of 202 positive signals were detected, of which injection site papule (ROR = 261.97) and intestinal fistula (ROR = 122.09) had the strongest signals. Unexpected significant AEs, including intestinal obstruction, immunodeficiency, abdominal abscess, and Takayasu's arteritis might also occur. In comparison with patients of all ages in the same time window, the median onset time of children was shorter (99 vs. 149 days). Most of the AE cases occurred in children within the first 1 (1.71%), 2 (8.12%), and 3 months (8.39%) and had early failure types after adalimumab initiation. Methotrexate, folic acid, prednisone, azathioprine, and mesalamine were the top five drugs used concomitantly for adalimumab-associated AEs. When adalimumab is used in children, especially in the first 3 months of treatment, in addition to the AEs recorded in the drug package insert, close attention should be paid to the new potential AEs off-label to ensure the safety of adalimumab in children.

Streamlining Considerations for Safety Measures: A Predictive Model for Addition of Clinically Significant Adverse Reactions to Japanese Drug Package Inserts.

The addition of clinically significant adverse reactions (CSARs) to Japanese package inserts (PIs) is an important safety measure that can be used to inform medical personnel of potential health risks; however, determining the necessity of their addition can be lengthy and complex. Therefore, we aimed to construct a machine learning-based model that can predict the addition of CSARs at an early stage due to the accumulation of both Japanese and overseas adverse drug reaction (ADR) cases. The target comprised CSARs added to PIs from August 2011 to March 2022. The control group consisted of drugs without the same CSARs in their PIs by March 2022. Features were generated using ADR case accumulation data obtained from the Japanese Adverse Drug Event Report and the U.S. Food and Drug Administration Adverse Event Reporting System databases. The model was constructed using DataRobot, and its performance evaluated using the Matthews correlation coefficient. The target for the addition of CSARs included 414 cases, comprising 302 due to domestic case accumulation, 22 due to both domestic and overseas case accumulation, 12 due to overseas case accumulation, and 78 due to revisions of the company core data sheet. The best model was a generalized linear model with informative features, achieving a cross-validation of 0.8754 and a holdout of 0.8995. In conclusion, the proposed model effectively predicted CSAR additions to PIs resulting from the accumulation of ADR cases using data from both Japan and the United States.

Do Nurses Follow The “Right Response”? Mixed Methods Research

Aim: Drug administration and management is an important procedure among clinical nursing practices and is one of the significant indicators affecting patient safety and quality of care. It was aimed to determine the nurses' monitoring of drug effects after drug treatment.&#x0D; Methods: In the study, sequential explanatory design from exploratory and mixed research methods was used. Quantitative data were collected using a data collection form and qualitative data were collected through in-depth and individual interviews using a semi-structured interview form. The interviews were recorded with a voice recorder.&#x0D; Results: It was determined that the average age, working years, weekly working hours, and daily number of patients cared for by the nurses were respectively 30.46±6.96, 7.1±6.31, 44.92±5.71, 15.42±11.89 years. It was found that 54.2% of the nurses checked the drug package insert before administering the medication, 74.5% of the nurses always considered the history of drug and food allergy to be of vital importance before drug administration, and 97.9% of the nurses reported unexpected side/toxic effects. As a result of in-depth interviews with the nurses participating in the study, three themes were identified: the approach of right drug administration principles, the approach of following the right response, and the follow-up status of nurses after drug administration.&#x0D; Conclusion: In the study, it was determined that nurses lacked knowledge about the right to correct medication, and could not implement the right to correct response due to high workload, low number of nurses and lack of time. It was observed that nurses gave the responsibility of correct response follow-up to the patient or the patient's relatives. By evaluating the reasons for not implementing the right to correct response, it is recommended that the number of nurses should be increased, the workload should be regulated, and nurses should receive training on correct drug administration and especially on the importance of correct response. It is also recommended that nurses receive training and counseling on their duties, authorities and responsibilities.

Physiologically Based Pharmacokinetic Modeling to Investigate the Disease-Drug-Drug Interactions between Voriconazole and Nirmatrelvir/Ritonavir in COVID-19 Patients with CYP2C19 Phenotypes.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis superinfection with cytokine storm is associated with increased mortality. This study aimed to establish a physiologically-based pharmacokinetic (PK) model to investigate the disease-drug-drug interactions between voriconazole and nirmatrelvir/ritonavir in patients with COVID-19 with elevated interleukin-6 (IL-6) levels carrying various CYP2C19 phenotypes. The model was constructed and validated using PK data on voriconazole, ritonavir, and IL-6, and was subsequently verified against clinical data from 78 patients with COVID-19. As a result, the model predicted voriconazole, ritonavir, and IL-6 PK parameters and drug-drug interaction-related fold changes in healthy subjects and patients with COVID-19 with acceptable prediction error, demonstrating its predictive capability. Simulations indicated ritonavir could increase voriconazole exposure to CYP2C19 intermediate and poor metabolizers rather than decrease it, in contrast to what is indicated in the drug package insert. However, the predicted ritonavir exposures were comparable across subjects. In patients with COVID-19, both ritonavir and IL-6 increased voriconazole trough concentrations, which may lead to CYP2C19 phenotype-dependent overexposure. In conclusion, COVID-19-induced IL-6 elevation and ritonavir increased voriconazole exposure, and the magnitude of interactions was influenced by CYP2C19 phenotype. Thus, caution is warranted when prescribing voriconazole concomitantly with Paxlovid in patients with COVID-19.

Medication Errors: An Update From the Central Region of Ghana

Objective: The study assessed the following medication error indicators: drug education by pharmacists, the clarity of physician prescription forms, patients’ and students’ drug package insert (PI) reading habits, and the adequacy of information on drug PIs.Design: A cross‐sectional study was carried out. One‐on‐one interviews were conducted with the pharmacists alongside the use of structured questionnaires to assess their involvement in drug education and experience with the clarity of physician prescription forms. A structured questionnaire was used to investigate patients’ and students’ PI reading habits. Drug PIs were collected from pharmacies, and their components were examined based on the World Health Organization’s (WHO) criteria for labeling pharmaceutical products.Setting: The study was conducted at four selected hospital pharmacies, four community pharmacies, and the University of Cape Coast, in the Cape Coast Metropolis, Ghana.Participants: The study included pharmacists working at the pharmacies, patients, and students of the University of Cape Coast, who visited any of these pharmacies.Results: Fifty‐three percent of pharmacists educate their patients on drug dosage, storage, and precautions during each patient visit, 17.6% hardly do, and 29.4% do not educate their patients. A majority of the sampled prescription forms submitted by patients to the pharmacists had illegible handwriting (63.7%) and unconventional prescription notations (78.0%). Of the 138 visiting patients, only a few (41.0%) read the PIs before drug use as compared to students (72.9%). Out of the 88 PIs collected, 90.2% had component deficiencies.Conclusion: Pharmacists’ drug education to visiting patients was poor, just as patients’ PI reading habits. Most PIs had component deficiencies, and the majority of prescription forms had some medication error‐provoking features. Going forward, pharmacists, physicians, drug manufacturers, and patients must perform their responsibilities toward the collective effort of minimizing medication errors associated with drug use.

Lack of information on gender differences in the package inserts of prescription drugs in Japan.

The package inserts of prescription drugs provide essential information for the proper administration of pharmacotherapy. The incidence of adverse reactions for several drugs is known to be higher in women than in men. However, no studies have examined whether information on gender differences is included in Japanese package inserts. Therefore, this study investigated information on gender differences in the package inserts of Japanese prescription drugs, using the drug information database JAMES provided by the Medical Information System Development Center and the Japan Pharmaceutical Information Center. Non-proprietary names of prescription drugs were yielded 1,679 in Japan. Of the 1,679 ingredients in package inserts of prescription drugs, 76 (4.5%) included information on gender differences. The number of inserts that contained information on gender differences in the "DOSAGE AND ADMINISTRATION," "ADVERSE REACTIONS," and "PHARMACOKINETICS" sections was 3, 16, and 62, respectively. Furthermore, in the "ADVERSE REACTIONS" section, 15 of the 16 inserts mentioned a higher frequency of adverse reactions in women compared with men. Importantly, most of the inserts with information on gender differences in the "PHARMACOKINETICS" section mentioned a higher area under the curve for women than for men. Most of the package inserts of prescription drugs with information on gender differences provide useful information aimed at preventing risks in women. However, there is an extreme lack of information on gender differences in the package inserts of prescription drugs in Japan, and we consider enhancing information on gender difference as an urgent issue.

A Study on Evaluation of Drug Package Inserts in Kashmir, India

Background: Drugs constitute a major part of the therapeutic modality for most of the patients. Accurate and authentic drug information is important for its safe and effective marketing. Drug package insert (PI) is the primary source of such information. They serve very important role in minimizing the medication errors. PIs need to be updated regularly, but despite regulations, studies have shown that Indian PIs provide inadequate information. Aims and Objectives: To check the completeness of information provided in package inserts of allopathic drugs. Material and Methods: This observational study was carried out for a period of 3months in the department of pharmacology, GMC Srinagar. 139 PIs were collected from local pharmacies and drug store of tertiary care hospital of Government Medical College, Srinagar.17 duplicate package inserts were excluded. The remaining PIs (122) were evaluated according to section 6.2, 6.3 of schedule D (II), Drugs and Cosmetics Act (1940) and Rules (1945).Data was entered in Microsoft Excel Sheet and then analyzed. Results: Among 122 PIs evaluated maximum package inserts were of antibiotics (15%) and anti-diabetics (15%) followed by CNS drugs (14%). Considering the dosage forms 60% inserts wereoral preparations followed by intravenous injections 17%. Regarding the various components of Section 6.2 of Schedule D (II), Drug and Cosmetic Act, posology and method of administration was present in 100% inserts, special precautions and warnings were present in 97%, side effects in 96%, contraindication in 94%. With regards the components of Section 6.3, excipients were mentioned in 78% inserts, incompatibility in 49% inserts, shelf life in the product package for sale was present in 28%, shelf life after dilution in 30%. Conclusion: Our study concluded that only a few inserts contained all the headings of Section 6.2 and 6.3 of Drug and Cosmetic Act (1945). Completeness of information has improved a lot as compared to past, still a lot needs to be done so that patients can derive maximum benefit from them. This demands strict scrutiny of inserts by regulatory authorities.

Predicting the Addition of Information Regarding Clinically Significant Adverse Drug Reactions to Japanese Drug Package Inserts Using a Machine-Learning Model

PurposeTo develop a machine learning (ML)-based model for predicting the addition of clinically significant adverse reaction (CSAR)-associated information to drug package inserts (PIs) based on information of adverse drug reaction (ADR) cases during the post-marketing stage in Japan.MethodsWe collected data on CSARs added to PIs from August 2011 to March 2020. ADR cases that led to CSARs resulting in PI revisions were considered as a positive case, and ML was used to construct a binary classification model to predict the PI revisions. We selected 34 features based on the ADR aggregate data collected 6 months before PI revisions. Prediction performance was evaluated using the Matthews correlation coefficient (MCC).ResultsWe found CSAR information added to PIs in 617 cases, 334 of which were due to the accumulation of domestic cases, and used only domestic case data for the prediction model. Among prediction models developed using several kinds of algorithms, the support vector machine with the radial basis function kernel with feature selection showed the highest predictive performance, having an MCC of 0.938 for the cross-validation and 0.922 for the test dataset. The feature with the highest importance in the model was the “average number of patients reported per quarter.”ConclusionOur model accurately predicted PI revisions using information on ADR cases that occurred 6 months before. This is the first ML model that can predict the necessary safety measures and is an efficient method for guiding the decision to adopt additional safety measures early.

Call to action for drug interactions between tirzepatide and heart failure guideline-directed medical therapy

BackgroundNo drug interaction between the guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) and glucose-dependent insulinotropic polypeptide (GIP)-glucagon-like peptide-1 (GLP-1) agonists is currently indexed in available drug interaction databases or package inserts for tirzepatide, the first dual GIP/GLP-1 agonist. The objective of our case series is to present 3 patients with HF who required modification in GDMT regimens for HFrEF or loop diuretic therapy after tirzepatide initiation. Case summaryThree patients older than 60 years with HFrEF receiving GDMT agents (angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) were initiated on tirzepatide for weight loss management. After initiating tirzepatide therapy, all 3 patients developed symptomatic hypotension. Two cases had acute kidney injury owing to tirzepatide’s direct vasodilation, natriuresis, reduction in extracellular volume, and weight loss. GDMT regimens and diuretic therapy were significantly modified to improve these adverse reactions. Practice implicationsClinicians must closely monitor vital signs and volume status after initiating tirzepatide for potential need to modify GDMT regimens. Authors request a call to action to index the drug interaction between GDMT agents and tirzepatide in major drug interaction databases for a potential hypotension or dehydration risk.

Dilemma Facing Patients Aged 75 Years and Older on Fluid Restriction When Drug Package Inserts Advise Use of a Lot of Water: A Cross-Sectional, Descriptive, and Hypothesis-Generating Study Using a Large Claims Database.

Several oral drugs are recommended to be taken with large amounts of water for reasons such as peptic ulcer prophylaxis. On the other hand, there are many patients with diseases that restrict water intake, and the actual frequency of patients receiving prescriptions in these conflicting situations is not clear. Using a large claims database in Japan, this study aimed to determine the proportion of patients aged ≥ 75 years on fluid restriction who received drugs whose drug package insert mentioned "a large amount of water intake is needed when taking the drug". We performed a prescription survey of older patients over 75 years of age using the Japan Medical Data Centre (JMDC) claims database. Out of approximately 8800 oral drugs used in Japan, we defined 29 drugs for which package inserts noted that a large amount of water intake is recommended during drug administration. We defined diagnosis codes for some common diseases for which restricted water intake is likely recommended: heart failure (NYHA class III or IV), liver cirrhosis with ascites, and chronic kidney disease stage 5, including dialysis patients. Of 5968 patients aged ≥ 75years (men 47.7%), 320 (5.4%) patients with heart failure (2.8%, n=170), liver cirrhosis (0.7%, n=40), or chronic kidney disease (1.9%, n=113), diagnoses likely associated with the need for fluid restriction, were prescribed drugs for which abundant fluid at intake was recommended. Among 29 identified drugs, 15 drugs were administered to older patients over 75 years with fluid restriction due to said diseases. Of patients 75 years and older with disease likely requiring water restriction, 5.4% faced the dilemma of following advice to restrict fluid intake due to their diagnoses or to adhere to instructions in drug package inserts to have abundant fluid intake when taking the drug. Our study raises awareness regarding the dilemma of water restriction and intake in clinical settings, highlighting the importance of considering individual patient needs. These real-world findings emphasize the need for information and guidelines to assist healthcare professionals in navigating this dilemma and making informed decisions for the benefit of their patients.

Psikiyatride Yaygın Olarak Kullanılan Antidepresan İlaç Prospektüslerinin Okunabilirliğinin Değerlendirilmesi

The understanding of a written text is directly related to the readability level of that text. Readability can be measured objectively using specific formulas. In this study, we aimed to determine the readability level of the drug package inserts of antidepressant drugs. A total of 51 drug package inserts were grouped according to antidepressant types. Title and drug license information was removed from the texts for standardization. These were evaluated using the Ateşman, Bezirci–Yılmaz and Çetinkaya–Uzun readability formulas, applicable to Turkish texts. The average Ateşman readability score was determined as 71.4. Accordingly, it was seen that the drug package inserts require a grade 7-8 of education for readability. The readability level of the Bezirci-Yılmaz formula was, similarly, of grade 7-8 (primary education) level. The Çetinkaya-Uzun readability score was calculated as 45.4 and an 8-9th grade level was determined. It was ascertained that the drug package inserts were readable at the secondary education (7th-9th grade) level on average. Considering the average education level in Turkey, it was established that the readability level was therefore high. We believe that writing the drug package inserts based on the average education level will increase readability and therefore intelligibility.

Supporting the Safe Use of the Dorsogluteal Intramuscular Injection Site: An Evidence-Based Quality Improvement Project.

Administering intramuscular (IM) injections is common in the adult mental health patient care setting, using the deltoid, vastus lateralis, ventrogluteal, or dorsogluteal site. Mental health nurses frequently use the dorsogluteal site to administer short and long-acting IM injections as specified in the drug package insert or because of patient agitation. However, the site is often not recommended due to the potential risk of nerve injury. Aims of this evidence-based quality improvement project were to (1) determine the best evidence for supporting the safe use of the dorsogluteal site for short and long-acting IM injections and (2) implement this evidence through nurse education. This project had two phases: Determining best evidence through an integrative literature review and implementing the recommendations to use the dorsogluteal site when directed by the drug package insert, clinical need, nursing judgment, or patient preference. Implementation followed the Plan-Do-Study-Act quality improvement process and involved written resources and simulation. Evidence supported the use of the dorsogluteal site in four instances and the importance of education. Nurses were highly satisfied with the education and opportunity to practice their skills with feedback during return demonstration. After studying nurses' follow-up survey results, a refresher simulation and medical center guideline were completed. There were no reports of IM injection patient injuries after 2 years and approximately 768 dorsogluteal and ventrogluteal IM injections in the academic medical center. Pursuing recent and possibly overlooked evidence provided guidance in supporting the safe use of the dorsogluteal site for IM injections.

EPH2 Using Drug Package Insert Data to Identify Statin-Related Prescribing Cascades - an Evaluation of Findings from Side Effect Resource (SIDER) and Commercial Claims Data

Statin-induced adverse events may prompt additional pharmacotherapy resulting in prescribing cascades. We previously performed untargeted prescribing cascade signal detection using high throughput sequence symmetry analysis (HTSSA), identifying 57 plausible prescribing cascades. However, this endeavor requires access to big data sources and significant computational efforts; false positives are common. We evaluated whether a targeted approach – using Side Effect Resource (SIDER), a public database containing pharmaceutical package inserts data – captures similar findings more efficiently.

Association between Progesterone-Only Emergency Contraceptive Pill and Ectopic Pregnancy

Context: Ectopic pregnancy remains a significant cause of morbidity and mortality in the developing countries, where mortality rates are 10 times higher than in the developed countries. In Kenya, there is however no recent data on ectopic pregnancy. Objective: We sought to identify if using an emergency contraceptive pill predisposes to ectopic pregnancy and assess other risk factors for ectopic pregnancy at the Kenyatta National Hospital. Methods: We conducted a case-control study of 120 consecutively sampled women matched for age diagnosed with ectopic pregnancy. Data were analyzed using a statistical package for the social sciences (SPSS software) [version 18.0]. Multivariate logistic regression analysis was performed to calculate the odds ratios (OR) and the corresponding 95% confidence intervals (CI). Results: Of the 120 cases and 120 controls recruited, 27.5% of the cases and 2.5% of the controls had taken Levonogesterol emergency contraceptive (LNG-EC) pill during the menstrual cycle leading to the current pregnancy. Of the cases, 72.7% took the LNG-EC within 24hrs after coitus, while all the controls took the pill within 24-48 hrs. The risk of ectopic pregnancy (EP) increased 12-fold in women who had used LNG-EC (OR=12.44, 95% CI 3.1-49.84) after adjusting for other confounders. EP was associated with an early sexual debut (p= 0.039), and a history of subfertility/infertility (OR=6.87, 95% CI 2.14-22.03). Conclusions: Progesterone only emergency contraceptive pill is as a risk factor for ectopic pregnancy and should be included in the client information leaflet in the drug package insert.

ANALYSIS OF PACKAGE INSERTS OF ANTIMICROBIAL DRUGS UTILISED IN A TERTIARY CARE HOSPITAL OF NORTH KARNATAKA

Objective: To evaluate the package inserts of antimicrobial drugs utilized in a tertiary care Hospital of North Karnataka Methods: A cross-sectional, observational, prospective study was undertaken to analyze the package inserts of antimicrobial drugs utilized in a tertiary care hospital in North Karnataka for two months. 218 that belonged to antimicrobials were included in our study and analyzed based on criteria mentioned in Schedule D of the Drug and Cosmetic Act of 1945. Results: None of the Package Inserts analyzed by us adhered to the standard guidelines. Legibility, Approved generic name of active ingredients, and Content of active ingredient per dosage was mentioned in all. In contrast, the least mentioned criteria included References (n=2) and Retail price of the drug (n=9). Conclusion: Updating the existing ones and stricter adherence to the PI with the standard guidelines will achieve better quality and, in turn, improve health care in our society, especially by these antimicrobial agents, which can prevent the development of antimicrobial resistance.

Comprehensive guidance for antibiotic dosing in obese adults: 2022 update.

Drug dosing in obese patients continues to be challenging due to a lack of high-quality evidence to guide dosing recommendations. We first published guidance for antibiotic dosing in obese adults in 2017, in which we critically reviewed articles identified from a broad search strategy to develop dosing recommendations for 35 antimicrobials. In this updated narrative review, we searched Pubmed, Web of Science, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific generic antimicrobial names, obese, pharmacokinetics, and others. We reviewed 393 articles, cross-referenced select cited references, and when applicable, referenced drug databases, package inserts, and clinical trial data to update dosing recommendations for 41 antimicrobials. Most included articles were pharmacokinetic studies, other less frequently included articles were clinical studies (mostly small, retrospective), case reports, and very rarely, guidelines. Pharmacokinetic changes are frequently reported, can be variable, and sometimes conflicting in this population, and do not always translate to a documented difference in clinical outcomes, yet are used to inform dosing strategies. Extended infusions, high doses, and therapeutic drug monitoring remain important strategies to optimize dosing in this population. Additional studies are needed to clinically validate proposed dosing strategies, clarify optimal body size descriptors, dosing weight scalars, and estimation method of renal function in obese patients.

Revision of precautions for drug package inserts in Japan

Revision of precautions for drug package inserts in Japan

Medication package inserts do not present adequate information on potential risks for older adults in Brazil

Objective: To compare information on the risks of potentially inappropriate medications (PIMs) for older adults in the Beers criteria with data in the package inserts made available by the Brazilian Health Regulatory Agency. Methods: This is an observational, cross-sectional study that compared information on the package inserts of 33 brand-name drugs in the Brazilian market with specific recommendations for older adults contemplated in the Beers criteria, categorizing them into: complete, incomplete, absent, or discrepant. Results: Among the analyzed package inserts, 21.21% did not present a specific section dedicated to the use of these drugs by older adults and data were scattered throughout the text; 63.64% were classified as incomplete; 33.33% lacked data; and 3.03% had discrepant information. Conclusion: The analyzed package inserts presented incomplete data or lacked information characterizing the drugs as PIMs for older adults. This study demonstrated that some package inserts of drugs used in Brazil are not satisfactory, warranting higher caution in the medical community when prescribing these medications and guiding patients.

Association between Post-marketing Safety-related Regulatory Actions and Characteristics of New Drugs Approved in Japan between 2005 and 2016

The pharmacovigilance activities of new drugs are usually planned and conducted based on the clinical safety information obtained at approval. Revealing pre- and post-marketing drug characteristics associated with post-marketing safety-related regulatory actions (PSRAs) would help facilitate pharmacovigilance activities as these activities are not sufficient for early detection of safety signals that require warning. Therefore, we investigated the association between PSRAs and characteristics of new drugs in Japan. New active substances approved in Japan between fiscal year 2005 and 2015 were analyzed. PSRAs were defined as "revisions of precautions in drug package insert" instructed by the regulatory authority within the first 5 years after the initial approval (up to 2021). Drug characteristics included therapeutic area, number of Japanese subjects in clinical trials, dose-response study in Japanese subjects, approval lag between Japan and the United States or Europe (US/EU), novelty of the drug, estimated number of target patients, and number of supplemental approvals. Negative binomial regression and path analyses were performed to investigate the association between PSRAs and drug characteristics. PSRAs were more common among antineoplastic agents and drugs with a larger estimated number of target patients and were less common among drugs with a longer approval lag between Japan and the US/EU. Supplemental approval was more common among antineoplastic agents, and there were fewer target patients for novel drugs. For new drugs with the characteristics identified in the present study, it is important to proactively collect post-market safety information by intensifying patient monitoring.